- Email: [email protected]
5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: More than 30 years of research
Pergamon
Associate
Pharmac. T/w. Vol. 65, pp. 319-395, 1995 Copyright (0 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0163-725X/95 $29.00
01617258(94)00065-4
Editor: B. E. LEONARD
5-HYDROXYTRYPTAMINE-INTERACTING DRUGS IN ANIMAL MODELS OF ANXIETY DISORDERS: MORE THAN 30 YEARS OF RESEARCH GUY GRIEBEL* Laboratoire
de Psychophysiologie,
7 rue de I’iJnicersiti,
67000 Strasbourg,
France
Abstract-An overview of the behavioral data arising from the vast literature concerning the involvement of 5hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating S-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals’ emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT,,, 5-HTzA or 5-HTZc receptor subtypes; (3) anxiolytic-like effects of 5-HT1 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes. are involved in the genesis of anxiety. Keywords-5-HT (serotonin), 5-HT conditioned paradigms, unconditioned
ligands, 5-HT paradigms.
receptors,
animal
models
of anxiety,
CONTENTS 1. Introduction 2. Animal Models of Anxiety Disorders: Attempts at Classification 3. Behavioral Effects of Drugs Modulating 5-Hydroxytryptamine Neurotransmission Animal Models of Anxiety 3.1. Behavioral actions of central application of 5-hydroxytryptamine and peripheral administration of 5-hydroxytryptamine indirect hgands 3.1.1. 5-Hydroxytryptamine 3.1.2. 5-Hydroxytryptamine reuptake inhibitors (SRls) 3.1.3. p-Chlorophenylalanine 3.2. Behavioral effects of direct-acting 5-hydroxytryptamine hgands 3.2.1. 5-HydroxytryptaminelA receptor ligands 3.2.2. 5-HydroxytryptaminelH receptor agonists 3.2.3. 5-HydroxytryptaminezA and 5-hydroxytryptamine2c receptors 3.2.4. 5-Hydroxytryptaminei receptor antagonists 4. Perspectives and Summary Acknowledgements References
320 367 in 367 367 367 370 370 371 372 372 373 374 374 377 377
Abbreviations-CER, conditioned emotional response; DPAG, dorsal periaqueductal gray: 5-HT. 5-hydroxytryptamine; S-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; mCPP. I-(3-chlorophenyl)piperazine; PCPA, p-chlorophenylalanine; SRI, 5-hydroxytryptamine reuptake inhibitor; TFMPP, l-(3-trifluoromethylphenyl)piperazine. *Present address-Synthhlabo Recherche (L.E. R.S.), CNS Pharmacologic Group, 31. ~IIYVIUOPaul Vaillant-Couturier, B.P. 110. 92225 Bagneux Cede.u, France.
320
G. Griebel 1. INTRODUCTION
It has been suggested on the basis of previous behavioral studies that 5hydroxytryptamine (5HT) could be considered as a central neurotransmitter involved in the modulation of emotional behavior (Sudak and Maas, 1964; Geller and Blum, 1970; Wise rr al., 1972; Stein et 01.. 1973; Crow and Deakin, 1981). This view mainly arose from some observed activity of 5-HT antagonists in operant conflict paradigms (Robichaud and Sledge, 1969) as well as from an association between reduction in turnover of 5-HT and the anxiolytic effects of benzodiazepines (Goldberg et al., 1967). It is now acknowledged that a reduction of the function of brain 5-HT pathways often leads to an anxiolytic-like effect, whereas increased activity of ascending 5-HT pathways usually results in an anxiogenic-like effect (Gardner, 1986; Chopin and Briley, 1987). However, the picture is nowhere near as clear. The behavioral effects of drugs decreasing the activity of the central 5-HT system are often more variable than the effects of standard anxiolytics, and not all findings are accounted for by the classic hypothesis. There are a few instances in which these compounds produce effects opposite to those of standard anxiolytics, suggesting an anxiogenic-like action. Moreover, in some studies, drugs known to possess a 5-HT-stimulating action displayed anxiolytic-like properties, while in others they potentiated animals’ emotional reactivity. Finally, a great number of studies found no evidence for an anxiolyticor anxiogenic-like effect of drugs modulating central 5-HT neurotransmission. This is exemplified by Fig. 2, which illustrates the variability in behavioral effect of some of the most studied compounds interacting with the 5-HT neurotransmission. As an illustration, the central application of 5-HT results in an anxiogenic-like action in half of the studies. whereas in the other half, authors obtained the opposite effect. This variability is probably due to a number of factors, including administration routes (Treit. 1991). doses used (Soderpalm et al., 1989), species differences (Barrett and Gleeson, 1991). the sex of the animals (Hughes, 1993) or the environment in which a test is conducted (Wettstein, 1992; Griebel et al., 1993). Certain authors point to a determining role of the experimental paradigms used when studying 5-HT agents in animal models of anxiety disorders. Variation in the effects might reflect differences in the degree to which the models themselves represent fear or anxiety (Handley, 1991; Treit, 1991; Wettstein, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a,b,c). These behavioral tests have been useful in the preclinical testing of benzodiazepine-type anxiolytics, in studying the functional relevance of the benzodiazepine receptor system, and in characterizing the effects of benzodiazepine antagonists, partial agonists, and inverse agonists (for recent reviews, see Barrett and Gleeson, 199 1; Treit, 199 1). However, the validation of these paradigms has depended primarily on their sensitivity to benzodiazepines only, and the recent introduction to clinical practice of non-benzodiazepine anxiolytics such as buspirone has challenged the validity of these tests as general models of anxiety disorders. The possibility that these tests may be less sensitive to agents not acting at benzodiazepine receptors has been advanced to explain these inconsistencies (Richards PI ul.. 1991). The main objective of this review is to provide an overview of the developments in research involving the 5-HT system and anxiety. The emphasis will be on a review of the results of animal models used to evaluate these drugs with the help of a synoptic table that summarizes the studies investigating the behavioral effects of 5-HT compounds in this area from 1961 to November 1993 (Table 1). This table is composed of following sections: (I) name of drug (starting with 5-HT. p-chlorophenylalanine (PCPA), 5-HT reuptake inhibitors, and ending with 5-HT, receptor antagonists); (2) its affinity for 5-HT receptors; (3) animal models of anxiety used; (4) animals and strains used and their weight or age; (5) efficient doses or doses tested; (6) administration route and latency period; (7) effect observed; (8) comments; and finally, in column 9 the pertinent references are indicated. In Section 2, we will briefly review some aspects of the literature concerning the animal models of anxiety disorders used in investigations of the behavioral actions of psychotropic drugs. Section 3 will focus on the studies evaluating the behavioral actions of 5-HT compounds in animal models of anxiety. The results obtained with these agents will be considered and discussed for the most important 5-HT receptors. Outcomes of some of the most studied compounds, such as 5-HT. 8-OH-DPAT, buspirone, mCPP or ondansetron, will be illustrated graphically with attention to the types of behavioral procedures used. This will allow examination of the possibility that involvement
5-HTP (5-HT precursor)
5-HT
Compounds
3.1
5.HT,A
3.4
5-HT,e
2.8
5.HT,n
2500
5-HTu
Affimt~es (Ki, no)
3.1
5-HTx
22’
5.HT,
test
Modified Vogel’s test FR50
_ + _
40 40
25-100
Wistar rats (I 5CL2OOg)
Mice
i.p. 60 S.C. 60 i.p. 30
25 2.5-160 5-50
30
t.p.
30
30
p. 30
Fear-potentlated Ltster rats (375415g) startle reflex Shock-probe Wtstar rats (25&280g) burying test Marble burymg test Female MFI mice
pmol
40
28448
i. p. 30
10&400 50 50
i.m.
p. 30
I8
+
0
_
Locomotion reduced
ef al.. 1990
er al., 1990
el al., 1989
Njung’e
199lb
1986a
Continued
and Handley,
Meert and Colpaert,
1989
er al., 1990 Glenn and Green,
Kshama
Cheng e, al.. 1992
Kshama
Kshama
_
Saderpahn
and Ferster,
er al.. 1987
_
Aprison
Hjorth
_ In combination with tranylcypromine In combination with tranylcypromine and asymmetric compartments Asymmetric compartments In combination with tranylcypromine
Kilts et al., 1982
VI21
_
i.p. 120
er al., 1984
Davis er al., 1980b
1961
Geller and Blum, 1970
_
15
SpragueeDawley rats (2OOg) Sprague-Dawley rats (180-2500) White Carneau Pigeons (6 months) Sprague-Dawley rats (25s35Og) Wistar rats (15&2OOg)
rats
10 IO
Schiitz et al., 1985 Graeff er al., 1986
DPAG, DPAG,
+ +
5-20 nmol 5-20 nmol
Wistar rats (25s300g) Rats
Thiibot
+ +
et al., 1991
1993
et ol., 1988d
al., 1973 e, ol., 1987 al., 1972 er al., 1982
Geyer er al., 1975
Higgins
Griebel,
Costall
Stein el Hodges Wise er ThiCbot
i.c.v., 8 days i.t. Dorsal raphe
IO nmol
Sprague-Dawley
References Wise er ol.. I972
200 /Jg
LLF HLU
Asymmetric compartments
CRF
VI20
Comments
_ + +
_
+ +
_
_
Effects
Amygdala, 5 Dorsal mph&, 5 i.c.v.
i.c.v., 30
Dorsal raphC
i.c.v., 0 Amygdala, 0 i.c.v., > 20 Dorsal raphe
i.c.v., IO-20
100-10000 ng 20-100 ng I-15.625 fig
2.5-5 pg
Rats
Swiss mice (10 weeks) Lister rats @l&280 g) Sprague-Dawley rats (320-400 g) Rats (30&4OOg)
20 pg l-5 pg I-10 pg l&100 nmol
Rats Rats (382446 g) Rats Wtstar rats ( 195-205 g) Mice (25-35 g) IO ng
I-10 /lg
Rats
Animals
Routes administration, latency (min)
in Animal Models of Anxiety.
Efficient doses or doses tested (mgikg)
5-HT Neurotransmission
Wistar rats (IS&ZOOg)
test
maze
test
Holeboard
Light/dark
Elevated-plus
Conflict
Vogel’s conflict test
Geller-Seifter
Conditioned emotional response DPAG-stimulation
Fear-potentiated startle reflex
Social interaction
Light/dark
GellervSeifter conflict test
Models
Table 1: EJJects of Drugs Modulating
322
G. Griebel
t
+
+Gs++
i.p. 14 days i.p. during 3 days i.p. during 2 days i.p. during
100 32&900 300 75-150 316
Rats (25Og)
+
i.p. I5 1.p. I5
5 5
Geller-Seifter conflict tet
5.7-DHT (5.HT neurotoxin)
1 Pg 2 vg 1 KS 2 Fz
Dorsal raphe, I5 days Ventromedian tegmentum, 12 days Dorsal raphe, I5 days Substantia nigra. I5 days
3 fig
Wistar rats (195-2058) Wistar rats Sprague-Da&y rats (25&3OOg) Wistar rats
Dorsal raphe, 21 days
100 vg
Rats
I.C.“., 2
0
i.p. 2-15 hr
5
Sprague-Dawley rats (250-3008) Sprague-Dawley rats (300-400g) Sprague~Dawley rats (25&3OOg)
Fear-potentiated startle reflex
+
+
+
0
0
+
0
i.p. 9 and 8 days
0
+
0
IO
i.p. 30
i.p. 60
+
VI21
CRF/FR7
CRFIFR7
CRF
Modified Vogel’s test Modified Vogel’s test
199lb
1975
1973
cf ul.. 1982
ThiCbot <‘I ol., 1983
1976
1976
Thiebot P, al., 1984 Tye CI rrl., 1977
Thiebot
Stein PI al., 1975
Davis and Sheard.
Davis et al., l988a
Davis and Shard,
Chojnacka-Wbjcik and Przegalinski, 1991 Przegalinski PI al., 1992
Njung’e and Handley,
Kilts er al., 1982
Ogawa PI rrl., 1993
Ogawa rr al.. 1993
Kiser and Lebovitz,
_
+
Lecci er al.. 1990
Wistar rats (lSG22Og)
l-10
0.25-I
and Advokat.
Fechter, 1974 Davis cf al.. 1988a
Carlton
0
0
0
i.p. 9 and 8 days
SpragueeDawley rats (2009) Female MFI mice (23s35g)
Wistar rats (7-S weeks)
p.“. 60 p.“. (7-8 weeks) p.“. 60
,.p. 3-18 days
3 days
Hard PI al.. 1982 Hard E, al.. 1982
+ +
_
Tenen, 1967
+
Conner r, al., 1970
Trelt et al., 1993
+
IO
GellervScifter conflict text
190r
S.C. 14 days
300
Long-Evans rats (70 days) Sprague-Dawley rats (175-2008) Rats Sprague~Dawley rats (3WWg) Swiss mice (25-306)
25-50 5-50 25
1.p. during 4 days 1.p. during 3 days
300 100
Rats (15-25 days) Rats (416 days)
ICR mice (7-8 weeks)
p.“. dung
100
rats 3 days
i.p. during 4 days
130
rats
Sprague-Dawley (25G35Og) Sprague-Dawley (3OOg)
Vogel’s conflict test Wistar rats (lSt%22Og)
5.6.DHT (5-HT “eurotoxin)
PCA (5-HT neurotoxin)
test
Vogel’s conflict test
Fenfluramine (5-HT stimulant) Marble burying
Unavoidable stress (gastric lesion) Passive-avoidance test
SC-48274 (S-HT stimulant)
Stress-induced hyperthermia DPAG-Stimulation
Shock-probe burying test Disruption of drinking induced by stress Freezing Ultrasonic ‘distress’ vocalization Fear-potentiated startle reflex
6
E:
s. fi z 2 5’ 09
3
r
324
G. Griebel
21000 inhibitor)
Fluoxetme (5.HT rcuptake inhibitor II500 (ICr, = 27 n~)ll’
Clomipramine (5-HT reuptake
Citalopram > 10000 (5.HT reuptake inhlbitor) (ICr, = 3.8 “MY”
Cianopramine (5-HT reuptake inhibitor) (ICw = 1.5 “M).1”’
6170
4266
> IOOOP
1820
180
269
r::
II220 *,u
test
Swiss mice (I 0 weeks)
Wistar rats (15&22Og)
test
Rats Wistar rats (15&2OOg)
Holeboard Wistar rats (15&2OOg) Ultrasonic ‘distress’ Wtstar rats (9-l I days) vocalization Wistar rats (9-l I days) Novelty-suppressed Long-Evans rats (30&325g) feeding
Light/dark
0
+
,.p. 30-120
30 30 30 i.p. 60 during 21 days (xl)
20 IO
i.p. 30 30
+
+ _
0
_
+ _
+
i.p. 30 30
+ 1-p.
0
0
+
+
_
_
+
0
_
+
_
+
S.C.
IO 5m20
1.25~10 10
5-10 IO
5 LED = IO 15
Rats Adult rats Rats (25Og)
Ultrasonic ‘distress’ vocalization DPAG-Stimulation
30 i.p. 30
S.C.
I
l-50 3-10
S.C. 45 i.p. 30 i.p. 30 i.p. 30 i.p. 30
Rats Rats
Vogel’s conflict test Rats Elevated-plus maze Wistar rats (15&2OOg)
i.p. 30 i.p. 21 days (xl)
i.p. 30 i.p. during 21 days (xl) i.p. 30
dung
10 l&30 l-30 30 l-20
4
l-10 IO IO
I-IO IO
IO
Cold condltlon
Warm condition
Asymmetric compartments
Chronic and acute treatments
FR8, weak effect
Bodnoff er al., 1989
_
i.p. 60 21 days (xl) 60 during 21 days (xl)
IO +
0
i.p. 30
I-8
during
Gardner.
0
S.C. 60
I986a
1976
Mos and Olivier, 1989 Bodnoff er al., 1989
Kshama PI rrl.. 1990 Mos and Olivier, 1989
Handley and McBlane. Kshama er ul.. 1990
Handley and McBlane, Kshama Ed ul.. 1990
1992
1992
Winslow and Insel, l99lb Molewijk PI nl., 1993 Kiser er al.. 1978
Schoenfeld, File, 1985
Winslow and Insel, 199lb
Broekkamp and Jenck, 1989 Griebel 6’1a/ ( 1994 Griebel P, al., 1994 Griebel cf a/., 1994 Njung’e and Handlcy, 199lb
HascoEt er al., 1992
Griebel PI al., 1994
Griebel CI al., 1994
Griebel e, ul.. 1994
Bodnoff et al.. 1988
1985~1
Meert and Colpaert.
Costall CI al., 1989b
0.6340
Asymmetric compartments and sedation (“)
1991
i.p. 45
Klint,
30
0
S.C. 30
0.1~1
Vogel’s conflict test Social interaction
Vogel’s conflict test Rats Elevated-plus maze Wistar rats (15~-2208) Light/dark test Swiss mice (I 0 weeks) Free-exoloration test Swiss mice (IO weeks) Marble’ burying tesi Female M‘FI mice (23-358) Ultrasonic ‘distress’ Rats vocalization
Rats
test Swiss mace (IO weeks)
test
maze
Geller-Seifter conflict test
Free-exploratmn
Light/dark
Elevated-plus
Shock-probe Wistar rats (25&2X0& burying test Ultrasonic ‘distress‘ Wlstar rats (9-12 days) vocalization Novelty-suppressed Long-Evans rats feeding (30&325g) Long-Evans rats (30&325g
Light/dark
Sprague-Dawley rats (200&25og3 BKW mice (20 3Og)
;=: vl
?
g O9
2 3 6
i.
5.HT,,
(5-HT reuptakc
lllllpMlll”~
mhlbltor)
2lOOOh
Fluvoxamme > 10000 (5.HT reuptake Inhlbttor) (ID,, = 5 mg kg)“’
Compounds
5.HT,n
5.HT,,
,lM)
>
260’
I00
5.Hl’x
1000”
5-HTzs
Affimtles (KI.
5708
S-HT?
Animals
j-10 LED = 20 5.-20 0.6340
Wistar rats (400-5OOg) Wlstar rats (25&28Og)
Social competitton Ultrasonic ‘distress’ vocalization Conditioned emotional response Shock-probe burying test
IS
Long-Evans rats (105-117 days) Wistar rats (12Og) Adult rats
3.16
Defense test battery
mice
S.C. 60
i.p. 30
i.p. 30 1-p.
1.p. 60 i.p. during II days (xl) i.p. 60 1.p. durmg 1 I days (xl) i.p. during 3 weeks (xl)
i.p. 30
i.p. 30
i.p. 30 p.o. 60
s-15 l-30 I-4
30
I-30 8 32
20
Female JCR-DUB (l7m35g)
+
t.p. during l-5 weeks (x2)
25
Female Long Evans rat (I2 weeks)
test
Light;dark
Llster rats (2504OOg) SpragwDawley rats (170~2OOg) ICR mxe (20-358)
0
i.p. 30
I - IO
I “I. 15
Modified
_
1.p. IO
7. I-20
0
+
0 +
0 o +
+
0
0
0
T
1973
Vogel‘s test
TransitIons and AsymmetrIc compartments Locomotmn decreaxd and Asymmetw compartments Saline mJectron
Co”l”ll~sarls.
1991~
IYXY
CI N/
1993
1990 Meert and Colpaert.
Sanger,
1986a
Joly and Singer. 1991 Molewijk (1, ol.. 1993
Blanchard
Dwyer and Roy. IYY3
Young and Johnson.
Onaivi and Martm.
Pclloa PI f/l 1985 Luscombe er nl lY90
I088 Nanry PI N/.. lY9l Martin. lY93
Fontanuand
Vogel’s test Fontsna and Commissar~s. IYX8 VI21 Kilts PI ul.. 19x1
L’, ol.. 1983
Sanger. 1992 Cook and Dawdson. Kilts E, nl.. I981 Vogel’\ test McCown
Caffeine-pretreated rats
Modified
Modified
_
i.p 30
VI30 V1301FRIO FR40
Mos and Olivier, 1989 Molewijk E, nl., 1993 Van DiJken ef o/.. IYY?
Cold conditmn
1989
199lb
Mos and Ohwer.
I O&300
0
References Olivier er ul., 1989 Njung‘e and Handley,
Warm condition
mxe
Comments Isolated
i.p. 30 p.0. i.p. 20 0
+ + 0 o
0
+
_
ElT&S
20 0.55-17.7 I-IO
30 1.p. 1-p. 30 I p. during I4 days (xl)
30
5-20 LED=3 3-30
1.p. 30
5 -20
1.p.
Routes administratm”. latency (min)
I I-20
Open-field
maze
Elevated-plus
Wistar rats (180~2OOg) Rats SpragwDawley rats (20&3203) Vogel’s conflict test Sprague -Dawley rats (2% 3oog) Female Sprague-Dawley rats (225-275~) Sprague~Dawley rats (20s32Og) Female Sprague-Dawley rats (225-2753) Conflict test White Carneau pigeons Shuttle box Rats Geller-Seifter confhct test
DAP mice (22-3Og) Female MFI mice (23-358) Ultrasomc ‘distress’ Wistar rats (9-I I days) vocalizatto” Wlstar rats (9-l I days) Adult rats Freezing Wlstar rats (2%3OOg)
Models Social interaction Marble burymg test
Efficient doses or doses rested (@kg)
Table 1. Continued
0 1.
0
Inhibitor)
agonist) 7.1
1698~ agorust)
2-Me-S-HT (non-selective
stimulant)
Y-Me-S-HT (non-selective pKo s
Txaneptme (5-HT reuptake
Zmzlidme (5-HT reuptake inhibitor)
s3344 (5-HT rcuptake
Paroxetine > 10000 (5-HT reuptake inhibitor) (ED>,, = I .9 mg/kg)
724
6.0
Indalpine 9120 4467 (S-HT reuptake inhibitor) (ICV, = 2.x IIMP”
1800’
6.2
3630
>10000”
6.6
489’
7.2
3235
> 3OO@‘V
> IOOOP
794
210‘,?”
maze
‘distress’
Wistar rats (15&2OOg) Wistar rats (150-200g)
Rats
Rats
CD rats
Lister rats (20&25Og)
Wistar rats (220g)
Female MFI mice ,?I ng,
maze
test
Social interactmn
Light/dark
GellervSeifter conflict test Conflict test
Social interaction
Elevated-plus
pigeons
Lister rats (210-2808)
BKW mice (25-30%)
Mice (25-35g)
White Carneau
Female CFN rats
Rats
Lister rats (20&25Og)
Lister rats (200-250g)
Wistar rats (15&2OOg) Female MFI mice (23-358) Ultrasomc ‘distress’ Wistar rats (9-l I days) vocalization Wistar rats (9-I I days) DPAG-Stimulation Wistar rats (25&3OOg) Rats Wistar rats (200-250g) test
maze test
Holeboard Marble burying
Elevated-plus Ltght/dark
Social interaction
Ultrasonic
Social interaction
Elevated-plus
Vogel’s conflict test
1200”1v Marble burymg test
test
Rats Long-Evans (325-500~) Fear-potentiated Sprague-Dawley rats startle reflex (300-4OOg) Passive-avoidance test Wistar rats (22&24Og) Conditioned place Long-Evans rats aversion (8 weeks) Cork gnawing Long-Evans rats (435-64Og)
Marble burying
30
l-10
0.001~.1 0.001~.0025
O.OOOOOOl~.OOOl
0.0000001-0.0001
1-3
0.3-2
IO 2.5-10 2.5-10 5-10 2.5-10
100nmol
100 nmol
IO0nmol
20 days (xl) 20 days (xl) 30
Dorsal raphe Amygdala or median raphi Amygdala. 5 Dorsal raphC
Dorsal raphe
i.m. 0
i.p
i.p. 5 i.p. during 5 i.p. durmg
30 DPAG, IO DPAG, IO DPAG, IO OT 20
30 i.p. 30
40 l-30
3-10
30 30
40 40
2.5-20
I i.p. 15
pa during 3 weeks (xl) pa during 3 weeks (xl) S.C. 3 weeks (xl)
3 3
i.p. 30
5
i.p. 30
0
p.0. 30
4-32
I-20
0
7.5-30 2-24
Modified
u al.. 1990 er al.. 1990
LLF HLU and LLF
_
F15/FR30
V130/FRIO
1972
and File, 1993
1991
1991
Higgins tv ul.. 1991
Costall PI ol.. 1989~
Costall er a/., 1988~
Graeff and Schoenfeld.
Winter.
Andrew
File and Mabbutt,
File and Mabbutt.
Mos and Olivier. 1989 Schiitz cr al., 1985 Graeff ef al.. 1986 Audi PI al.. 1988
Cold condition
Weak effect
Mos and Olwer.
1989
Kshama r, ul.. 1990 NJung‘e and Handley.
Kshama Kshama
1970
l99lb
and Insel, 199lb
ef RI.. 1992
PI al., 1992
File, 1984a
Winslow
Lightowler
Cadogan
l99lb
1991
1981
Warm condition
Asymmetric compartments
Weak effect
Asymmetric compartments Asymmetric compartments
0
Njung’e and Handley,
Pollard and Howard.
Sanger P, al., 1989 Erwin er al.. 1987
Vogel’s test Petersen and Lassen,
_
0
0
+
0
0
+
+
+
+
+
0
+
_
_
+
+
+
0
+
0
Cassella and Davts. 1985
0 o
i.p. 5 i.p. during 3 weeks (xl) .p. 30 .p. 60
5-10
Craft e, al., 1988
+
i.p. 30
416
5 I?”
0.32” agomst)
08 agontst)
antagomst)
antagonist)
7 9D antapomrt)
Lisuride (non-selective
Bromo-LSD (non-selective
DMT (non-selectwe
Metergoline (non-selective
39 8b
199
5.HT,.
5-HT,,
5.CT (non-zelectlvc
Comoounds
0 79”
36 6
2s
S-HT,,,
Aflinitics
Ih
5.01”
633”
0.64”
19.9
630”
~-HT~A 5-H-f.<
(Ki. no)
7400’
5.HT?
Models
test
Animala rats rats rats rats
(210-27Og) (200-25Og) (200 -25Og) (2lO-270~)
rats(200-2508)
pigeona
Female MFI mice (23-358) Ultrasonic ‘distress‘ Wistar rats (Y-12 days) vocalization Fear-potentiated Sprague-Dawley rats startle reflex (32&35Og)
Shock-probe boring test Marble burying test
Social interaction
Sprague-Dawley rats (20&25Og) Rats Wistar rats (18&2OOg) Sprague-Dawley rats (200-2508) Wistar rats (25&28Og)
70
i.p. 30
0.1-10
I p.
i.p. 30
O.IC-I
I
S.C. 60
0.63-10
i.p. 60
0.1&X62
p.0. 30 S.C. 40
1.p. 30 i.p. 40
4 4 0.05-10
5-20 2.5
i.m. 30 i.m.
0
i.p. 60
2-4 0.56 0.03-0.3
0
i.p. 180
0.25-2
0
+
+
+
0
0
0
0
+
+
+
+
0
+
p.0. 1.p. 10
2.5-20 0.25-2
0
_
+
+
+ +
+ +
Effects
Rats Sprague-Dawley rats (20&225g) Sprague-Dawley rats (20% Wistar rats (18&22Og)
0
5 5
5 5
p.o. 25
i.p.
im
i.p. 30 i.p. IO
Dorsal mph&, Dorsal raphe, DPAG, 0 Dorsal raphC, Dorsal raphe,
20
2-7
0.1-3
0.05-O. I 0.05-0.8
0.0001-0.001 0 00002-0.0005 l-10 nmol 0.00002 0.00002-0.0001
Routes administratton. latencv (min)
Rats
Female CFN rats
White Carneau
Wistar rats Sprague-Dawley rats (320-35Og)
L1ster Lister Llster Lister Lister
Pigeons Columbia livia Squirrel monkeys (550-9lwg) maze Rats Ltster rats (2%35Og) Mice (2%35g) test
test
Open-field
Light/dark
Elevated-plus
Conflict
Vogel’s conflict test
Geller-Seifter conflict test
Geller-Seifter conflict test
Conflict
Vogel’s conflict test Fear-potentiated startle reflex
Open-field Social Interaction
Vogel‘s conflict test
Efficient doses or doses tested (mnlkel
Table I. Continued
al., al.. al., al.. al.,
1987 1988 1992 1987 1988
References ef er er tv er
1972
1986
decreased Myorelaxation
Locomotion
HLU
1970
Kilts er al., 1982
Sullivan er al., 1985 Commissaris and Rech, 1982
Deacon and Gardner.
Wmter,
Graeff and Schoenfeld,
Akai PI al.. 1991 Svensson, 1985
Higgins Higgins Beckett Higgins Higgins
Svensson.
Gardner,
1985
l985a
NJung‘e and Handley,
Meert and Colpaert.
199lb
l986b
File, 1981 Guy and Gardner. 19X5 Kennett CI al., 1989
Lucki cf al., 1989
File CI al., 1987 Pellow rr al.. 1987 Costall er al.. 1988~
Vogel’s test Choinacka-W6icik and Przegalinski, 1991 Leone er al., 1983 FR30 Brady and Barrett, 1985
Sedation and asymmetric compartments
Moddied
VI21
VI30/FRIO
VI30
FI5/FR30
HLU
Comments
Methysergide (non-selective
25h antagonist)
1584h
3.Yh
2.Sh
2.5h
Sprague-Dawley rats (20s32Og) Female CFN rats Wistar rats (l98-260%) Rats Rats Rats (3824468)
Open-field
Sprague-Dawley (2ocr25Og) Rats Sprague-Dawley
rats
Stress-induced colonic motor alterations DPAG-Stimulation
VI21 VI21
_ 0 0
i.p. 30 i.p. I i.p. I i.p. 30 im. 0 i.m. i.p. 30 i.p. 40
IO I-IO l-18 0.3-3 2-20 0.1-3 0.1~1 l-10 0.05~10
i.p. 30
It&30
i.p. 30
2-10
Rats
30
0.3-3
i.p. 30
i.p. 30
5-10
0.1
S.C. 60
IO
Wistar rats (250.300g)
S.C. IO
0.3-10
5-10
L
+
0
0
VI21
_
i.p. 30
IO
i.p. 30
VI21
+
Kilts ef al., 1982
Kilts et al., 1981
Kilts e/ al.. 1982
Kilts et al., 1981
Meert and Colpaert,
File, 1981 Mansbach and Geyer,
Lucki PI al., 1989
Costall cf al., 1988~
Kilts CI al., 1981
High level of illumination
Clarke and File, 1982
1991b
1986b
et nl.. 1993
CUP c, al.. I993
1988 l986b
1989
Meert and Colpaert,
Tokuyama
Mos and Oiivier.
decreased Njung’e and Handley. Warm condition Cold conditin
Locomotion
LLF and HLU
Sedation, ataxia and asymmetric compartments
FR40
Vogel’s test Petersen and Lassen, 1981 Gardner, 1985b FIS/FR30 Graeff and Schoenfeld, 1970 FR30 Brady and Barrett. 1985
Modified
Witkin
VI20 FR30/FRIO
+
1975b
1989
and Perez, 19X9-1990
Winter, 1972 Graeff, 1974 Cook and Sepinwall. Stein e/ al.. 1975 Hodges er al., 1987
3 IO I .25-5 IO 0.0005~.0025 0.25-5 0.1-30
V130/FRIO FIl/FR5 FRIO/VI30
Kilts cf al., I981
+ + +
FR40
Schiitz CI al.. 1985 Jenck el al.. l989a Graeff ef al., 1986
Nanry and Tilson, Gardner, l985b
i.p. i.p. 30 1.p. I i.p. 0 Amygdala, i.p. I5 i.p.
0
0
+
0
0
DPAG, IO t.p. 35 DPAG, IO
S.C. I80
1-p. 30
l-18
10 nmol O.l&lO IO nmol
Wlstar rats (250-300g) Wistar rats (37045Og) Rats
Sprague-Dawley rats (330-37083 Vogel’s conflict test SpragueeDawley rats (20&320e) Spra&-Da&y rats (2OOg) SpragueeDawley rats (200&32Og) Sprague-Dawley rats (2OOg) Wistar rats (220g) Rats Conflict test White Carneau pigeons Squirrel monkeys (55&9OOg) Conditioned Sprague-Dawley rats emottonal response (200-32Og) Light/dark test Mtce (25-358)
Geller -Seifter conflict test
0.5-2 IO 20
CD rats (9-13 weeks) Rats
Social interaction Fear-potentiated rats startle reflex Shock-probe Wistar rats (25&28Og) burying test Marble burying test Female MFI mice (23s35g) Ultrasonic ‘distress’ Wistar rats (9-1 I days) vocalization Stress-induced ddY mice (I 8-20g) anttnociception Defecation-micturition Rats
195OOk
Conditioned emotional response DPAGStimulation
:
E1-
z
fi $ g,
6’
5-H-f,,,
antagonist)
5.Y
125”’ antagonist)
19h antagonist)
Compounda
Alprenolol (non-selectwe
Cyanopindolol
lsamoltanc (non-selective
( - )Pmdolol (non-selective
4l@
Il74”J
630qh
112,”
15 80
5-HT,u
17
5-HT,e
5.HTx
5.HTI
PI al.. 1989 1992
Kennett Kennett.
0
0
0
0
0
1.p. 30
S.C. 40 S.C. 30
i.p 30 i.p. 30
5
6 3-6
2.5-20 2.5-20
Swiss Webster mice (20-35s) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (25@-32Og) Wistar rats (292-368) Wistar rats (144-1968)
maze
test
maze
Stress-mduccd antinociception DPAG-Stimulation
Shock-probe burying test
Marble burying
Social interaction
Open-field
Llght)dark
19800h > lOOO+ > 10000” Elevated-plus
DPAG-Stimulation
Elevated-plus
mteraction
0
+
0
0
0
+
1.p. 30 i.p. 30 i.p. 60 S.C. 30
i.p. 30 i.p. 30 i.p. 30 i.p. 30
3.1 IO l-6
S-10 3.1 3.1 l-3
Swiss mice (2&3Og)
Rats
Swiss Webster mice (20-35g) ddY mice (I S-20@
SWISS Webster mxe (20-3Og) Sprague-Dawley rats (ZOO-25Og) Sprague-Dawley rats (25G-3208) Rats Female MFI nnce (23-358) W1s1ar rats (30&35Og)
0
0
+
0
+
i.p. 30
I 0.1l&c.25 2
Rats PVC (20&28Og)
+
DPAG
WI&II rats
nmol
(18&25Og) 4-32
Fernindez-Gust1 PI al., 1992a Fernzindez-Guasti (‘I nl.. 1992a
0
i.p. 30
5
Shock-probe burying test
0
i.p. 30
References
(k)
LLF
increased Kennett,
Locomotion
1989
I993 Jenck ef al.. 1989b
Fernindez-Guasti PI ol., 19Y2a Fernlndez-Guasti P, nl.. l992a Tokuyama er u..
Critchley er al.. 1987 Npmg’e and Handley.
1992
mcreased Lucki rf al,
1987
1991
199 1b
and 1990 i’f ol.. 1992
and Handley.
and Grxff.
FernPndez-Guastl L6pez-Rubalcaw. Lbpez-Rubalcava
Crltchley
Noguelra
IY9l
, Almeida
(‘I rrl
PI
Almeida
Locomotion
Observatmns durmg IO mm
Rats were well-nourished Rats were malnourished
Colpaert PI ol.. 1992 Fernindez-Guastl and L6pez-Rubalcava, 1990 Lbpez-Rubalcava PI ul.. 1992
5
FR30
Swiss Webster mice w3og) Wistar rats (300-350g)
Comments
0
0
Pigeons Swiss mice (20-30g)
Effects
im. 5 i.p. 30
0.63-10 5
Animals
Models Conflict test Lightfdark test
1. Continued Routes administration. latency (min)
Table Efficient doses or doses tested (%/kg)
31622” > 10000’ > lOOO@ SowI
5.HT:4
Afiimt~es (Ki. no)
Eltoprarmc
(non-srlecti\e
hgand)
40
52
540’
(f)
14@
(+)
390
(i)
1700
(?)
XI
(&)
SSX,’
85. I”
(+)
C-J
158”
2490”
IOOOCP 758”
(-)
(-)
(k)
3162h
46.8”’
antagomst)
Propra”olol
(non-selective
I300
(i)
4000
test
mue
test
interaction
reflex
‘diatres\‘
test
stress
dark
a”cr\Io”
Cot~ditwned
place
‘dl\trcsz‘
YoCilliidtiO”
mice (25-328)
CD-I
mice (324Og)
rats (I 50-2OOg)
(200-3OOg)
mxe
CD-I
(9
days) I I days)
II
309)
(250
3OOg)
Evil”% rat\
rat\
(9.
“I!CC (22
I
IO
I 3
0 3-3
I 20
5 I5
IO
( I2 weeks) (I 2 weeks)
nmol
mg: L
I .25%X IO
weeks)
2.2-8.8
2.5
l-10
1040
I
20
IO
12.4-24.9
I .5-6
I6
l&40
IO
I.5
12.4 -24.9 mg/L
IO
0.0001
rats (150-22Og)
mice (6-X
rat,
Long
Wlrtar
Wistar
DAP
32g)
rats (200&25Og)
mice (25
I days)
Swiss n~tcc
Wtrtar
DBA,2
Wlstar
(Y-l
rats
rats (250~2XO&)
Sprague--Dawley
Wistar
Rats
Rate
(200-25og)
rats
(324Og)
Sprague-Dawley
CDI
(?OO-25Og)
rats
rats (ISC-200g)
rats (I 5&2OOg)
Sprague-Dawley
Wistar
Wistar
CD I mice (324Og)
CDI
Wistar
rats
2.5
CD-COBS
CD-I
5-10
mice
CDI
5 nmol
IO nmol
5 nmol
IO nmol
IO nmol
2.5
IO
5-10
I- 5.6
I O-30
(22 24g) mice (25-32g)
RdlS
rats (2OOm25Og)
Female
Wistar
rats (I 5&2OOg)
Rats
rats (250-3508)
pigeons
Ltster
Carneau
rats (22Og)
Wistar
White
Wistar
test Swiss nwc
test
maze
interaction
Ultrasonic
Social
Free-exploratory
Light
Elevated-plus
DPAG-Stimulation
Restraint
vocallratlo”
Ultrasonic
burying
Shock-probe
t’cedmg
Novelty-suppressed
startle
Fear-potentiated
Open-field
Social
Holeboard
Ltghtidark
Elevated-plu\
test
conflict
conflict
Vogel’s
5
IO
30
durmg
30
30 30
IO or 20
1P-
30
30
p.o. 60
,.p, 30
,,p. 30
1.p.
I p.
DPAG.
i.p. 30
SC
S.C. 60
i.p. 60
--IS days (xl)
pa.
i.p. 30
S.C. 40
30
i.p. 30
days (xl)
p.0.
12-15
p.o. during
30
ICV.
1.p. 30
t.p.30
DPAG
DPAG,
DPAG
1.p 30
30
I. p. 30
I m.
p. 30
C-J
FR30
Vogel’s
D.L L
L
Asymmetric
AsymmetrIc
+ _
0
_
+
+
0
+
+
+
+
Asymmetric
L
Cold
Wartn
mice
mcreased
condition
conditwn
Isolated
Locomotion
compartments
or ol.,
(‘I ol..
<‘I ol..
CI II/..
I993
1989
cr (I/..
C0,lr;lrrretl
1984, lYY3a
and Olivw.
I993
199la
IYSY
1990
I990
PI rrl.. 1992
and Oliwer.
Rocha
Mos
Mos
Olivia
Griebel
Griebel
Griebel.
1988
and Dunn, PI I!/.. Rodgers
Audi
German
and Insel.
l986b
1992~
and Colpaert. Winslow
Meert
1991
1979
rr rrl.. 1989
and Cutler.
1989
1985
1992~
nl . 1990 rr al..
1993
1993
I981
1992~
1990
and Gardner,
er
Rex PI al,.
Davis
Lucki
Gao
cl ol..
and Cutler,
Kennett DL,
and Dunn,
1992
1991
and Cutler.
Guy
Gao
Gao
Kshama
0
+
cf al.,
Car11 er nl , l989b
German
0
+
1990
CI cl/.. 1991
Kshama
compartments
DL.
co”1partme”ts
Asymmetric
compartments
DL,
only
1990
I987
and Dunn, 0, ul..
De Angelis.
Graeff
Audi
Graeff
German
er al..
c, al.,
1986
and Lassen,
r, al..
Kshama
Pellow
Durel
test Petersen
0
+
0
0
Stressed Transitions
0
mtce
IO tmn
D.L
(k)
durmg
Observations
Modified
+
+
+
+
+
+
+
0
0
+
O
ti
&I,
Ei-
Gz
g.
z
5’ iD”
?
332
G. Griebel
from
Timeout
rats (IS&220g)
Wistar
Carneau Carneau
White Whtte
Elevated-plus
emottonal maze
response
days)
free
pigeons
pigeons
pigeons
pigeons
Wtstar
rats
rats
(150~2OOg)
(200-3OOg)
SpragueeDawley
(250-3OOg)
rats
PVC
Sprague-Dawley
rats (2%3508) rats (20&26Og)
Ltster
(200&28Og)
rats
PVG
(ZSO-280s)
rats (40&5OOg)
(SO-120
Rats
rats Wistar
specific-pathogen
Holtzman
Pigeons
Carneau
(48%5288)
Carneau
(80&105Og)
White
White
monkeys
rats (20&25Og)
Squirrel
rats (2OC-280~)
rats
Lister
Wistar
Rats
rats (l8&22Og)
Rats
rats (21&27Og)
(20&3Oog)
rats
Wistar
Wistar
Lister
rats
rats (20&25Og)
CDCOBS
Lister
(190-2lOg)
Sprague-Dawley
(200-3oog)
rats rats
SpragueeDawley
rats
SpragueeDawley
( I ?o-2lOg)
SpragueeDawley
procedure
test
Conditioned
avoidance
test
conflict
Conflict
Vogel’s
Ra1s
rats
(382-446~)
Wtstar
Rats
rats
rats (186200g) Wistar
Wistar
(2%350g)
rats
Wistar
I5
I5
I5
I
I25
I
I5
15
30
raphe,
60
raphe,
IO
0.25
0.2
0.012550.
0.05~~. I
0.25
0.015~1
0.01w.03
0.1-I
0. l-l
0.005~.81
0.0331
0.3-3
0.1-3
0.03-3
0.001~.3
0.001-0.0025
I
Nucleus
IO
IO
15
30
I5
5
IS
0
0
30
S.C. I5
s.c. I5
i.p.
t.p,
i.p.
i.p.
i.p.
i.m.
i.m.0
i.m.
i.m.
i.m.
i.m.
accumbens,
Htppocampus,
0.00054.001
30
raphe,
30
I5
i.p.
Dorsal
i.p.
i.p.
Hippocampus
Dorsal
i.p.
Dorsal
i.p.
S.C. 30
S.C.
S.C. I5
i.p.
i.p.
i.p.
t.p,
S.C. 60
0.25
0.OooO2~.005
0.5
0.025~.05
0.0254.
0.0000040.0005
0.5-2
0.001
0.0624.25
0.005xt.
0.050.
0.03-a.
0.5
0.1&0.3
0.25
0.034.
0.0551
0.0070.
5
5
5
5
5
_
+
+
+
+
+
+
+
0
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
+
+
+
+
0
0
Modified
Vogel’s
Vogel’s
open
arm
Decreased
test
test
total
during
during
during
entries
IO min
Observations
IO min
Observations
IO min
Observations
effect
VII5
FR30
FR30
FR30
FR30
FR30
FI3
Weak
Modified
Modified
test
test
rats
Vogel’s
Stressed
Modified
FR8
VI20
VI30
GellerrSeifter
Stefanski
Kshama
Moser.
Moser
Critchley
Pellow
Critchley
Critchley
Sanger.
Galizio
Colpaert
Ahlers
1988
1992
1991
1987
1987
1988
1992
1991
l992b
l992a
1991
1988
1990
and
cc nl..
l989b
P, nl..
1992 1990
1992
1990
1988
1987
1986
1990
corrr;mrefi
l9RR
1987
Handley,
Handley,
er nl..
c, nl.,
and
and
I990
cr al.,
PI al..
Barrett,
1992
1988
1987 er al.. e, ol..
l993a Barrett.
et al.,
1993
1986
and Seredenin.
er al.,
er al.,
er al.,
er al..
PI al..
et al.,
Samanin.
Ed al.,
1984
1990
Moser,
CI al.. Mansbach
Witkin
Gleeson
Stefanski
Korneyev
Higgins
and
<‘I al..
and
De Vry
er al..
er al.. e, al.,
1991
Bennett,
e( al.,
and
1992
PI al..
et ol..
Stefanski
Plaznik
Higgins
Carli
Higgins
Engel
Moser
Hibert
Moser
Hascoet
De Vry
Hodges
Amrick
Sanger.
Thiebot
:
%
2
a
r.z
8,
F
6.
334
I
I
00
c
t!-t
+
+
+
+
t+l
+
+
tt
t
+
t
Ultrasonic ‘distress’ Vocalization
Shock-probe burying test
Marble burying test
Staircase test Novelty-suppressed feeding
Anxietvidefense ., test battery
Open-field
Holeboard Social interaction
0.5
Rats Wistar rats
0.25%0.5 0.0075~.03 0.14.2 0.1-l 0.54.8
Wistar rats (IO days) Wistar rats (9-l I days) wistar rats Sprague-Dawley rats (320&35Og)
0.054.2
Sprague-Dawley rats (25&35Og) AP mice (4-6 days)
i.p. I5 i.p. IO
S.C. IO 30
IS
S.C. IO
1.p. I5
i.p. I5
1.p. 15
i.p. IO
S.C. 30
+
+
0
+ +
+ +
+ + +
Hippocampus,
5
+
Hippocampus
+
+
+
Hippocampus i.p. 15
0.03 0.3%10
0.1254.75
o
+ +
5
0
+ + + + _
0
0
_ _
i.p. 0
IP S.C. IO
Wistar rats (28%35Og)
60
5
5 5 5
Nucleus accumbens. S.C. 60
SC
S.C.
S.C. 30 Dorsal raphi, Dorsal raphi, Dorsal raphe, i.p. IO Dorsal raphe, DPAG, 0
30
0.05-0.5 0.0324. I25
0.5
0.0001~.001 0.0005 0.01-l
0.025~. I 0.025Il.05 0.005
2.5-S
0.000-0.005 0.1254.5
0.1254.5
0.05-6.25 0.00002JJ.001 0.001 0.000040.005 O.l254l).25 0.00002~.001 3-25 nmol 0.0254.4
0.25
Male and female Long-Evans rats (98-I I I days) Rats Sprague-Dawley rats (270-32Og) Rats Female MFI mice (23-35g) Wistar rats
Wistar rats (I SC-200g) Rats DAP mice (22&3Og) Lister rats (201X2808) L1ster rats (200-2508) Lister rats (210~27og) Wistar rats (225-250~) Lister rats (2OlX28Og) Lister rats (2Ol-25Og) Sprague-Dawley rats (28&320g) CDJZOBS rats f20&3OOej Wista; rats (18c22Og) CDXOBS rats (20&3oog) Sprague-Dawley rats (20&25Og) Rats Wistar rats (18&22Og) Rats CD-COBS rats (2W25Og) Wistar rats (I 8&220g) rats
Warm condition Cold condition
+ 537.DHT
decreased
+ 5.7.DHT
Locomotion
Stefanski er al., 1993a Carli PI al.. 1989a
Carli PI al.. 1989a
Kshama er ol., 1990 Crltchley e! al.. 1987 Olivier et al.. 1989 Higgins ef a/., 1992 Higgins et al.. 1987 Higgins et al.. 1988 Dunn er al., 1989 Higgins er al.. 1992 Beckett er al.. 1992 Ahlenius er al., 1991
cr al.. 1992
er al.. 1993a
(‘I al., 1991
De Vry er al.. 1991 Svensson. 1985
Hdrd and Engel. 1988 Mos and Olivier, 1989
Nastiti
FernPndez-Guasti PI al., 1992b Fernindez-Guasti and Hong, 1989 Meert, 1989 Fernlndez-Guasti er al.. 1992b Treit PI a/., 1993
Rex e/ al., 1991 Njung’e and Handley.
199lb
Boaventura rr al., 1986 Fletcher and Davies, 1990
Blanchard
Stefanski
Plaznik ec al.. 1991 Stefanski et al., l992a Stefanski QI al., l992b Carli er al.. 1993
increased Lucki er ol., 1989
65 dB noise
Locomotion
Stressed rats
Non-stressed
HLU
LLF Isolated mice LLF HLU
E:
#
6 g 2.
3 5.
r
5-HT,”
160
5.HT,s
810
LY 228729 (5-HT14 agonist)
agonist)
1.7
5-HT,A
LY 165163 (5.HT,,
%xinoxan Full agonist)
Compounds
Atlinitles
no)
4500
5.HTla
(Ki.
5-HTI
> 10000 > 10000”
5-HTx Rats CD rats (9-13 weeks) Wistar rats (20@25Og) Rats Sprague-Dawley rats (3MOOg) Rats Sprague-Dawley rats NMRI mice Swiss mice (25-308)
Animals
0.1254.5 l-3 2.5-10
+
i.p. 30 i.p. 35
0.1-I 0.032-I
Conflict
0.54
Elevated-plus test
S.C. 30
i.p. 30 r.p. during I4 days (xl) 0.3-3
Sprague-Dawley rats (2Oa-3OOg) Rats
i.p. i.p. p.0.
0.3-3 LED = 0.3 >I
maze
30
0.3-3
i.m.0 i.m. 5 Acute and chronic
0.00-3 0.04 0.14.5
i.p. 30 S.C.
iv.
0.034.3
i.m
+
i.p. 30
0.05-O. I
References er al., 1986 and Tilson. 1989 e, ol., 1991 er al.. 1986 rr al., l988a
+
_
+
+
+
+
+
+
Foreman
(01nl.. I993
Moser.1989b
Van Dijken CI nl.. 1992
Schipper et al.. 1991 Molewijk et a/.. 1993 Schipper er ol., 1991
Schipper er al., 1991 Mos and Olivier. 1989 +
_
+
1993
1990
+
Barrett, 1992 Colpaert YI al, 1992 Rodgers CI ol.. 1993
Barrett P( ol.. 1989
Gleeson and Barrett.
Korneyev and Seredenin. Jenck er ol.. l989a
Cue er ol., 1993
Schipper ef al.. 1991 Sanger and Joly. 1989-1990 Klint. 1991
Davis, 1993 Mansbach and Geyer. 1988 De Vry er 01.. 1991 Lecci er al., 1990
Davis Nanry Hijzen D&s Davis
Schipper PI al.. 1991 Griebel. 1993 Ahlenius cl al., 1991
Warm condition Cold condition
FR30 FR30 AdditIonal measures of anxiety
FL3
Comments
+
+
+
+
+
0
+ _
+
i.p. 30 S.C. 30
+
+
+
+
0
0
0
_ _
Effects
0.3 0.1254.5 0.01-l
0.02+. I 0.2-3.2
test
Squirrel monkeys (800-105Og) White Carneau pigeons (45MOOg) Whtte Carneau pigeons pigeons maze Mice
test
!+-I.
i.p. IO i.p. 30 S.C. 30
0.124.25
S.C.
i.p. 0, IT, 30 S.C. 5 i.p. 5 i.c.v., 30 in. 0
0.63-10 0. I 14 0.5-8 0.05-0.1 2.5-10
Routes administration. latency (min)
Mice Swiss mice (IO weeks) Open-field Sprague-Dawley rats (280-32Og) Four hot-plates Mice Ultrasonic ‘distress’ Wistar rats (9-l I days) vocahzation Rats Adult rats Mice Stress-induced hyperthermia Freezing Wistar rats (25&3OOg)
Light/dark
Elevated-plus
Conflict
Passive-avoidance
Mice test Wistar rats (22&24Og) Sprague-Dawley rats (200-2500) Stress-inducedcolonic Wistar rats (25&3OOg) motor alterations Hot-plate Wistar rats (20&25Og) DPAG-Stimulation Wistar rats
Aggression-provoked Stress-induced hyperthermia
Models
Eficient doses or doses tested (mg/kg)
Table 1. Continued
cl
8 ‘p
$.
0.95”
s20500 (full agonist)
5-MeODMT (agonist)
2.5’
0.19‘
S20499 (full agonist)
U-93385 (full agonist)
0.35w
39Q
6.3
Sl4671 (full agonist) 9.3 pKi”’
s20244
6.55
0.1 Ir?y
MKC-242 (full agonist)
630h
Sl4506 (full agonist) p&l’ 9.01
0.79”
MDL 72832 (full agonist)
7.8
39Xh
l5d
16
6.64
I 5Xh
57‘
7.8
7.50
501’
6
test
Sprague-Dawley rats (20&25Og) Swiss mice (IO weeks)
Pigeons Wistar rats
Pigeons Wistar rats
Rats
i.p. 30 i.p. 20 i.p. 0 i.p. 5 DPAG, IO DPAG. IO
0.12-X 4 0.552 nmol l-2 nmol
i.p. I5
0.5-2.5
IO 0.2555
i.p. 12
l-3
IO 3-10
+
+
_
+
_
_
_
0
+
+ _
+
during I6 days (xl) p.0. i.p. Subchronic
Mice Rats
0 SC
I-IO 22
Rats
S.C.
+
i.p.
10
Mice
+
+
+
i.p. 30 i.p. 20
+
+
+
+
i.p. 20 t.p. 30 during 14 days i.p. 20
+
0
+
S.C. 30
i.m. 60 S.C. 30
p.o. and i.p.
16 2-4
I-3
4
l-3
0.05-I
0.0025-0.16 0.0006-2.5
i.m. 60 S.C. 30
3-10
Rats DAP mice (2&3Og) Marble burying test Female MFI mice (23335g) Fear-potentiated Sprague-Dawley rats startle reflex (300-3508) CD rats (9-13 weeks) DPAC-Sttmulation Wistar rats (25&35Og) Rats
Social interactton
Colpaert er ol., 1992 Millan and Brocco. 1993
+
0.0025-0.63 0.00062.5 0
Egawd et a/.. 1993
4cute and chronic
+
LED = 0.0625
Sanger and Joly, 198991990
+
Shephard CI al.. 1982
Schreur et al.. 1993 Lahti ef al.. 1993
Schreur er al., 1993
Schreur ef al., 1993
Schreur PI al., 1993
Griebel rr al.. 1992
Porsolt CI al.. 1992 Lesourd PI al.. 1993 Griebel er al., 1992 Porsolt EI al., 1992
Griebel et a/.. 1992
Curie PI al., 1991
Millan and Brocco, 1993 Millan and Brocco, 1993
Nanry and Tilson. 1989 Schiitz PI nl., 1985 Graeff er al., 1986 C0Il~iIIl4e~
Davis ef n/.. 198Oa
Observations Critchley and Handley. 1987 during IO min LLF Critchley er al.. 1987 Isolated mice Olivier et al.. 1989 Locomotion decreased Njung’e and Handley. 199lb
FR30
FR30
Moser, l989b
i.p. 30
isomer
0.25-I
(-)
_
Moser. I989a
S.C. 30
isomer
0.054.X
(+)
S.C. 30
0.4-3.2
Mice
Geller-Seifter Female Alderley Park conflict test rats (241-315g) Elevated-plus maze PVC rats (200-28Og)
Social interaction Stress-induced increases in corticosterone
Isolation-induced aggression Shock-induced aggression Center test (thigmotaxis)
Vogel’s conflict test Wistar rats (195-2458) Swiss mice (IO weeks) Light/dark test
Vogel’s confltct test Wistar rats (l95-245g) Elevated plus-maze Rats Light/dark test Swiss mice (IO weeks)
Light/dark
Elevated-plus maze
Conflict test Elevated plus-maze
Conflict test Elevated plus-maze
Conflict test (?)
Sprague-Dawley rats (200-3008) Sprague-Dawley rats (200-3OOg) Passive-avoidance test Wistar rats (22&24Og)
Elevated-plus maze
Compounds
~-HT,A
8.7
Buspirone (partial agonist)
25h
BP 554 (5-HT14 agomst)
BMY 7378 (partial agomst) PK;“‘.
BAY R 1521 (5.HT,, agonist)
&API 59 28‘ (selective agomst)
125890h 31622”
4.4
~-HTIR 5-HT,u
794h
5.7
5-HT,,,
Affinities (Ki. no)
7940h
6.6
5.HTx
> 10000”
< 6.0
5.HTJ Models
Animals
test
test
maze
maze
Geller~Seifter conflict test
Elevated-plus
Ultrasonic ‘distress’ vocalization
Ltghtidark
Conflict
Elevated-plus
SpragwDawley rats (33Om3708) Ovariectomised Long-Evans female rats
Wistar rats (229-2718) Sprague-Dawley rats Sprague-Dawley rats Rats Rats Sprague-Dawley rats (20&225g) Sprague-Dawley rats (420-48Og) Rats
Wistar rats (25tK27Og) Wistar rats Wistar rats (40&5OOg)
Wistar rats (18&2OOg) Rats Rats Rats
Rats
CD rats (16&2OOg)
Adult rats
Squirrel Monkeys (800&105Og) White Carneau pigeons White Carneau pigeons pigeons Female T/O mice (22m3Og)
PVG rats (I 8&26Og)
Wistar rats (ItO-200g)
Vogel’s conflict test Wistar rats (I 70-2OOg)
i.p. 30 r.p. 30 S.C.
2
5-10 5 5
O.lf5.6
p.o. 60
p.o. 60
p.0. 30
5-40
I
S.C. 1-p. 60
i.p. 30 1.p. I5 0” 30 i.p. 30 i.p. 30 i.p. 30 S.C. 60 1.p. I5 1.p. 30 p.0. 30 i.p. 30 i.p. p.0. 30
SC
p.o. 60
i.p.
,.m. 5 i.m. I5 im 5 S.C. 30
i.m
i.p. 30
p-0. 60
p.0.
Routes administratlon. latency (min)
2 0.04-10 I-IO I .25-5 IO-40 0.3 0.25-15 2.5-5 IO 0.5 0.3-3
‘
_(
5 I-10 0.5-10
0.1-3
LED=3
0.03-3 l-5.6 0.16
0.003~. I
O.l&l.2
I t&60
3-10
Efficient doses or doses tested (w/kg)
Table 1. Continued
I
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
0
0
0
0
0
+
+
+
+
+
+
0
+
testNagatani
e, RI.. 1991
References
Gleeson
and Barrett,
PI al., 1992
1986
1990
and Pollard.
1990
Witkm and Perez. 1989~1990
SoubriC. 1989
Young tv nl.. 1987
Zhang and Loo, 1993 Hartmann and Geller. 1981 Geller and Hartmann. 1982 Sullivan et al.. 1983 Baduel el ol.. 1986 Mason E, al.. 1987
Brocco ef nl., 1990 De Vry P, rd. 1991 Sanger. 1990
Sanger. 1992 Amrick and Bennett. Gardner, 1986 Soubrie. 1989
FRI FRIO Rats never Howard treated before (effects were always weak)
Trial I Trial 2 FR30/FRIO
VI30/FR30
Weak effect
VI/FR4
Trtal 2 Trial 3 VI30
VI30
1986
et rrl.. 1992
C, ol.. 1993
Baduel er al,
Luscombe
Molewijk
Gleeson er ul.. 1989 FR30 and weak effect Ahlers z, ul., 1992 FR30 Colpaert of ol., 1992 Asymmetric Bill (‘I al.. 1989 compartments
F13
Crltchley
Vogel’s test Takao cf nl., 1992
Vogel‘s
Observations during IO min
Modified
+
comments Modified
Effects
2
50
Rats Rats Wistar rats (30MOOg) Rats Rats C&COBS rats (20&3OOg) Wistar rats (22s240g) Female Long-Evans rats (22ft249g)
Wistar rats Sprague-Dawley rats Sprague-Dawley rats (2&3OOg) Female Long-Evans (225-249g) Wistar rats (I 5&l 66g) Lister rats (20&28Og)
Sprague-Dawley rats (200-3OOg) Lister rats (21&27Og) Sprague-Dawley rats (24@3OOg) Sprague-Da&y rats (17&2lOg) CDCOBS rats (20@3OOg) Sprague-Dawley rats (225-2758)
Rats CD rats (8s1OOg) Sprague-Dawley rats (2OOg) Rats Rats Sprague-Dawley rats (25&35Og) SpragueDawley rats (20&25Og) Rats Lister rats (200-25Og) Female rats (225-25Og)
0.5-I 1.25 0.005
Rats Wistar rats (18&2OOg) Vogel’s conflict test Wistar rats (18&22Og)
+
Median raphe, IO i.p. 10 i.p. during 8 weeks (x2) i.p. 30 S.C.
0.001Al.005 0.125-2 24
S.C. 15 p,o. 60 Dorsal raphe, S
0.125 I c-20 0.0002
30
i.p. Dorsal raphe, 5 i.p. IO S.C. IO i.p. 30 p.0. 30 Dorsal raphe, 5 S.C. 30 p.0. 30 s.c. 30
5.6-10 o.000&Oo.oo2 0.25-I 0.125-I 5-10 20 0.000~.01 0.254 l-50 0.25-2
S.C.
+
S.C. I5
0.61.2
5-10 0.054. I5 0.25-I
p.0. 30 p.0. i.p. I5
90 I-IO IO
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
Hippocampus p.o. 60 p.0. 30
S.C. 60 S.C. I5
0.04-10 0.125-0.625
0
0
0
0
0
0
+ + -
+
+
1&SO 0.5-5
i.p. 30 p.0. p.0. Dorsal raphe, IO
p.0.
I-IO 2-10 2-10 0.0001-0.01
I .25-20
i.p. 30
0.25-2
Wistar rats (25&35Og)
i.p. 30 Hippocampus, 5 Nucleus accumbens, 5
i.p.
0.25-2
Rats
test
test er al.. 1991
er al.. 1990
Goldberg PI al., 1983 Sullivan PI al., 1983 Sanger et al., I985 Budhram er al.. 1986 Gardner, 1986 Carli ef al.. 1989b
Hascoet ef al.. 1992 Sanger, I992 Stefanski er al., 1993a
Thiebot
Thiebot
1986
Carli PI al.. l989b
Moser er al.. 1988
Higgins PI al.. 1988 Vogel’s test Gower and Tricklebank,
Vogel’s test Shimizu er al.. 1987
Heym YI ol., 1987 Higgins er al.. 1987 McCloskey PI al., 1987
Pith and Samanin.
Unpredictable
PI al.. l99la
1988
Wada and Fukada, 1991 Higgins PI nl., 1992 COlIlriJU&i
shocks Costello
Modified Vogel’s test Schefke PI al., 1989 and weak effect in acute treatment De Vry CI al.. 1991 Hibcrt and Moser. 1990 Moser ct al.. 1990
Modified
Modified
Weak effect
Modified
File, 1985 Taylor er al.. 1985 Vogel’s test Eison PI al., 1986
Modified Vogel’s test Brocco er a/., 1990 Costello et al., l99la Predictable and moderate predictable shocks Plaznik cf al., 1991 Oakley and Jones, 1983 Modified Vogel’s test Weissman er al.. 1984
Modified Geller-Seifter Modified Geller-Seifter FR8 VI30
Compounds
5.HTw
5.HT,s
5-HT,o
5-HT:n
Affinities (Ki. no)
5-HTx
5.HT?
test
SPRD rats (2OOg) Wistar rats (195-245~) Wistar rats (180-2208) Rats Wistar rats (18&200g) Sprague-Dawley rats (21 I-347g) Wistar rats (200-2508) Wistar rats (12 weeks)
A”l”lals
Conflict
Rats Squirrel monkeys Squirrel monkeys Squirrel monkeys Monkeys Squirrel Monkeys (80&1050g) Squirrel monkeys Cynomolgus monkeys (4-7 kg) Squirrel monkeys (0.7-0.8 kg) pigeons White Carneau pigeons pigeons White Carneau pigeons (480-5288) White Carneau pigeons White Carneau pigeons White Carneau pigeons (500-6OOg) White Carneau pigeons White Carneau pigeons pigeons White Carneau pigeons White Carneau pigeons (1 year) Timeout from Holtzman avoidance procedure specific-pathogen free rats (SO-120 days) Holtzrnan specific-pathogen free rats (SO-120 days) Conditioned Wistar rats (40&5OOg) emotional response
Models
i.m. i.m. 60 p.0. 30 im. im. 5 i.m. 0 i.m. 5 i.m. 0 i.m. 0 i.m. 5
im. i.m. ,.“I. i.m.
i.p. 15
i.p. 15
1-p. 30
0.25-l 5 0.5-5 3-30 0.03-10 0.03-10 0.03-3 0.1-5.6 0.1-10 0.1-10 0.63 0.3-5.6 0.1-3 0.63 0.03-3 0.1-3 0.5-2
0.3-l
I .25-5
15 5 0 0
i.v. 10 i.m.
p.0.
5 IO I .25-2.5 0.01-0.3 0.0034. I
3-5 IO
0.62-2.5 0.62 340 IO p.o. 60 D.O. 30 p.o. diring 7 days i.p. 30 i.p. 30
i.p. 30 i.p. 30 i.p. 30
0.04 8
Routes administration. latency (min)
El&lent doses or doses tested @g/kg)
Table 1. Continued
+
0
0
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
+ _
+ +
+ + + + + +
Effects
VI15
VII/V13/FRIO VI3/VII/FRIO VI
FR30 FR30 FR30
FR30 FR30 FR30
FR30
1981 1982
er al., 1984 er al., 1986 and Barrett, 1986 et al., 1987
el al., 1984
Sanger.
Galizio
Galizio
1990
t’f ol.. 1993
(‘I al., 1990
Nader, 1991 Nanry er al., 1991 Colpaert et al.. 1992 Barrett and Vanover, 1993 Wojnicki and Barrett, 1993
Mansbach PI al.. 1988 Mansbach er al., 1988 Brocco PI al., 1990
Barrett Barrett Witkin Witkin
Weissman
Hartmann and Geller, Geller and Hartmann,
Modified Vogel’s test Korneyev and Seredenin, 1993 0.16 and Meneses and Hong, 1993 0.32 mA shocks Miyauchi PI al., 1993 Sullivan PI a/., 1983 Goldberg er al., 1983 Sullivan er al., 1983 Wettstein. 1988 F13 Gleeson and Barrett, 1990
Modified Modified
Modtfied
References
Horvith CI al., 1992 Porsolt et al., 1992 Vogel’s test Stefanski el al., 1992a Stefanski er al., 1992b Vogel’s test Takao PI al.. 1992 Vogel’s test Amano cf al., 1993
Comments
g
ti.
s
Q
Light/dark
test
Shuttle box Elevated-plus maze
S.C.30 S.C.during 16 days (x2) S.C. 30 S.C. 30
0.25-I 1 0.1252 l-2
r.p. 30 p.o. 60 Acute and chronic i.p. during 5 weeks (x2) i.p. 20 30 S.C. 15 i.p. 30 i.p. p.0. S.C. 30
0.125 0.01-3 0.63-5 IO
2 0.1 0.064 3.1610 10-56.2
Sprague-Dawley rats (25&35Og) Wistar rats (213-263g) Wistar rats (15&2OOg) Rats Mice (25-350)
Female T/O mice (22-308)
I
I
30 i.p. 15
2 I-10
Wistar rats (345405%) Rats Lister rats (25&35Og) Rats Lister rats (30@4OOg) Wistar rats (151&202g) PVC rats (20&26Og) SPRD rats (2OOg) Wistar rats (225-25Og) Wistar rats (18&22Og) Sprague-Dawley rats (25&35Og) Wistar rats (I 5s200g) DBA/Z mice (12-14 weeks) Wtstar rats (3454058) CD rats (I 6&2OOg) Mice i.p. 40 p.o. 60 ;.p. 30 i.p. 30 i.p. 30 Hippocampus, 20 S.C. 10
i.p. 30
0.025-5
i.p. 30
i.p. I5
1.25
0.5-20 0.5-20 2 2.5-20 0.05 0.08-l .25 0.5-I 0.0025 882048 nmol
S.C. I5 S.C.30
0.8 0.1-I
i.p. 30
S.C.30
0.0152
I4
I
30 i.p. 30 s.c. 30
I 4-8 0.125-2
0.06, 0.254
Sprague-Dawley rats (200-3OOg) Sprague-Dawley rats (34&23Og) Rats Sprague-Dawley rats (2~300g) Lister rats (i8Og) Sprague-Dawley rats (20&250e) Long-Evans-rats (32&34Og) PVC rats (18&26Og)
Rats Lister rats (25C-35Og) Sprague-Dawley rats (25&3OOe) Sprague-DawEy rats (20@3OOg) -
Kostowski et al., 1990 Moser cr al., 1990
Redfern and Williams,
Moser, 1989b
Moser. 1989a
Martin, 1993 Pellow er al., 1987 Moser PI al., 1988
+ +
+
+
0
c
Asymmetric
Asymmetric compartments Weak effect Asymmetric compartments
Bill et al.. 1989 COlIliflU~~
Young and Johnson, 1988
Pith and Samanin. 1986 Costall cr nl., 1988a
Zhang and Luo, 1993 Kshama tv al., 1990
Kostowski er 01.. 1992 Luscombe PI ol.. 1992 Additional measures Rodgers PI al., 1993 of anxiety Siiderpalm cf al.. 1993
+
Saderpalm et al.. 1989
Locomotion decreased Critchley PI al.. 1992 and observations during 10 min Kostowski er al., 1992 Onaivi. 1993 Pellow and File. 1986 File cr al., 1987 Moulton and Morinan, 1990 Wada and Fukada. 1991 Observations during Critchley er al., 1988 Horvlth er al., 1992 IO min Dunn er al.. 1989 Kostowski CI al., 1989
Lal e( al., 1991
Kshama PI al., 1990 Lee and Rodgers, 1991
+
1989
File and Andrew% 1991 Locomotion decreased Klint, 1991
PCPA pretreatment Decreased total open arm entries
Caffeine-pretreated rats
+ +
0 +
0
0
Cl
-
_ _
_
_
_
_ _
+
:
%
6
E:
rz
2 c.
Compounds
S-HTIA 5-HT,e
5.HTm
~-HT:A
Affimties (Ki, no)
5-HTxc
5.HT,
Open-field
Holeboard Social interaction
Models
+
+ + +
i.p. 30
i.p. 45 i.p. during 7 days (xl) i.p. 30 i.p. 40 30 i.p. 15 30 pa. 30 i.p. 30 i.p. 45 S.C. I5 Dorsal raphi, 5 S.C. I5 pa. 30 Dorsal rapht. 5 Dorsal raphe, 5 S.C. 30 i.p. 30 pa. during 5-10 days (xl) i.p. I5 i.p. 40 pa during 12-14 days Dorsal raphe, 5 i.p. 30 Drinking fluid during 6-8 days i.p. I5 i.p. 20 S.C. 15
l-5
0.125-4 0.25-2 3.1617.8 0.25-2
0.25-2.5 5-10 0.3-10 0.12>2 0.24.8 0.00004-0.0002 0.2 5-20 0.0004-0.002 0.0040.01 IO 5-10 2.3-2.6 1.25 l-2 3.4 0.00004-0.0002 l-5 12.8 mg/L
0.1-l
ICR mice (2&35%)
BKW mice (3C-35g) Mice Female ICR-DUB mice (I 7-350) BKW mice (25-3Og) Wistar rats (1 SO-200g) Wistar rats Rats Rats Wistar rats (18&2OOg) DAP mice (22-30g) Sprague-Da&y rats (225-2758) Lister rats (18Og) Lister rats (20&28Og) Rats Wistar rats (18&2OOg) Lister rats (20&25Og) Lister rats (21&27Og) Mice Wistar rats (225-2508) Male and female DBA/Z mice (24-368) Wistar rats Lister rats (25&3OOg) CD1 mice (40-440) Lister rats (200-280%) CD1 mice (3545g) Female CD1 mice (30-35g) Wistar rats (213-2638) Sprague-Dawley rats (33&42Og) CIXCOBS rats (20+3OOg)
0.0410
2f5
*
+
i.p. 45
0
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
0
0
0
0
+
+
+ + +
0.25-l
Effects
S.C. 15 Median raphe, 10 S.C. 20
0.1 0.005 0.1-10
CD-COBS rats (2W3OOg) Mice C57Bl/6J (18-2Og) BKW mice (2&3Og)
Animals
Routes administration, latency (min)
Efficient doses or doses tested (mgikg)
Table 1. Continued
Comments only
Non-stressed
l5W rats
HLU Home cage Neutral cage Oestrous mice Dioestrous mice
HLU HLU and LLF
HLU
Familiar congener HLU LLF
Familiar congener Isolated mice HLU
HLU
Asymmetric compartments and rears Transitions and asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments
Transitions
References
and Johnson,
l993b Zhang and Luo, 1993 Panickar and McNaughton, 1991 Carli t’f a/.. 198%
Gao and Cutler,
Higgins CI al., 1992 Gao and Cutler. l993a
De Vry er al., 1991 Costall P, al., 1992a Gao and Cutler. 1992a
File and Andrew, 1991 Higgins er al., 1992 Andrew and File, 1993 Guy and Gardner, 1985 Higgins er al., 1987 Higgins er al., 1988 Schreur, 1988 Dunn et al., 1989 Cutler, 199la
199lb
1991
1989
Costall PI al., 1992a Kshama er al., 1990 De Vry er al., 1991 File, 1984a File, 1984b Guy and Gardner, 1985 Olivier et al., 1989 Barnes er al., 1991
Young
Costall and Naylor,
Barnes e, al., 1991
Onaivi and Martin,
Costall PI al., 1989b
Kilfoil et al., 1989
Carli et al.. l989b
Q 3.
P
K.
burymg
Unavoidable stress (gastric lesion) Avoidance test Conditioned avoidance test
Aggression-provoked Stress-induced hyperthennia
Fear-potentiated startle reflex
Conditioned
Sprague-Dawley rats Wistar rats
Mice ICR mice (7-8 weeks)
Rats Sprague-Dawley rats (300-4OOg) Sprague-Dawley rats (3MOOg) Sprague-Dawley rats Sprague-Dawley rats (33MOOg) Wistar rats (2OOg) NMRI mice Swiss mice (25-308)
Long-Evans rats (325-500g) Wistar rats (20&25Og)
Wistar rats (18&22Og) CD-COBS rats (20&3OOg) Rats SPRD rats (ZOO& Wistar rats (18&22Og) Rats Male and female Wistar rats (180 days) Wistar rats (18&220x) Rats Staircase test Adult male and Defense test battery female R. rattus Ultrasonic ‘distress’ Wistar rats (9-I I days) vocalization Wistar rats Rats AP mice (4-6 days) Sprague-Dawley rats (9-l I days) Rats Adult rats Wistar rats (12Og) Social competition Female mice MFI Marble burying test (23-35g) Shock-probe Wistar rats (25&28Og) burying test SpragueeDawley mts (25&35Og) Wistar rats 30 S.C. 30 S.C. i.p. i.p. 30 i.p. 30 xc. 60 S.C. i.p. 30
3-6 0.3-3 0.03-4.3 LED=1 O.&l.25 I-20 0.6340 0.05-l 5
IO
!.P. 30 1.p. 45
S.C.
IO p.0. 2.5-5 p.o. 60 2-10 p.o. during 3 days 0.5-7.5 i.p. 30 EDw = 3.64, 18.2 i.p. p.0.
5 3-30 IO
1.25-5 5
0
O&5
S.C.
S.C. 0
p.0. IO
0.6 5-10
5-20
i.p. 30
i.p. I5
I-IO
8-64
30
Hippocampus, p.0. 1.p. 30
i.p. 30
Hippocampus i.p. 30 i.p. 30
5
Nucleus accumbens, S.C. I5
l-3
0.0025-0.005 I l&20 1O-20
0.62 0.3-2.5 0.62-2.5 I .25-2.5
0.0001~).005 0.1-I 5
o
+ +
0
+
+ + +
+ ++
+ +
Auditive
stimulus
Lesion of the septum
Fernindez-Guasti er al., l992b Craft et al.. 1988
++
1988
l986a
Geller and Hartmann, Allen cr nl.. 1974
Schipper et RI.. 1991 Ogawa er ol.. 1993
Munonyedi er al., 1991 De Vry PI ol.. 1991 Lecci CI al.. 1990
1982
Mansbach and Geyer. 1988 Melia and Davis, 1991
Kehne CI al.. 1988
Davis. 1988 Davis er al., l988a
Hijzen PI al.. 1991
Treit and Fundytus,
+
0
Meert and Colpaert,
+ 5,7mDHT
Locomotion
1989 De Vry et al.. 1991 Schipper PI al.. 1991 Nastiti er al., 1991 Winslow and Insel, 199la
Mos and Olivier.
Stefanski PI al.. l993a Boaventura er al., 1986 Blanchard CI al., 1989
Plaznik rr al., 1991 Horveth ct al., 1992 Stefanski et ol.. l992a Stefanski PI al.. l992b Hughes, I993
Stefanski PI al.. l993a Carli et al.. 1989a
Winslow and Insel, 199lb Molewijk er al., 1993 Joly and Sanger. 1991 decreased Njung’e and Handley. l99lb
Warm condition Cold condition
Sedation?
65 dB noise
Stressed rats
0
+ + + +
+ + + + + +
+ + +
+ + + + +
+
rz a 2 B
8 3 0 r’.
A.
7
5-HT,*
FG5893 (agonist)
0.7
E-4424 101”” (selective agonist)
Comoounds
5-HT,.
5-HT,n
~-HT.A
Affinities (Ki. tt~)
5-HTr
5-HT,
Animals
threat
Ultrasomc ‘distress’ vocalization Passive-avoidance test
Human
Social interaction
+ +
p.0. 30 p.0. 30 i.p. 30 i.p. 30 i.p. 30
8832 3 0.555 I-10 1
i.p. between 25 and 24 hr i.p. during 3, 7 or 14 days (x2) i.p. i.p. 40 S.C. between 40 and 96 hr
0.0001xt.5
+ +
0.1 Rats
+
+
+
+
+
+
+
+
0.05
0.000-0.5 0.001~.5 0.0001~.001
i.p. 30 i.p. i.p.
2.5-10 0.0001~.5 o.000-n.5
+
+
+
HLU
+
S.C. 45
0.1-I
Rats
Rats Lister rats (25&3OOg) Marmoset Callithrix jacchus (295-3358)
BKW mice (25-300)
+
S.C. 45
0.051
+
+
er al., 1992 er 01.. 1992
Andersson Andersson
Costall el al., 199la Costall CI al.. 1992a Costall CI 01.. 1992a
Costall er 01.. 1992a
Korneyev and Seredenin, Costall et al., 199la Costall et al., 199la
et al., 1993
t-tal.. 1993 Tokuyama CUP
er al., 1993
1993
1991
1990
Nishimura
Pollard et al., 1992
Pollard and Howard,
Costall er al., 1992a
Barnes er al.. 1991
Fletcher and Davies,
Bodnoff er al., 1989
0.5-2.5
0
Ogawa et al., 1993 Ervin ef al., 1987
+ + +
p.0. 60 i.p. 60 p.o. 60 i.p. 60 during 21 days (xl) S.C. 30
25 0.555 I-10 4
e, al., 1989 er al., 1989 and Jolv. 1989-1990 1991 .
Sanger Sanger Sanger Klint,
i.p.
+ + + +
Asymmetric compartments Asvmmetric compartments
References Shimizu ef ol., 1987
Comments
+
Effects
30 i.p. 30 i.p. 30 S.C. 30
p.0. 30
Routes administration, latencv (mitt)
510 5-10 5 0.01-I
EDro = 69
Effictent doses or doses tested fmelke)
1. Continued
Sprague-Dawley rats (Zoo-3OOg) Active-avotdance test Wistar rats (22&240g) Passive-avoidance test Wistar rats (220-24Og) Wistar rats (22&24Og) Sprague-Dawley rats (20&25Og) Wistar rats (7-8 weeks) Long-Evans rats Conditioned place aversion (8 weeks) Novelty-suppressed Long-Evans rats (30&325g) SpragueDawley rats (270-320~) Human threat Marmoset Callithrix jacchus (35&44Og) Marmoset Callithrix jacchus (350-4408) Cork gnawing Long-Evans rats (435-g) Ovariectomised Long-Evans CD (300g) Sprague-Dawley rats Straw suspension (14&17Og) Stress-induced ddY mice (18-2Og) antinociception Stress-induced Wistar rats (25G3OOg) colonic motor alterations Hot-plate Wistar rats (20&25Og) Elevated-plus maze Rats Light/dark test Mice
Models
Table
s % z
0
Gepirone (partial agonist)
79.4”
125893h > lOOO@ 3800”
251 lgh
> 10000’
test
Ultrasonic ‘distress’ vocalization
Defense test battery
Social interaction
Open-field
Light/dark
Conflict test Conditioned emotional response Elevated-plus maze
Vogel’s conflict test
Geller-Seifter conflict test
S.C. 15 i.p. 15 i.p. 30 S.C. I5 Dorsal raphe 5 i.p. 30 i.p. 30 im. 0 i.p. 30 i.p. 30 i.p. 30
I .25-5 IO 2.5-10 I .25 0.001 0.3-1.25 0.3-0.62 3-5 0.1-I Z-20 3-10 0.1-5 IO l-10
Female Long-Evans rats (225-249%) Sprague-Dawley rats (250-35Og) Wistar rats Female Lone-Evans rats(22G49g) Lister rats (200-2808) Wistar rats (18&22Og) Rats Wistar rats (20&25Og) White Carneau pigeons Wistar rats (40&5OOg) Wistar rats (220-2508) PVG rats (18&26Og) Wistar rats (22&25Og) Wistar rats (22&250g)
I-IO
0. I MO.62 0.34.62 2.5-5 0.0002-0.001 5-10 I .25 0.0002~.001 5-20
1.p. 15
i.p. 15 Dorsal raohe 5 i.p. 30 i.p. 15 Dorsal raphe 5 i.p. 30
i.p. 30
i.p. 30
IO
Wistar rats (22&25Og)
2.346
pa. 60 i.p. during 2 weeks (xl) Added to drinking water during 14 days S.C. 30
0.00-3 IO
Female T/O mice (22-308) Sprague-Dawley rats (44lg) Wistar rats (18&22Og) Rats Wistar rats Lister rats (20&28Og) Wistar rats (225-250~) Wistar’ rats -’ Lister rats (20&28Og) Adult male and female R. Rattus Wistar rats
i.p. 30 S.C. IO
I-2.5 8-2048 nmol
Wistar rats (225-2500) Sprague-Dawley rats (25&35Og) CD rats (I 6%2OOg) Wistar rats (22&25Og)
IO
i.p. I5 S.C. 15
10 0.125-I
Wistar rats Wistar rats (25&350g)
i.p. 30 i.p. 30
SC
30
S.C
pa
0.125-l
rats 0.3-10
2&80
rats
SpragueeDawley (420-48Og) Sprague-Dawley (33&37Og) Rats
+
+
+
+
+
Cl
+ _
+
_
0
+
+
+
+
+
0
0
0
Cl
_
+ + + + + +
+ +
+
+ +
+ et al.. 1990
rats
HLU HLU
LLF LLF
65 dB noise
After a 2-weeks period of isolation Asymmetric compartments
Isolated
Observations durine IO min Is&ed rats After a 2-hr period of isolation After a 2-week period of isolation
et al., 1993
De Vry
et al.. 1991
Stefanski et al., 1992a Stefanski PI al.. l992b De Vry PI al.. 1991 Higgins et al.. 1992 Dunn et al.. 1989 De Vry et al.. 1991 Higgins PI al.. 1992 Blanchard PIal.. 1989
PIal., 1992
et al., 1989 Knapp
Bill
Maisonnette
Luscombe er al., 1992 Motta et al.. 1992
Dunn ef al., 1989 SGderpalm PIal.. 1989
Motta et al., 1992 Maisonnette et al.. 1993
Motta et al.. 1992 Critchley et al., 1992
Higgins et al., 1992 Vogel’s test Stefanski t-t al., 1992a Stefanski PIal., l992b Modified Vogel’s test Korneyev and Seredenin. FR30 Mansbach et al., 1988 Sanger, I990 Modified
De Vry CI al., 1991 Costello er al., 1991b
Vogel’s test Eison et al., 1986
Shocks moderate
Modified
De Vry er al., 1991 Modified ThiCbot PI al., 1991 Geller-Seifter test Unpredictable shocks Costello er al.. l99lb
Thiebot
1993
and Perez, 1989-1990
Witkin
+ FR30/FRIO and weak effect Modified Geller-Seifter test
Young CI al.. 1987
+
2 B
a
z
g 5.
3 A. 2 ip
r
lpsaplrone (partial agonist)
Compounds
19”
~-H&A
5-HTIU
12589”
S-HT,s
125892h
2700’
5-HTz,,
.Affinities (Ki m)
31622h
5.HI-:<-
> 10000”
5-HTI
Animals
IO 30 30 30
Squirrel monkeys (SoCrlO5Og) White Carneau pigeons White Carneau pigeons White Carneau pigeons Conditioned Sprague-Dawley rats emotional response (30&325g) Wisiar rats (4Oi&5OOg)
i.p. 30
2.5-20
5 I5 0 15
i.m. i.m. i.m. i.p.
1.m.
i.p. 30 1-p. 30
0.1-10 l-3 0.1-53 0.5-5
0.01~1
0.002 1.25-10 0.3-1.25 0.3-0.62 3-10 3.1-10
Lister rats (200-280g) Wistar rats (18&22Og) Wwar rats (18&22Og) Rats Wistar rats (200-2508) Wistar rats (12 weeks) Confhct test
Dorsal mph&, 5 Dorsal raphk, 5 i.p. 30 1.p. 30
0.002 0.004-0.01 2.5-15 I .25-20
Dorsal raphC, 5 i.p 30 i.p. 30
1.p. 30 i.p. 30
S-20 I-IO
i.p. 25
i.p. 30
during 21 days (xl) p.0. 30
S.C.
i.p. i.p. i.p. i.p.
i.p. 60 21 days (xl) S.C. 0
1-p. 30 ip p.0. 30
2.5
SC.
during
40 i.p. i.p. 30
2.5-20 3-5.4 0.5..60
Rats
5-10
3-10 I O-20 2.5-10 20-30 IO 61 8-32
1.25-10
4
2.5-5 0.1-I 5-20
Routes admmistratlon, latency (min)
W1star rats (4OG5OOg) W1star rats Sprague~Dawley rats (42048Og) Wistar rats (IgO-200g) Vogel’s conflict test Wistar rats (12 weeks) Rats Lister rats (2OC-250g) Lister rats (21&27Og) Wistar rats W1star rats (18&22Og)
Geller Seifter conflict trebt
AP mice (46 days) Adult rats Female MFI mice Marble burying test (23-35g) Novelty-suppressed Long-Evans rats feeding (30&325g) Fear-potentiated Sprague-Dawley rats startle reflex (3MOOg) Sprague-Dawley rats Active-avoidance test Wistar rats (22&24Og) Passwe-avoidance test Wistar rats (220-2408) Aggression-provoked NMRI mice Center test Rats (thigmotaxis) Long-Evans rats Cork gnawing (435wz4Og) Hot-plate Wistar rats (200-25Og)
Models
Efficient doses or doses tested (mgikg)
Table 1. Continued
0
+
0
+
+
+
0
+
+
+
+
+
+
+
+
+
+
+
0
+
+
+
Vogel‘s test Vogel’s test
Vogel’s test
FR30 FR30
F13
Modified Vogel’s test 0.16 mA shocks
Modified Modified
Modified
1986
1986
1993
Sanger,
1990
Gleeson P, ol., 1989 Nanry er nl.. 1991 Barrett, 1992 Lorens CI nl.. 1989
Gleeson and Barrett,
1990
Sanger, 1992 Menescs and Hong. 1993 Schuurman PI nl 1986 Higgins ef al., 1987 Higgms cr al., 1988 De Vry PI nl., 1991 Chojnacka-W6jcik and Przegalinski. 1991 Higgins PI al.. 1992 Przegahnski er al., 1992 Stefanskl P! ui.. 1992a Stefbnskl PI ol., l992b Korneyev and Seredenin. 1993 Meneses and Hong. 1993
Sanger. 1990 Amrick and Bennett, Young PI ol.. 1987
Deacon and Gardner.
Korneyev and Seredenin,
0
+
1991
Mansbach and Geyer. 1988 Sanger e, al., 1989 Sanger er al., 1989 De Vry et al., 1991 Schreur er al., 1993
Kehne rf al., 1988
Bodnoff rt ol.. 1989
Pollard and Howard,
VI30 0.32 mA shocks
Locomotion
References
Nastiti et al.. 1991 Vivian and Miczek. 1993 decreased Njung’e and Handlcy, 199lb
Comments
+
+
+
+ + + +
0 + +
+ + +
Effects
E
b 2’
Q
%! m
test
maze
+
+
+ +
i.p. 30 ,.p. 30 i.p. 30 p.o. 60 S.C. 30 i.p. 30 i.p. 30 i.p. 40
i.p. 30 i.p. 30
0.5-2.5 0.5 0.25-5 0.01-l 1.5 2.5-5 17.8-31.6 l-5 5 5 0.3 I-I .25 0.3-0.62 0.0002
Wistar rats (292-368) PVG rats (I 8&26Og) CD rats (16l&2OOg) Femdk T/O mice (22-3Og) Swiss mxe (20-3Og) Female ICR-DUB mice ( I7-35g) BKW mice (25-30g) Mice Swiss Webster mice (20-309) Wistar rats (18&22Og) Rats Lister rats (200-28Og) Rats Llster rats (20%25Og) Rats Lister rats (21&27Og) DAP mice 22-308) Wistar rats Rats Lister rats (25&3OOg) Lister rats (200-2808) Rats Rats
I
l-3 l-3 5
0.0004xl.01 IO I .25 0.634 0.025-10 l-5 0.0002 l-2.5 2
0.002
+
S.C. IO
8-2048 nmol
Rats Sprague Dawley (250-3508) Rats
Lister rats (240-3008) PVG rats (20&26Og)
i.p. durmg 2 weeks (x2) i.p. 5-20 i.p. 30
0.01-I
5
i.p. 30
30
i.p. i.p. 40 Dorsal raphe. 5 i.p.
Dorsal raphe. 5 i.p. 30 i.p. 15
Dorsal raphi,
Dorsal raphe. 5
+
+
+
+
+
+
+
+
++
+
+
+
+
+
0
+
+
+
+
+
+
+
+
+
0
0
0
0
Warm condition Cold conditions
HLU HLU
Isolated mice HLU et LLF
HLU LLF
LLF
65 dB noise
Asymmetric compartments Asymmetric compartments Asymmetric compartments Transitions only
Asymmetric compartments Transitions only
Observations during IO min Rats were well nournished Observations dung IO min
Observations during IO min
Rats were
Lister rats (200-270g)
1.p. 30
i.p. 30
0.1 2.5-10 0.5-5
PI al., 1992
Critchley
Kaltwasser.
1991
Mos and Olivier.
Colltinurd
1989
Carter and Smith. 1992 Costall et ol.. 1992a Higgins e, ol., 1992 Boaventura et nl.. 1986 Rex (‘I rrl.. 1991
Stefanski PI nl., l992a Stefanski PI al., 1992b Higgins et al.. 1992 Schuurman er ol.. 1986 Higgins er al.. 1987 Critchley PI al.. 1987 Higgins er al.. 1988 Olivier er ol., 1989 De Vry 6’1al.. 1991
Fernindez-Guasti and L6pez-Rubalcava. 1992 L6pe&Rubalcava er ol.. 1992
Costall E, nl., 1992a
Fernindez-Guasti and Lbpez-Rubalcava, 1990 Young and Johnson, 1991~
Luscombe el nl.. 1992 Bill P, a/., 1989
rf al.. 1991
Almeida
Graeff er al., 1990
SGderpalm cr al.. 1989
Wright e, ol.. l992b Critchley er al., 1988
Wright er a/., 1992a
Wright PI al.. l992a File er a/., 1987 Almeida el ol., 1991
Moser, 1989b
Decreased total open arm entries
_
S.C. 30
IO
_
Pellow e, al., 1987 Moser, 1989a
_
i.p. 30 S.C. 30
2.5-10 0.15-10
Lister rats (25&350a) Sprague-Dawley rats (20@3-3oog) Sprague-Dawley rats (2w3OOg) Lister rats (200-270g) Rats Wistar rats (144196g)
Staircase test Novelty-suppressed feeding Ultrasonic ‘distress’ Wistar rats (Y-l I days) vocalization Wistar rats (22s240g)
Social interaction
Open-field
Light/dark
Elevated-plus
ii. fz n 2 %
F @ 2
5.
5-HT,a
6
5-HT,s
Spiroxatrine (agonist)
7.94
125892
RS-30199 (5.HTIA ligand) pKo”’ 1.9 < 5
LY 165.163 (agonist) pKn’ 8.2
Compounds
7943
< 5
6
5-HTio
630h
5.9
5.1
5-HTx
Affinities (Ki, no)
7943
<5
6.2
5.HT:r
5.HT, Animals AP mice (&6 days) Rats Wistar rats (20&22Og)
i.v. i.p. 30
0.5-2.5 2.5-5 +
i.p. 30 i.p. 30 p.0. 30 i.p. 30 DPAG
EDro = 2.2 I@30 l-3 3-10 l&440 nmol
0.01-0.3 0.3-3
Conflict test White Carneau pigeons Elevated-plus maze CD rats (16&200g)
+
Barrett, 1992 Luscom be PI al., 1992
Luscombe rr al., 1992
i.m. 0 p.o. 60
FR30
Weak effect
1990
Korneyev and Seredenin. 1993 Jenck er al., 198Yb Graeff ec al.. 1990
Traber er al.. 1984 De Vry et al., 1991 Pollard et al., 1992
Sanger er al., 1989 Sanger er al., 1989
Mansbach and Geyer. 1988 Schipper er al., 1991
Redfern er ol.. 1989 Moulton and Morinan, +
+
+
0
+
+
+
+
0
+
+ 5,7-DHT
Fernindez-Guasti and Hong, 1989 Bow/s et al., 1991 Fernindez-Guasti PI al., l992a Fernindez-Guasti er al., 1992a Fernlndez-Guasti et al., l992b Korte and Bohus, 1990 Korte et al., 1992 Davis PI al., 1988a
i.p. ,.p. 40
p.o. 60
+
i.p. 30 i.p. 30
2wo 1.2-10
0.03-3
+
SC. IO p.0.
+
+
+
+
+
I-10
5 i.p. 30 i.v., IO i.p. 0
i.p. 30
2.5-5
+
0.625-10 0.5-2.5 lo-40
i.p. 30
0.3-30 3
CD rats (16&2OOg)
+
i.p. 30
2.5-10 +
0
Molewijk et al., 1993 Sommermeyer er al., 1993 Njung’e and Handley, 1991b
+ +
p.o. 48 hr and during 21 days (xl) in. S.C. 15 i.p. 30
0.5 g/l LED=3 0.3-10 S-20
References Nastiti et ol., 1991 Schipper et ol., 1991 Baudrie PI al.. 1993
Comments
+ + +
Efiects
30
Routes administration. latency (min)
2.5-5
Sprague-Dawley rats Lister rats (300-4OOg)
Elevated plus-maze
Elevated-plus maze
Stress-induced hyperthermla Active-avoidance test Wistar rats (22&24Og) Passrve-avoidance Wistar rats (22&24Og) test Aggression-provoked NMRI mice NMRI mice Cork gnawing Ovariectomised LongEvans CD rats (33Og) Hot-plate Wistar rats (20&25Og) DPAG-Stimulation Rats Rats
Fear-potentiated startle reflex
Wistar rats (30&36Og) Wistar rats (29&34Og) Sprague-Dawley rats (3OwOOg) SpragueeDawley rats Mice
Swiss Webster mice (20-350) Wistar rats
Adult rats Wistar rats (20&25Og) Marble burying test Female MFI mice (23-358) Shock-probe Wistar rats (280-35Og) burying test Rats Wistar rats (30&35Og)
Models
Efficient doses or doses tested (mgikg)
Table 1. Continued
00
%
15.7”’
27
MDL 73005EF (partial agonist) pKo’
8.4
5.7
66”‘”
I
WY-50.324 (agonist)
272””
0.3
458”‘O
20
I 300”y
WY-48,723 (agonist)
6.0
> lOOtlOt
16.7
5.4
> 100000
WY-41.846 (agonist)
HT-9OB 0.4 (agonist/antagonist) (ICu$‘”
Umespirone (agonist)
Tandospirone (partial agonist)
6.2
2600
test
Geller-Seifter conflict test Vogel’s conflict test
Celler-Seifter conflict test Conflict test
Conditioned avoidance reaction
Geller-Seifter conflict test Conflict test
Geller-Seifter Vogel’s conflict test Conflict test
Vogel’s conflict test
threat
i.p. 60 i.p. 5-10 days p.o. 60 S.C. 60
5-10 IO
.
0
i.p. 30 Sprague- Dawley rats (170-2 I Og) SpragueeDawley rats
+
t.m. 20 0.03-10
White Carneau ptgeons (4506OOg) Wistar rats (l80-200g)
.
A
S.C. 0.1-3
_...
+
S.C. 30 0 3~3
0.3310
+
+
+
i.p.
20
0
+
0
0
0
+
IO
im
i.m. 20
0.1-10
0.03310
i.p. 30 i.p. 30 i.m.
l-20 I-20 O.Olxt.3
p.0.
+
S.C. 45
0.00-0.1
3-30
+
p.0. 45
+
0.00-10
p.0. 30
l&60
+
+
i.p. 30
5-20
0
+
+
p.0. 45
i.m. 15 im. 0 p.o. 60
I 0.3310 EDw > 300
0
+
+
O.ooOl-100
i.m.
0.01~.1
I
+
i.p. and p.o. 0
I .25520 +
0
p.o. 60
l-100
Rats
White Carneau pigeons (45&6OOg) Rats
Rats
CD rats (2OOg) CD rats (200-25Og) Squirrel monkeys (800~105Og) White Carneau pigeons (450-600&T)
Rats
Sprague-Dawley rats (22552758) Marmoset Cdirhrix jacchus (3504408)
Social interaction Human
BKW mice (30-35g)
test
Light/dark
Cork gnawing
Conditioned avoidance reaction Straw suspension
Conflict
Sprague-Dawley rats ( I SO-2OOg) Squirrel monkeys (80&1050g) White Carneau pigeons White Carneau pigeons Sprague-Dawley rats (200-3@)g) Sprague-Dawley rats (14&17Og) Ovariectomised LongEvans CD rats (3OOg)
Ovariectomised LongEvans CD rats (3OOg) Sprague-Dawley rats (320-37Og) Vogel’s conflict test Sprague-Dawley rats (200-30%)
Geller-Seifter conflict test
VI30
FR30
FR30
FR30
FI3
VI2
Asymmetric compartments HLU
FR30
I992
Hibert and Moser.
Moser CI ol.. 1988
Sanger.
Barrett and Zhang.
Morris er ol.. I989
Andree er nl.. 1988
Barrett and Zhang,
Andree ef al.. 1988
Barrett and Zhang.
1990
1991
1991
1991
er al.. 1993
Haskins e( al., 1989 Haskins er al.. 1989 Gleeson and Barrett.
Miyauchi
Barnes er al.. 1991
Barnes CI al., 1991
Barnes er al.. 1991
1993
1990
er al.. 1993 Pollard ef nl.. 1992
Nishimura
Pollard e( al.. 1992 Barrett and Vanover, Shimizu CI al., 1987
Modified Vogel’s test Shimizu er al., l992b + 5.7~DHT Gleeson and Barrett. 1990 FL3
Modified Shimizu ef al.. 1992a Geller-Seifter test Modified Vogel’s test Shimizu er al., 1987
Pollard PI ol., 1992
agomst)
21009
(S-HT,4
lndorenate
IC<,I*”
antagomst)
(antagomst)
(+ )WAY
IC.?
(antagonist)
(S)-UH-301
25
98
> 10000
042”’
616’
1.3’
IOh
5.HT,s
5-HTw
100135
agomst)
(antagomst)
SDZ
(!-HT,,
ND0 00X
(partial
NAN-190
Compounds
398”
790”
5-HT,”
Affinities
no)
> 10000
7200
10000”
218’
~-HT?A
(Ki.
110000
7150
501 Ih
602’
5-HTx
Models
reflex
test
maze
test
test
test
maze
test
CD
White
wistar
Wistar
rats
rats
(min)
30
30
125, 2-4
14
30
30
30
60
rats
(20-3Og)
SWISS Webster
MlCC mu
(20-30g)
(I?
L
90
+
+
+
+
+
5
i.p.
shocks
Moreau
and
mA
compartments Transitions
only
only
shocks
Asymmetric
Transitions
0.32
Hong.
Lbpez-Rubalcava
L6pez-Rubalcava.
Fernlndez-Guasti
1992
1992 CI al..
and
1990
1993 and
1992
1992
1991
Lbpez-Rubalcdva.
Fernindez-Guasti
and
CI nl..
Fletcher
Meneses
PI ol..
PI nl.. Fletcher
Fletcher
1992
1992
1992
1991
1992
1990
1989-1990
1992
1991
e, R/.. 1993
el cl/..
e, a/..
er (I/..
Przegalinski.
Bickerdike +
er a/,
er al..
ChoJnacka-W6jcik
Kostowski
Joly.
er al..
1992
1992 e, al.. and Kostowskl
Sanger
Luscombe
Colpaert
PI a/..
Przegalinski,
0
mA
and Ahlers
1990
1991
1990 Y, al..
Chojnacka-W6Jcik
Moreau
test
test
1990 1989 CI al,
Moredu
0.16
Vogel’s
FR30
FR30
Vogel’s
Hitchcock
1988
Moser.
CI al.,
and
c’r al.,
1990
References cf al.,
et al.. Misshn
Bill
Moser
Hibert
Moser
Moser
+
+
1.p. 90
1.p. 30
S.C.
Modified
Modified
compartments
A$ymmetrx
Comments
+
0
0
+
_
+ _
0
0
0
+ +
+
+ f + +
+
Effects
5
2.5-10
5.610
3.1&10
2
S.C.
I-30
Rats
s.c
3-10
S.C. 45
i.p.
i.p.
s.c
I p.
!.P. 30
30
Mice
I
0.3-30
2-8
0.125
O.Of&.
i.p.
2
60
1.m. 5 p-0.
15
60
0.003-3
i.m
i.p.
1.p. 30
S.C. 30
S.C.
S.C.
p.0.
S.C. 30
S.C. 30
latency
0.162.5
I-3
0.25-l
1.25%10
I .25%5
2
0.034
0.03-2
0.25-I
0.034.25
Routes administration,
Mice
weekr)
rats (250-280g)
(IO weeks)
rats
rats
(18&22Og)
(345445g)
Rats
rats (22&24Og)
SWISS mice
Wistar
Llster
pigeons
rats (16&2OOg)
pigeons
Carneau
rats (IS&220%)
Swiss mice
Wistar
Wistar
(IO weeks)
Rats
Swiss mice
Wlstar
T/O
(22&30%)
Female
mice
rats
(20&3OOg)
rats
SpragwDawley Sprague~Dawley
(2x-3clOg)
Sprague-Dawley
rats
0.1-3
(20&3OOg)
(mg/kg) rats
Animals
tested
Sprague-Dawley
test Wistar maze
reflex
conflict
Light/dark
Vogel’s
startle
test
mare
test
Fear-po!ent!ated
Llghtldark
Elevated-plus
Light/dark
Elevated-plus
conflict
Geller-Scifter
conflict
Elevated-plus
Passive-avoidance
Elevated-plus
test
conflict
Conflict
Vogel’s
startle
maze
test
Fear-potentiated
Light/dark
Elevated-plus
Vogel’s
I2021
5.HT,
doses
Efficient or doses
Table I. Continued
s
c,
64.y’ agonist)
1.9h agonrst)
RU 24969 (non-selective
1040 metabolite)
CGS 120668 (non-selective
I-PP (zapirone‘s
3.8’”
II&’
42”
>I0000
316”
12882”
A”’
3800’
test
maze
Swiss mice NIH (20-30g) DBA/2 mice (6-E weeks1 Liste; rats (20628Og) Sprague-Dawley rats (9-l I days) Rats
Social intcractlon Uhrasomc ‘dlslres,’ vocahzation
rats (20&28Og)
Wwar
Rats rats (Y-1
I
days)
Rats Lister rats (250-35Og) PVC rats (18&26Og)
PVG
Geller-Seifter Rats conflict test Vogel’s conflict test Wistar rats (20&25Og) Conflict test Squirrel monkeys (800-105Og) White Carneau pigeons Rats (25&28Og) Elevated-plus maze
Social interaction Ultrasonic ‘distress’ vocalization
Elevated-plus
i.p. I5 i.p. I5 i.p. 30 S.C. 0
1.25 3-10 1.25-10 0.5-40
Dorsal raphP 5 S.C. 30 S.C.
0.0025 l-3 I-3
0.3--J
0.1875-1.5 0.1875-1.5 0 5-2
0.5-3
0.03-3 0.08-3.6
0.5-2 0.003-0.
i.p. 20
2.5-10
30
i.p. 30 i.p. 30
i.p. 30
i.m. 5
i.p. 30 i.m.
p.0. 25
i.p. 30
3.125
I
i.m. 5 S.C. IO
i.p. 30 p.0. 30 p.o. during 7 days
5-10 25 5-25 0.01-3 8-2048 nmol
S.C. 30
p.0. 30
1-4
5-80
+ +
i.p. 90
Sprague-Dawley rats (420-48Og) Sprague-Dawley rats (240-3008) Wistar rats Sprague-Dawley rats (21 I-347g)
+
i.p. 90
Swiss Webster mice w35g) Wistar rats
0
_ _
+ _
0
+
0
+ _
_
0
0
0
+
0
0
_
0
+ +
+
0
+
i.p. 90
+
rats (300-35Og)
i.p. 90
Wistar
IO
rats (280-3508)
Wistar
Conflict test White Carneau pigeons Elevated-plus maze Sprague-Dawley rats (250-350%) Wistar rats Social interaction Wistar rats Ultrasonic ‘distress’ vocalization Passive-avoidance test Wistar rats (22&24Og) Sprague-Dawley rats Fear-potentiated (300-4OOg) startle reflex
Vogel’s conflict
Geller-Seifter
Shock-probe burying test
Young
f, al.. 1987
er al.. 1990
and lnsel, Deacon and Gardner.
Winslow
1986
1991 b
Higgins PI al.. 1992 Winslow and Insel. l99la
Rodgers PI al., 1992
Benjamin
Observations during IO min LLF Warm condition
and Handley.
1987
1986
Corrrb,ued
Critchley er nl.. 1987 Mos and Olivier. 1989
File YI al., 1987 Pellow r/ nl.. 1987 Crltchley cr nl., 1992
Critchley
Gleeson <‘f al.. 1989 Critchley and Handley.
Vogel’s test Korneyev and Seredenin, 1993 F13 Gleeson and Barrett, 1990
HLU
1988
Sanger and Joly. 1989-1990 Kehne et al.. 1988
De Vry er al., 1991 De Vry er nl., 1991
Barrett CI al., 1986 Saderpalm cf al.. 1989
De Vry et al., 1991 Vogel’s test Amano c, al., 1993
Vogel‘s test Cower and Tricklebank,
Observations during IO min Observations during IO min
Modified
Modified
Modified
f 5.7-DHT
Fernindez-Guasti and Hong. 1989 Fernindez-Guasti CI al., l992a Fernindez-Guasti PI al., l992a Fernindez-Guasti er al.. l992b
b.
E:
8
2 Lt.
z
210 agomst)
1.2 3938’
I-NP (agonist) pK,,“ DOI (agonist)
mCPP (non-selective
5-HT,4
Compounds
79
6.6 2041’
5-HT,tl
II00
7.8 720@
5.HT,,,
140
7.2 1.3”
5.HT?\
Affinities (Ki. no)
29
8.3 6.49
5-HTx
test
5 6’
2 -5
Wistar rats (2OG25Og)
test
SpragwDawley (2Wg)
rats
Rats Swiss mice NIH (20-3Og) Sprague-Dawley rats DBA/Z mice (6-E weeks) SpragueeDawley rats (25&3oog) Wistar rats (15&22Og) Long-Evans rats (320-34Og) Wistar rats (20&24013) Zero-maze SpragueeDawley rals Sprague-Dawley rals Llght:dark test (2Oc-25Og) Swiss mice (IO weeks) Swiss mice (IO weeks) Wistar rats (200-2508) Open-field Sprague~Dawley rats (2w25Og) Free-exploratory test SWISS mace (IO weeks) Social mtcrwtion Sprague-Dawley rats (2%28Og) Liater rats (200-X0@
Shuttle box Elevated-plus maze
Vogel’s conflict test
Marble burying
SpragueeDawley rats (9-l I days) Female MFI mice (23-35g)
i p. 30 i.p. during ?I days (xl) i.p. 30 i.p. 20
I -3 2 l-5 2.5-5
0.0005 0.0125
Dorsal mph& 5
0
1-p. during 21 days (xl) S.C. 30 1.p 20 I I 0 wI.75
i.p. 30 Amygdala.
o _ _
,,p. 30 i.p. I5
0.3-3 5
34 0.00 I
_
S.C. 20
0.5
o
_ o
o
_
1991 b
Higgins (‘I (I/.. I992
Griebel rf rrl., 1991 Whitton and Curzon.
1990
Griebel CI nl.. 1991 Griebel. 1993 Klodzinska (‘I [rl.. 1989 Sedation’? Locomotion decreased Luck! CI ol.. 1989
Griebel, 1993 Grewal r, nl.. 1993 Kenne~t c,
Griebel. 1993 Rezazadeh (‘I al.. 1993
e, a/.. 1993
_
i.p. 1.p. 30
0.5 l-4
Blackburn
Gibson er nl.. 1991 Rodgers e, nl.. 1992
_
_
Martm. 1993 Benjamm rr al.. 1990
_
Kilts PI rtl.. 1982
,.p. 30
VIZI, also decreased nonpublished responding
Njung’e and Handley.
4 1.56-3.125
+
i.p. IO
+
i.p. 30
Warm condition Cold condition Locomotion decreased Wmslow and Insel. 199la
Tomkins er ol.. 1990 Heaton er al.. 1988 Njung’e. I990 Nastiti PI nl.. 1991 Mos and Olivier, 1989
l-2
0.01-5
+
+
+ _
+
S.C. 30
30 30
0.25-0.5 0.3-3 0.034
1.p.
3
+
S.C. 30 0
Kennett.
+
i.p. 30
1992
Fern;indez-Guasti and Hong. 1989 Korneyev and Seredenin, 1993
+
ip ,,p. I5
References
Gardner. 1985~ Cold condition Mos and Olivier, 1989 Locomotion mcreased Njung’e and Handley. 1991 b
Comments
30 30
Effects
+ + +
ROUIeS administration, latency (min)
0.1
0.2-I
0.254.75
l-3 0.1-10
Wistar rats (9-I I days) Female MFI mice (23-35g) Wistar rats (28&35Og)
Rats
Animals
Sprague-Dawley rats (250-3208) Llster rats Rats Rats Ultrasonic ‘distress’ AP mice (4-6 days) vocalization Wistar rats (9-l I days)
Shock-probe burymg test Hot-plate
Marble burying
Models
Social mteraction 6.9 > lOOOo* Elevated-plus maze
5-HTI
Efficient doses or doses tested (mgikg)
Table 1. Continued
c:
m
Id
1ysn7
uoyomo3o7
svmwedwos s!,lauK”&V
+ + + 0 _
OE E
I-S 0
I-Z.0
E E’O
E-t.0
OE OE OE ‘J’S
‘d,!
OZ &I S-I
0~ _
0~ ,d,r 01-l
S-S’Z
_
0~ &I 5-S-Z SZ’YX’I
SlIq
Sit?,
,“,S!+,
, [m(j)
11~ 6)
(SLnP !FP) JJ!“J dV (Shp , 1-6) SlB, ,“lS!+, (Sh?,,
@@P
(~055-0023 La~m?a~an%?,ds
SIEJ iqmna ~an%n,ds (~OSZ~OOZ) SII?, Aa[.+tt!aman%,ds
sw
,V!,S!M
(~osz-ooz) SIB,
zlvsa
8~)
(~ozz-os I) SIB, ,&?lSl,+, (Swm
,l?lS,,+,
SWLalMt?a-an%,ds (8OOZ+lSl) SlI?JlW!M
Sl)?,
(%OEQZ) H,,,J SS!MS
av” aJ!“J
21-6)
(%OOZl)Sl) SlBJ JW!M
(Shp
S'O
Z9'ckIE'O
(~OOZIXI)
I-Z.0
SO
0~ .d.l
0~ .d.l
0~ .dy
_ _ _
+
OZ .d,l Of
5'0
(%oszmz)
OE
_
OE
_
0
0 '"I',
mo-osz) S”L?K~8”Ol
,elS!M
s”oa%!d nea”,es
s1e,
10'0
(%ZSFOSP)
aj!qM
Slp.1JW!M
0
0
I-I'0
SlBJ
,d,!
SY‘Z
SlEN (SAeP 11-6) SlQj
KalMea-an%,ds SWX
dalhwa-anhds
sle, Kalma-an%n,ds
(~055-002)
SlQJ sw Aa[Mea-an%?,ds (%OSZFOSZ) ^ slw napea-amwas
SW
SW
I-I'0 0
Sp .d.l
oz-I
OEtl;l
SC
0
0~ .d.l
.d.l +
+
1-1'0
pooo’*z~o’o
100'0
SO
I-SZ‘O
1'0
I'0 OIH'Z
I-I'0
p”l?
J,%““~N
“O!,OWOJO~
sn”olz?olW
pawanap
6861 'IJJaw ,661 "," ,,I!I!ISPN 6861 "a!A!lO P”r: sow 6536, ‘,a!.&!(0 put! SOW
yasu, put? mo,s”!M
“,”
6861 “/U Id uauuay 686,
.dalp”“H
686, “I” l.4 !yJ”T pasEa,3ap
F&$36, ‘,a”p,FtD
066, “/I7 Id uye~uag
a,661
9,661
+
+
"166, '[aS"lp"t! MO,S”!M
0
+
OZ .d.!
‘d,! 0 ‘snd”moddy 0 G’A.5’1
0, ‘J’S
6861 'l'=JW
S!Ma
Id
986,
“,U
9861 '.p 12 spea
_
0 _ _ _ _
1s31 ;i”!hnq zqo,dmyaoqs
“0!1pz!,&?50”
snld-pamalg
,ssa,is!p. 31”ore,~~n
azw
“Oy?Zy?SOA ,ssa,is!p. s!“osullfl w!k”ado
p,l?oqa,oH isai ~,ep/iq%g amw snld-palmal isai isg”o3
“oyam
“o!lep”!lS-f)Vda
amld pa”oyp”o3 “y,aq),adAq pampur-ssa,ig lsal 8”!hq alq,eW isal l”!,nq aqo,d-qaoqg “o!lszy?3oA ,ssa,is!p. 3!“ose,i~~
xaya, apis paiegualod-mad %“!paaj passa,ddns-,Q[aAoN
“0012
91’9
El
9L.P
ORL
069
6P
EO’S
(isluol~ 00s
ddW\l;ll
a.ynalas-“0”)
Zli-NW
,;.Uyd SE’S (ISI”O%Ba+salas-“0”)
79h
2600
Clorapme (Non-selective pKi’“: S-HT?< antagonist)
Methiotepm (antagomst)
ICI 169369 (antagomst) ICr,,““‘:
14@
5.6
Altanserin (antagonist): PKD”
Cinanserin (antagomst)
5-HT,ti
Compounds
50h
2000
6200’
6.0
5-HT,e
50.1”
6100
5.HT,n
76
I.5Sh
17.9
19h
8.6
5.HT:*
Affinities (Ki, no)
8.1
25h
19.2
I99h
6.9
5-HTx
3000’
1100
5.HTl Models test
test
Geller-Seifter
Fear-potentiated startle reflex
Shock-probe burying test
Light/dark
Marble burying test
Social interaction
Fear-potentlated startle reflex
Confhct test
Vogel’s conflict test
Geller-Seifter conflict test
Social mtcraction
Stress-induced hyperthermia DPAG-Stimulation
Marble burying
Animals
rats
SpragueeDawley rats contllct test
Sprague-Dawley (320-3508)
2 5-5 (260-320g)
i.p 60
J.
0
+
1.p. 70
0.31 0.1
0
0
i.p. 30
1p. 30
0
0
+
0
0.31
0.31
i.p. 30
1.p. 30
S.C. 30
i.p. I5
+
0
+
t
i.p. 30
0.25
Swiss Webster mice (2@3Og) Swiss Webster mace (20-358) Wistar rats (300-3500)
I-IO
6
IO
Swiss mice (20-3Og)
Sprague-Dawley rats (250-3208) Female MFI mice (23-35g)
i.p. 60
56 i.m.
+
i.p. 60 i.p. 30 i.p. 60
15-60 l&60 56
l-3
t
i.p. 60
60
0
0
i.p. 60
0
0
60 l&56
i.p. 0 or 80
S.C. 30
+
0
+
Effects
Rats Sprague-Dawley rats (200-320%) SpragueeDawley rats (4 months) Rats Wistar rats (22Og) Sprague-Dawley rats (20&32Og) SpragueeDawley rats (2OOg) Squirrel monkeys (55&9oog) SpragueeDawley rats (3OMOOg)
0 5-5
1.p. 45
i.p. 30
3-25
rats
5-20
I-20
(mg/kg)
Routes admmstration, latency (min)
Female CFN rats
Sprague-Dawley (25&3208)
Rats
Female MFI mice (23-3583 Swiss mice (25-3Og)
Efficient doses or doses tested
Table 1. Continued
References
1 1990
1972
1992
Geller er ol.. 1974
Sepinwall and Cook, Kilts ef al., 1981
Winter,
Kennett,
Jenck ef al., 1989b
Lecci e/ a/
Fl60IFRI
FR30
VI21
1992 199lb
Wiley CI al.. 1993
Fernlndez-Guasti ef al., 1992a Fernindez-Guasti er al., 1992a Svensson. 1985
Fernindez-Guasti and L6pez-Rubalcava, 1990 L6pez-Rubalcava e, al.. 1992
Njung’e and Handley,
Kennett.
Davis er 01.. 1988b
Brady and Barrett,
Kilts er nl., 1982
1975b 1981
1978
199lb
1985
Njung’e and Handley,
FRIO/VI30 Cook and Sepinwall, Modified Vogel’s test Petersen and Lawn, VI21 Kilts ef al., 1981
FR40
VI3O!FRIO
Locomotion decreased
Comments
E P
84Q
316h
Cyproheptadine (antagonist)
4.9
5.4
( - )Mianserin (antagontst) pK,,:,”
5.5
6390h
6.2
I OoOh
(+ )Mianserm (antagonist) pK/
Mianserin (antagonist)
39v
3.16”
1.2
8.6
7.9”
12.6D
7.0
7.9
IOh
263”
8.0
6.6
64.5**
rats
Rats
Sprague-Dawley rats (250-32Og)
Sprague-Dawley (25&32Og)
Long-Evans rats (25&3008) Long-Evans rats (280-3008) Wistar rats (37&45Og)
Rats
Swiss mice (10 weeks) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (25&32Og) Long-Evans rats (30&325g) Wistar rats (25&28Og)
Wistar rats (198-260g) Rats Sprague-Dawley rats (33&37Og) Vogel’s conflict test Sprague-Dawtey rats (2Wg) Wistar rats (22Og) Rats Conflict test White Carneau pigeons (48&528g)
Geller-Seifter conflict test
Social interaction
Social interaction
DPAG-Stimulation
Novelty-suppressed feeeding Shock-probe burying test Conditioned place aversion
Social interaction
Light/dark test Open-field
Sprague-Dawley rats (33&37Og) Rats Rats Sprague-Dawley rats (20&225g) Conflict test Squirrel monkeys (55&9Oog) Elevated-plus maze Wistar rats (150-2208) Lister rats (25&4OOg) Swiss mice NIH (24-2&g) Geller-Seifter conflict test
+ 0
S.C. 30 i.p. 60 during 21 days (xl) S.C.60
l-2
+ 5,7-DHT
i.p. 30 p.0. i.p. i.p. 30 i.p. 30 30 i.m. 0
I-18 I-IO 3 0.01
p.o. 25
S.C. 30
5.6 540 0. I-l
10
I
S.C.30
0
+
0
0
+
+
+
0
0
+
Kilts Y( al.. 1982
Graeff. 1974 Sepinwall and Cook, 1980 Witkin and Perez. 1989-1990
Deacon and Gardner, 1986
Kennett, 1992
Kennett. 1992
Cothturd
Modified Vogel’s test Petersen and Lassen. 1981 Schoenfeld, 1976 FR30 Witkm er al.. 1987
VI21
FIl/FRS FRlO/FR30 FR30/FRlO
_
i.p. 35
2z4
Rocha PI al., l993b
_
i.p.
IO 0.1-10 l-32
Jenck PI al., 1989a
Rocha PI al., 1993a
_
Rocha c, al., 1992
i.p.
Meert and Colpaert, 1986b
0
Bodnoff er al., 1989
Kennett, 1992
Kennett e/ al.. 1989
Griebel. I993 Lucki er al., 1989
_
+
Locomotion increased
Brady and Barrett, 1985
FR30
Griebel. 1993 Pellow er al.. 1985 Benjamin er al.. 1992
Van Riezen er al.. 1981 Sullivan P( al., 1985 Mason er al., 1987
Witkin and Perez, 1989-1990
Vl30/FRlO V130/FR30
FR30/FRlO
10
0.6340
IO
0
0
0
+
+
0
0
S.C.40
I c&20
2
_
+
5 2.5520 20 l-10 2.5-5
i.m
0.1-10
+
+
+
0
i.p. 30 i.p. 30 i.p. 30 i.p. 48 hr i.p. 18 days i.p. 30 i.p. 60
i.p. i.p. 60
0.74.5 3
10
i.p
0.3317
ti WI
6
%
oz
;. 6 a a.
H
selective
6309b
630”
1731’
5.HT,s
antagonist)
5.HT,*
antagonist)
(antagonIst)
Ritanserin
(5-HTzA
R 56413
(antagonist)
Pitozifen
(S-HTx
EGIS-3886
Compounds
1584”
5.HT,n
Affinities
IIM)
I .48h
4.4‘
5-HTl+
(Ki.
I 25h
7.9h
5.HTx
7244
42~
S-HT,
interaction
reflex test
mteraction
conflict
test
test
rats (2C+25Og)
MFI
conflict
test
Geller-Seifter
Rats rats
rats
(2%27Og) Rats
Wistar
rats
(33&37Og)
Sprague-Da&y W1star
rats
rats (25&28Og)
Rats
test
test
rats (25&28Og)
conflict
Shock-probe
Wistar
Wistar
rats
mice
rats (25&28Og)
Sprague-Dawley
Wistar
(25c-3208)
Sprague-Dawley
Rats
Rats
Rats
Rats
(23%35g)
Female
Rats
burying
rats
(30@4oog) Wistar rats (25&28Og)
Sprague-Dawley
rats
(ISO-200s)
rats (I 5&2OOg)
Sprague-Dawley
Wistar
Wistar
(15&2OOg)
(25-35g)
rats
Mice
Wlstar
(55&9oog)
monkeys
Animals Squirrel
Open-field
test
test
conflict
Light/dark
Vogel’s
Geller-Seifter
burying
Shock-probe
Social
Vogel’s
test
response
DPAG-Stimulation
emotional
Conditioned
mlcturition
Defecatvx-
burying
burying
Shock-probe
startle
Marble
maze test
Fear-potentiated
Social
Holeboard
Lighlldark
Elevated-plus
Models
2
3
0 lb-40
0.1-10
IO
2.5
0.01-0.63
0.16
2540
(33&37Og)
l-30
40
0.5-I
3
IO
l-5
2.540
5
2
0.5
0.5
0.05-10
0.S
0.1-l
@g/kg)
doses tested
Efficient or doses
Table I. Continued Routes (min)
15
30
30
25
+
0 +
p.0.
0
0
S.C. 60
’ P-
i.p.
+
+
+ +
S.C. 60
0
+
+
+
0
0
+
+
0
FRS.
weak
VI30
FR30iFRIO
test
effect
compartments
Asymmetric
and
Vogel’s Transitions
Modified
FR30/FRIO
and
P, rrl.,
1990
1986
l986b
1986b
1986
1989-1990
1992
Bennett.
ci rrl.. Hascoet
Perez.
Gardner.
Colpaert.
Amrick
and
1985
1985
Colpaert.
Brocco
Witkin
and
and
Deacon
and Meert
cr ol..
Meert
t,
n/~
Perez.
1986b
1989-1990
1991
1986~
199lb
1986b
1985
1982
Colpaert.
Colpaert
and
and
1992
,
File. er nl
and
I985b
Colpaert,
Colpaert
Witkin
Meert
Kennett.
Gacdlyi
Clarke
and
Handley.
Colpaert. and
and
1989
1990
1990
l988c
1988b
rr al..
PI al..
ec nl..
e, ol..
) 1990
Barrett,
References
e, a/
and
er al..
Gardner,
Meert
Njung’e
Meert
Davis
Kennett
effect
Kshama
Kshama
weak
Kshama Costall
0
and
compartments
Asymmetric
compartments
AsymmetrIc
and
Brady
0
_
-
Sedation
FR30
+ 0
Comments
Etrects
S.C. 60
i.p.
S.C. 60
S.C. 30
i.p.
i.p.
S.C. 60
i.p.
S.C. 40
30
30
1-p. 40
30
i.m.
latency
admimstration,
E
+
i.p. 45 S.C. 60 S.C. 60
0.1 0.05-0.1 and I 0.25 IO nmol 0.25 I 0.05-10
0.1-0.6 0.324.7 0.124 0.04-10
I
Lister rats Wistar rats (16196%) Lister rats (20&27Og) Lister rats (20&25Og) Lister rats (200-27Og) Rats Mice (25-35g)
CD1 mice Swiss mice (IO weeks) Wistar rats (25&28Og)
BKW mice (3&35g)
Novelty-suppressed feeding
Social interaction
Open-field
Light/dark
Rats
S.C. 40 i.p. 30 p o. 12-15 days
0.14.6 0.324.7 0.25
S.C. 60 t.p. 30
i.p. 40
i.p. during 2 weeks (x2) DPAG, IO i.p. during 2 weeks (x2)
i.p. i.p. 30
p.0. 90 i.p. 30 S.C. 30 i.p. 30
0.6
2.5-10 0.01&40 O.O‘&lO 0.04-0.63 l-5 5
i.p. 30 p.0. 12-15 days i.p. 30 S.C. 60
0.25-4 0.05XI.25 0.63-10 0.025-5
CDCOBS mice (24g) Lister rats (X0-300g) Wistar rats PVG rats (20&28Og)
Wistar rats (220-240%) Wistar rats (250-2808) Rats Wistar rats (22&24Og) Wistar rats (lSl&22Og) Rats Rats Sprague-Dawley rats (20&25og) CDI mice
+
i.p. 30 i.p. 30 i.p. 30
0.25-10 0.25-10 0.05JJ.25 0.05-I
test
i.m. 5 i.m. 5
S.C. 60 i.p. 30
+
+
0
0
+
+
+
+
+
0
0
+ _
+
+
+
+
+
+
0
0
0
0
0
_
_
+
+
+
+
+
0
2.5 1-5 2.5-5 0.03-10 0.1&2.5
0
Wistar rats (25s280g) Wistar rats (18&22Og) Rats Conflict test White Carneau pigeons White Carneau pigeons (500-6OOg) Elevated-plus maze Rats Lister rats (25&35Og) Lister rats (20&27Og) Wistar rats (292-368)
60 i.p. 60 SC.
O.l&40 0.254.5
conflicttest Wlstar rats (22C-24Og) Wistar rats (IS&22Og)
Vogel’s
Unfamiliar and neurral box
LLF
65 dB noise
Transitions and Asymmetric compartments Asymmetric compartments Sedation ?
Sedation, ataxia and Asymmetric compartments Asymmetric compartments
Rats were malnourished
Observations during IO min
Rats were well nourished
l993a
Rex er ol.. 1991
Gao and Cutler.
ColtriI1rred
1993a
Meert. 1992 Meert, I986 Meert and Colpaert. 1986b Meert. 1992 Stefanski YI al., 1992a Stefanski er al., l992b Critchley cr al.. 1987 Kennett r, ol., 1989
Barnes er al., l992a
Griebel, 1993 Colpaert PI al., 1985
Gao and Cutler.
Onaivi. 1993 Costall e, al.. 1988~
Audi PI al.. 1991 Wright et al.. l992a
Wright PI al., l992a
Tomkins e, al., 1990 Almeida ef al., 1991
e, O/q 1991 Wright e, al., 1992~1 Millan and Brocco, 1993 Critchley and Handley. 1987
%UtZ”ldfltl
File er al., 1987 Pellow CI al., 1987 Wright CI al., l992a Almeida P, al.. 1991
Vogel’s test Brocco EI al.. 1990 Vogel’s test Chojnacka-Wbjcik and Przegalinski, 1991 Modified Vogel’s test Colpaert er al., 1985 Modified Vogel’s test Stefanski ec al.. l992a Stefanski er al., 1992b Gleeson ef al., 1989 Brocco PI al., 1990 FR30
Modified Modified
2. 8 a 2 %
5-HT,a
125Sh
Compounds
Ketanserin (antagonist)
l9lOh
5-HT,s
1000”
5-HTIU
3.1‘
5.HT!n
Affimties (Ki. no)
97.7b
5.HTx
test
30 i.p. 30 i.p. 60 i.p. 30 i.p. 30
2.5-5 l-5 0.1-0.2 2.5-20 0.1~10
AP mice (46 days) ddY mice (18-20g) Swiss mice (25-308) Wistar rats (22C-2408) Male and female Long-Evans rats (IO&l03 days) Rats Wistar rats (20s2508) Rats Wistar rats (18s2508)
Open-field
i.p. p.0. i.m. i.m. 5 1.p. 30 i.p. 30 i.p. 60
S.C. 40 S.C. 30 S.C. 180 i.p. 30 i.p. 30
0.3-30 10 0.1-3 0.3-10 1 O.lwI.5 10
0.2 0.2-l I4 l-10 0.1-I
DPAG DPAG DPAG
30
0.3-3
Wistar rats (9-l I days)
IO nmol IO nmol IO nmol
S.C. 30
0.3-3
Sprague-Dawley rats (330-3700) Wistar rats Conflict test Squirrel monkeys (55&9OOg) White Carneau pigeons Elevated-plus maze Wistar rats (220-25Og) PVG rats (20&28Og)
Geller-Seifter conflict test
DPAG-Stimulation
Stress-induced antinociception Stress-induced hypcrthermia Passive-avoidance test Defense test battery
Ultrasonic ‘distress’ vocalization
Wistar rats (25&28Og) Female MFI mice (23-358) SpragueeDawley rats (9-l I days) S.C. 60 i.p. 30
Routes administration, latency (min)
2.5 l-20
Rats
Marble burying
Animals
Models Shock-probe burying test
Sprague-Dawley rats (20&25Og) Rats Social interaction Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (2%3208) CD rats (9-13 weeks) Fear-potentlated (25&32Og) Female MFI mice Marble burying test (23-358) Stress-induced colonic Wistar rats (25&3OOg) motor alterations
> lOOO@
S-HT,
Efficient doses or doses tested (mg/kg)
Table 1. Conhued
References
0
+
0
0
0
0
0
+
+
+
+
0
0
0
Locomotion decreased
LLF
Observations during IO min
FR30
and Perez, 1989-1990
1991
1992
GuC CI ol., 1993
1987
l99lb
1989 Njung’e and Handley.
Nanry and Tilson,
Kennett.
Critchley CI al.. 1987 Kennett CI al., 1989
Lucki et al., 1989
Gleeson er al.. 1989 Motta PI al., 1992 Crttchley and Handley.
Amrick and Bennett, 1986 Brady and Barrett. 1985
Witkin
Jenck er a/., l989b Audi et al.. 1988 Graeff, I988 Nogueira and Graeff,
ef al., 1992
Sanger and Joly, 1989-1990
Lecci er al., 1990
Nastiti BI al.. 1991 Tokuyama P, al., 1993
1989
and Insel. 199la
Mos and Olivier,
Winslow
_ 0
l986b
Meert and Colpaert. l986a Njung’e and Handley, 1991 b
Meert and Colpaert.
Shepherd
FR30/FRIO
Warm condition Cold condition
Locomotion decreased
Comments
0
0
0
+
+
0
0
_
+
+
0
Effects
2
LY
53857
antagonist)
>4000
151
68.5,”
1258
6215
antagonist)
DAU
(S-HTI
antagonist)
46470A
(Selective
BRL
(antagonist)
Anpirtoline
(agonist)
Phenylbiguanide
(5-HTla
Seganserm
(antagonist)
RP 62203
(antagonist)
Pirenperone
(antagonist)
>10000
28
3162
>10000
>10000
0.42’
I.58h
50”
>10000
29’
50
7.9
0.32”y
3@‘X
13Ok
b1000”’
interaction
test
place
observation
Free
Four
test
test
maze
test
hot-plates
Staircase
Light/dark
Elevated-plus
conflict
Geller-Seifter
interaction
test
maze
test
test
maze
Social
Light/dark
Elevated-plus
Light/dark
Light/dark
Elevated-plus
Elevated-plus
maze
test
Conflict DPAG-Stimulation
test
conflict
Geller-Seifter
hyperthermia
Stress-induced
Social
conflict
Geller-Seifter
DPAG-Stimulation
aversion
Conditioned
(33&37Og)
rats
ICR-DUB
mice
mice mice
CDI CDI
CD1
mice
CD-l
NMRI
NMRI
mice
Wistar
Wistar
mice
mice
(2&22g)
rats
rats
(3G35g) Cynomolgus monkeys
Female
(250-3000)
rats
(4@44g)
(4&55g)
(4C-55g)
Sprague-Dawley
mice
(2%3008)
rats
(25-30g)
(I 7-35g)
CDI
(24g)
(20&28Og)
Sprague-Dawley
BKW
mice
rats
(3704508)
CD-COBS
rats
Female
PVG
Mice
Wistar
(55&9OOg)
monkeys
(33&37Og) Squirrel
rats
(25-308)
Sprague-Dawley
mice
(25c-32Og)
rats
rats (37&45Og)
Rats
Sprague-Dawley Swiss
rats
rats (25&3008)
Sprague-Dawley
Wistar
Wistar
(25&3OOg)
Long-Evans
,.p. 45
0.014l1
0
0
i.p. 0.001-0.1
45
+
i.p. 45
0
0
+
+
+
+
-t
S.C. 2s or 45
60
IS days
days
fluid
(xl)
+
+
+
0.01-l
p.o.
during
during
68
S.C. 30
days
Drinking
12-14
p.o.
30
30
30
+
0
+
+
+
0
0
0
+
0
+
0
0
0
0.015-0.15
0.01-l
0.001~.1
40 /Jg/l
0.0001-0.1
30
30
p.o. during
i.p.
0.0025-2.5
p.0.
IO
IO
90
i.p. 45
i.p.
i.p.
p.0.
i.p.
35
60
i.m.
i.p.
i.p.
i.p.
0.01
35
S.C. 30
i.p.
i.p.
DPAG
DPAG
i.p.
0.0025
0.0001-0.1
0.000001-0.001
I-31.6
0.5
0.25-4
0.1-I
0.001~.3
0.03-3
1.5-3
2-s
0.03-3
I-IO
IO nmol
10 nmol
I-IO
10 min
and
Familiar
Oestrous
compartments
mice
mice
Asymmetric
Dioestrous
box
neutral neutral
and box
Familiar
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
during
Observations
FR30
FR3O/FRIO
FR3O/FRlO
and
and
and
et al..
6’1 trl..
Cutler.
Cutler.
.
cl nl.. er al..
Borsini
ef nl.. Borsim
PI nl.. Borsini
CI ul..
er al.
Borsini
Borsin!
Piper
1992
1993b
1993
l992a
l992b
l992b
1993
1993
1993
1993
1993
1993
1992
Ciao and Cutler.
Blackburn
Gao
Gao
Gao
Blackburn
er al..
Johnson.
1987
1991~
1991
1985
1989-1990
1989-1990
Handley,
er al..
1989a
Barrett,
Perez,
1990
Cutler,
and
Metzenauer
Young
Critchley
Perez,
and
et nl.,
and
and
PI al.,
Stutzmann
Jenck
Brady
Witkin
Lecci
1986
1985
1993a
1989a
1992
and
cf al.,
Kennett.
Witkin
Jenck
er al.. er al.,
Graeff
e, al.,
Schiitz
Rocha
6
%
B
2.
F ;:
4 5.
>lOOO@
antagonist)
Granisetron
(selective
5-HI-,<
Compounds
>lOOo”
5.HT,s
5.HT:,
(Ki.
IIM)
5.HTx
>10000”>10000”>1000~
5-HT,n
Afimties
1.41”’
5-HTI
test
motor
test
alterations
colomc
observation
threat
interaction
Stress-induced
Free
Human
Social
Light/dark
maze
test
conflict
Elevated-plus
Vogel’s
conflict
Geller-Seifter
feeding
Male
rats (21s28Og3 Ca//ithri.v monkeys
(295-3358) rats (25&3OOg)
Cynomolgus
jacchus Wistar
mice
female
(2436g)
female
Marmoset Marmoset
Wistar
and
DBA/Z
Male
mice
and
Gerbils
0.1-l
0.01~.1
0.001~.1
0.000001-0.
0.00001~.0001
0.01
0.01
0.0015-0.15
p.o.
I
days
i.p.
30
p.0.
S.C. 45
5
fluid)
7-10 Amygdala.
(in drinking
5
(xl)
. (xl) aur,ng days during
S-IO
(xl) during days p.0.
II
p.o.
3 weeks
during
0.1 2
Gerbils
p.0.
p.0, 45
45
p.0,
0.0001-0.1
p.0.
0.0001xl01
0.1-10
60
Rats
rats (20@2SOg)
Lister
(200-2508)
p,o.
Amygdala
I
0.00001~.001
(21&28Og)
Rats
rats
60
60
i.p. 45
p,o.
rats
DBA/Z
during days
p.o.
12-16
0.1-l
O.OOl--0.1
0.1 2 p.o,
i.p. 45
0.00001
-0.001
1.p 45
0.00001~.001
50
i.p.
i.p.
P 0. p,o. 60
0.00001~.001
0.001-1
0.01-l
0.0005~50
p.0.
rears
0
+
+
+
+
+
+
Weak
HLU
HLU
LLF
LLF
effect
and
+
HLU
HLU
+
+
HLU
+
HLU
LLF
and
HLU
HLU
HLU
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
and
compartments
Asymmetric
compartments
+
+
0
0
0
+
+
+
+
+
0
0
0
0
Gui
Piper
1992a
198Ya
lY89b
l988a
File.
File.
PI cl/
1991
1988
1989a
l988a
1993
.
PI ol..
er nl..
1988
1989
I988
I990
1989~
Piper.
er rrl.,
l99lb
l99la
and
I990
1989
CI ol..
cf ~1.. 1988
and
c! ul..
1991
Johnston,
PI al..
1990
e, nl.,
er nl..
P, ol..
Costall
Costall
Higgins
Cutler.
Cutler,
Cutler
Cutler.
Tyers,
Costall
Piper
Johnston
I989
and et nl.,
1990
and Higgrns
File.
File
Barnes
Cutler.
Costall
Costall
1988
1993
1993
1993
er 01.. 1988 Morinan, Costall
cf ul..
PI cl/.,
ef al..
1993
References PI al..
r, ol..
Johnston
Piper
PIper
Borsini
0.0005~50
Borsmi
0
30
+
Borsmi
Borsmi
i.p.
Asymmetric
Comments
0.001-0.1
0
+
Effects
S.C. 30
(xl)
5 h
(ml”)
i.p. 45
0.1-l
Lister
Wistar
latency p-o. during
0.0154.3
0.001&0.1
0.001~.01
administration.
rats (25Og)
(3&35g)
tested
@g/kg)
or doses
ROIJlCS
Rats
mice
(2&3Og)
(2@3Og)
Gerbils
mice
Mice
rats (21 days)
BKW
Lister
(200-2508)
Rats
rats
mice
BKW
rats
rats
tmce
monkeys
rats (200-25Og)
BKW
Wistar
Lister
Lister
Wistar
aversion
Stress-suppressed
place
CD-COBS
CD-I
Cynomolgus
Animals
Conditioned
hyperthermia
Stress-induced
Aggression-provoked
Models
doses
Efficient
Table 1. Continurd 0
s!
pK:“:
<4
>10000”>1000~>10000’
antagomst)
205-930
(selectwe
ICS
antagonist)
(selective
CR68755
17000’?
5.2
>lOOOo^
<4
0.81”
9.8
test
maze
test
test
Social interaction
Open-field
Light/dark
Elevated-plus
Conflict test
conflict
conflict Vogel’s
test
interactmn
GellervSeifter
Social
Light/dark
rats
Wistar
(21&28Og)
(30&35Og)
rats
mice
0.00001-0.001
I-10
0.01
0.0001~5
0.0000001-l
Amygdala,
1.p. 30
S.C.
p.0.
i.p.
5
(18-20g)
T/O
mice
(2G35g)
(2&3Og)
0.01
0.00~1
0.00001~).001
I
(22-300) Wistar rats (25&27Og) 0.187-20 Wistar rats _ O.OOOOOl~.lXlOl Rats Wistar rats (18&22Og) 0.ooo1~.01 Rats 0.001~.1 Wistar rats 0.000001~).00001 0.000005 Rats 0.01-I Sprague-Dawley rats 0.05-I (200-2508) Wistar rats (21&28Og) 0.0001~.001 0.00005-0.005 Rats 0.0001~).01
Female
mice
ICR
mice mice
BKW
C57Bl/6J
-
0.000000010.00001 0.0001~. I
BKW mice (2s30g)
ng/kg
0.00001~).01
Mice
0.001
0.0000-0.01
Mice
BKW mice (25-30g)
0.0001&0.01
Mice
2
0.1
Gerbils
0.00001
Amygdala, Dorsal rapha 5 i.p.
Nucleus accumbens septi p.o. 60 S.C.40
i.p. 60 Hippocampus Accumbens i.p. 60
S.C. 30
i.p. 30
i.p. 30 i.p. 45
Dorsal raphe or Amygdala 1.p. 45
i.p.
i.p.
p.0. during 12-16 days (xl) i.p.
Rats Accumbens 0.0001-0.01 Wistar rats (ISO-22Og) i.p. 60 0.001~.01 Rats W1star rats 0.000005-0.00001 Hrppocampus Nucleus 0.00001 &cumbens septt White Carneau pigeons 0.001x-l.3 i.m. 5 Rats p.o. 60 0.1 Wistar rats (20%2508) 10.25+).5 i.p. 30 BKW mice (25-30g) 0.00000001 Median raphe
rats
Wistar
Rats
Lister
BKW
+
0
0
0
+t
+
+
+
0
0
+
+
+
+
+
+
+
+
+
0
0
+ + + +
+ + + +
o
0
0
+
+
Asymmetric
Vogel’s
Vogel’s
test
Gel&
LLF HLU
HLU
+ 5,7-DHT
65 dB noise
, 1991
Thiebot ef al., 1990
Hagan er al.
Costall er a/., 1991b
1989
Costail cr ol.. l987a
Higgins PI ni., 1991
Corltirlued
Johnston and File, 1988 Kennett CI nl.. 1989
Papp and Przegalinski, 1989 Stefanski PI al.. l993b Plaznik er al.. 1991 Stefanski YI 01.. 1992a Stefanski PI (I/.. 1992b Stefanski PI nl.. l993b
Bill PI al., 1992
Onaivi and Martin,
Kilfoil er al., 1989 Costall et al., l989b
Costall CI al., 1989a
Costall er al., 1989~
Costall PI al.. 1988b
Tyers er al.. 1987
Costall CI ol.. l987b
Cutler, 1990
Gleeson er al.. 1989 Johnston and File, 1988 Dunn e/ al.. 1991 Costall e, al., 1989~
Dunn P, al., 1991 Higgms CI al.. 1991 Plaznik CI al., 1991 test Stefanski et al.. l992a Stefanski et al.. l992b Stefanski of a/., 1993b test
Asymmetric compartments and rears Transitions and Asymmetric compartments Asymmetric compartments
Asymmetric compartments Asymmetric compartments Asymmetric compartments and rears Asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments
Weak effect
Modified
Modified
Seifter
Modified
HLU
compartments
> 1000””
5.HTu
antagonist)
72222
(selective
MDL
Comnounds
> 1000”
5.HT,.
> 1000”
5.HT,,,
Affinities
no)
6 3””
5-HTI
> 1000“’
5-HT,<
> 10000”~’
~-HTQ
(Ki.
test
test
maze
interaction
DPAG-Stimulation
Social
L&/dark
Elevated-plus
test
conflict
Conflict
Vogel’s
Geller~Sclfter
DPAG-Stimulation
test
test
place
Passive-avoldance
averston
ConditIoned
threat
burying
Human
Marble
feeding
Novelty-suppressed
Models
(200-25Og)
rats
45Og)
(210-28Og)
(20-3583
Wistar
rats
(37&45Og)
(25C-3008)
rats
rats (21@28Og)
Llster
Rats
Rats
rats
mice
mice
Wistar
Lister
ICR
T/O
(2&3Og)
(24m35g)
Female
mice
rats (I 5&22Og)
BKW
rats (20&25Og)
plgeons
Wistar
Rats
Carneau
rats (300-35Og)
Rats
conflict
test
(370
(25&27Og)
Rats
rats
rats
27Og)
Wistar
White
Wlstar
Wistar
Wistar
rats (250
(295-3358)
.jacchus
Cullirhr,.~
Marmoset Marmoset
mice
rats
Callrrhrr.~
(35&4OOg)
jacchus
Marmoset
Wistar
MFI
Rats (23-358)
Female
(270-3208)
SpragueeDawley
(21&28Og)
rats (25&3OOg)
Wistar
Gerbils
Mice
rats
Wistar
Lister
p.0.
1.p. 30
3 weeks
60
i.p.
S.C. 30
0.3-3
45
35
i.p
0.1-22
30 Amygdala
i.p.
p.0.
raphi
0.001-0.01
20
IO
0.001~.1
Dorsal
Amygdala
0.0010.01 0.00005~.005
i.p.
0.001~1
30
i.p. 45
IO
1-p. 30
1.p. 30
5
30
35
i p. 60
i.p.
i.m.
10
30
S.C. 45
i.p.
i.p.
S.C. 30
0.01&3 IO
45
Amygdala,
during
i.p
45
p.0.
(min) 45
p.0.
latencv
i.p.
IX75
Routes administration,
5-20
0.5-X
10
0.01~10
0.0937-O
0.125-I
0 I-I
0.0001-n.00l
0.0001~.01
0.1-10
0.001
0.01-I
0.00014.001
1
0.12
0.0000-0.1
0.0000-0.1
(meika) 0.00001~.001
Rats
tested
Animals
doses
Efficient or doses
Table 1. Continued
5
5
5
5
(xl)
0
+
+
+
+
0
+
+
rears
HLU HLU
LLF
compartments
Asymmetric
Transitions
compartments
Asymmetric
and
Asymmetric compartments +
and
effect
Vogel’s
LLF
7mm
FRX
HLU
and
Weak
Modified
HLU
during
Observations
HLU
HLU
Comments
_
+
+
+
+
0
0
0
0
+
+
+
+
+
0
+
0
+ +
+
+ + +
Effects
test
1989b
1991
1991
Jenck
er nl..
198%
1991
1991
rr al.,
Dunn
cf al..
er 01.. 1990 Higgins
ef al., Dunn
1987
CI al.,
Martm.
Tyers
Higgms
and
1989 1990
1991
P, a..
C, al.. Onaivi
Bill
Costall
1993
er al.,
Dunn Griebel,
er al..
1992 1991 et ni..
rr rrl.. Dunn
Gleeson
Dunn
1990
l9X9a
er a/..
cf ol..
Dunn Haacoi;t
1989a
l988b
1987
Handley.
Przegalinakl. c( ol..
and
1988
c, al..
e, al.,
er a/.
and
Jenck
Papp
Papp.
Costall
Costall
Tyers
Njung’e
1991 Davies, 1991
and
cf ol..
er ~1.. 1991
1989
1989
l99lb
1990
1989
1989a
Dixon,
1990
and
c, al.,
1987
References er al..
Rex CI ol.,
Fletcher
Higgins
Dunn
Cutler,
Cutler
Costall
Tyers
Ondansetron >lOOO~ (selective antagonist)
3700’
>lOOO@ >lOOO~
5000”
13.5,”
Zero-mare Light/dark test
0.01 0.01 0.00~1 0.001~10 0.1 0.00005-0.01
0.00005-0.01 0.00005--0.01 0.00005~0.01 0.0001~1 0.0000001 iI 00001 0.0001 0.5-5
0.00005~1
Wistar rats (I 5&2OOg) Mice
Mice Mice BKW rmce Mice BKW mice (25-30g)
BKW mice
BKW m,ce (25-309)
0.04
0.01
0.1-1.5 I.5 0.001-n.0025 0.001~1 0.01&0.1 0.01&l 0.1 0.01~1 0.0075~.015 0.01xJ.1 0.054. I 0.00014). I
O.Ol-a.1 0.0005-I .6 0.01&O.I 0.0005~5 0.05ll.3 0.0001~.01 0.00001xl.015
0.0005~5
Long~Evans Rats (240-2608) Female rats (160-18Og) SpragueeDawley rats Wistar rats (21 days) DAP mice
Rats Wistar rats (IgO-220g) Rats Wistar rats Conflict test White Carneau pigeons Cynomolgus monkeys Elevated-plus maze Rats Wistar rats (15l&2OOg) Lister rats (2OOG27Og) Wistar rats Rats Wistar rats (20&25Og) Wlstar CFY rats (250-3OOg) Lister rats (200&27Og)
Lister rats (200-2508) conflict test Rats Vogel’s conflict test Rats Lister rats Lister rats (200&25og) Wistar rats (30&35Og) L1ster rats (210~28og) Wistar rats
Geller-Seifter
i.p. 45
1.p.
i.p.
i.p.
30
1.p. 30 S.C. 30 i.p. 50 p.0. 30
1.p. 2 weeks (x2) i.p. 60
i.p. 45
i.p. Dorsal raphe or Amygdala Median raphC 1.p. 45
dung
1.p. 30 p.0. 30
Hippocampus i.m. 5 p.0. p.o. 60 30 i.p. 30 S.C. 25 or 45
i.p. 1.p. 30 p.0. i.p. 30 Amygdala 5 Nucleus accumbens septi Accumbens i.p. 30
p.0.
+
+
+
+
+
+
+
+
+
0
0
0
+
+
+
+
+
+
+
0
0
0
0
+
+
+
+
+
0
0
0
0
0
0
0
0
Asymmetric compartments Weak effect Asymmetric compartments and rears Asymmetric compartments
(‘I
E, nl., l988b
Costall
Costall
CI ol.. l989a
CI ol.. 1989b
Young and Johnson. Costall er
Jones 6’1al., 1988
Costall
1988
s, 6
1
Cofrtirrrted
(‘r al.. 1990
Tyers CI al., 1987
Costall
Kshama
Vasar rr nl., 1993 Grewal PI al.. 1993 Morinan. 1989 Mos PI al.. 1989
Prather e, ol., 1993
Wright CI al., 1992a
Cutler. 199la Vogel’s test Stefanski a al.. 1992a Stefanski PI al., l992b Stefanski et al., l993b Gleeson CI nl., 1989 Jones er al., 1987 Johnston and File, 1988 Kshama c, al.. 1990 Wright E! nl., ‘1992a Borsini <‘I [rl.. 1993 Dunn CI ol.. 1990 Dunn CI al.. 1991 Upton and Blackburn. 1991
Asymmetric compartments Asymmetric compartments Asymmetric compartments and rears Asymmetric compartments Asymmetric compartments Asymmetric comoartments
Modified
Modified Modified
Dunn er al., 1990 Jones er nl.. 1987 Jones ef al.. 1988 Piper CI al.. 1988 Vogel’s test Dunn et al., 1991 Vogel’s test Higgins cf al.. 1991 Stefanski er al.. 1993b
Piper a al., 1988
Compounds
5-HT,a
5.HT,s
5-HT,,,
Affinities
IIM)
5-HTz*
(Ki,
5-HTx
S-HT,
test battery
mteraction
reflex
‘dlarreae‘
vocahzation
Ultrasonic
feeding
Novelty-suppressed
startle
Fear-potentiated
Defense
Social
Rats
+
p. 30
o.o1a).1
60
p.o.
Rats
rats (200-25Og)
Lister
rats
Long-Evans
(375415g)
Rat\
Rats
L1ater rats
(I 54-253~)
female
rats (210-28Og)
Lister and
rats(25&300%)
W1star
Rats
Rats
(2OOGZSOg)
rats
Lister
Rats
rats (IX&23Og)
O.l&lO
0.1
0.001~1
0.001
0.01
0.001~).1
O.OOOOOOl~.OOOl
0.05
0.01~1
0.01~1
0.0005a.
I
I
0.0005-0. 0.001-1
I
0.0005~).
0.00005~.01
0.00005~.005
30
45
1.p.
30
1.p. 45
i.p. 45
Amygdala.
i.p.
i.p.
5
0
+
+
0
+
+
+
+
+
+
+
+
+
+
45
p.0.
5
HLU
LLF
HLU
and Higgins
and
MO,
1987
(‘( ril..
rrl
1989
1991
1989
1991
1989
1988
1993
1991
1991
Naylor.
1990
I989a
1988
1988
Green.
CI
l987a
1991
1987
6’1 ol..
Rex 8, rrl..
Glenn
Shepherd
P, al..
Costall Dunn
PI nl.,
er al..
Costall
PIper
PI al..
Jones HLU
PI nl.,
Tyers
er al..
er al..
1990
HLU
HLU
File,
l993b
1992b
1992a
1989
1991~
1991
1993b 1991
Johnston.
and
CI ol..
CI a/..
er al..
Costall
Higgins
a/.. E, al..
Jones
HLU
and
and
rl
Ed al..
HLU
LLF
File. 0
0
p.0.
45
p.0.
5
File
Johnston 0
HLU
Stefanski
+
0
Stefanski
+
p-0. 45
45
i.p.
raphi. p.0.
Dorsal
Amygdala,
0.1&I 0.0001~.001
RalS 28Og)
60
septi
accumbens 60
Nucleus
Plaznik Stefanski
i.p.
noise
+ +
Accumbens 30
Stefanski
0
1990
1993
1992
Przegalinski.
PI nl..
er al..
and
Hippocampus
Borsini
er al..
1992
1992a
Johnson,
Naylor,
er al.,
and
and
e/ al., Fontana
Bill
Barnes
Papp
65 dB
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
0
p.o.
rats (210
Asymmetric compartments
Young
60
i.p.
0.1-l
0.00-0.0025
0.001~.1
0.1-1.5
0.25-20
Asymmetric compartments
Costall
1989
References PI al..
Kshama
+
30
0. I
Asymmetric compartments
Mos
0
+
30
i.p. 45
0.001
p.0.
+
O.OO~l 0.00-3
+
p. 45 S.C. 30
0.0000-0.1
rats (25Og)
Rats
rats (2ooG25og)
Male
+
p. 30
0.00005~.01
compartments
Comments Asymmetric
+
(min)
EffeCtS
latency
p.o.
rats
Routes administration,
S.C. 30
0.1
(mg/kg)
tested
0.01~1
Wistar
Rats
rats (18&22Og)
rats
Lister
Lister
Llster
g)
(15&2OOg)
(2&22
mice
rats (25G27Og)
rats
mice
Wistar
Lister
Wistar
Wistar
Open-field
CD-I Wistar
C57
(22-300)
mice
(3&35g)
T/O
mice
Female
BKW
ICR-DUB
(I 7-358)
mice
Mice
mice
Animals DAP
Female
Holeboard
Models
doses
Efficient or doses
Table 1. Continued
% -
Q 3.
P
Zacopnde > I0000’ > I 000~ (selectwe antagomst)
Y-25.130 (5-HT, antagomst)
WAY 10028’) (selective antagontst) <5 PK;
> I0000’
< 54
<5
3600’
26Op
0.3?’
8.8”
test
Marmoset Marmoset Callirhri.v /uccl~us (295m335g) Cynomolgus monkeys
Cynomolgus monkeys Marmoset Ca//ithri.v ,jacc/1us (35&4OOg)
Mice CD-I Female DAP mice Cynomolgus monkeys (3.1-5.4 kg)
0.000001~1 0.00001-0.001
Lister rats (295-335g) Marmoset
ddY mice antinoaception
Female T/O mxe (22.3Og) Lister rats (250-285g)
Rats Mice
I- IO 0.01 I 2 0.1~0.3
0.03xX I (I 8-2Og)
0.03-0.3
0.1-10
0.003&l 0.0000003~30
0.003-I 0.0000003~30
0.000001-10
Mice
Rats Mice
0.000000-0.0001 0.000003-3
i.p. 30 i.p. p.o. 60 30 i.p. 30 30
i.p. 30
p.0. 45 s.c 30 S.C. 30
i.p. i.p.
i.p. ,,p.
i.p. 40 S.C. 40
p.0. i.p. 40
I.D. 40 p.b. 30
+ +
p.0.
during I5 davs (xl) _. ’ 1.p. 60 i.p. 30 i.p. 35
O.OIut. I 0.125-I 0.0625XI.5 0.1~10
+
S.C. 45
0
+
0
0
0
+
+
+
+
0
0
0
+
+
+
+
+
0
+
+
i.p.
0.001 0.0001-0.001 0.1-l
+ + + +
0 0 + +
0
0 0 + 0
p.0. p.0. p.o. during 5 hr S.C. 45
i.p. 30 p.0. 3os.c. 30 p.0.
i.p. 45
30 i.p. 30
30
0.01~.1 0.01-0.1 0.1 0.0001~.01
0.01-0.1 0.001~10 0.001 o.o1a).1
0.0001~.1
2.5-5 0.01-l
0.3-3
Lister rats (295-335g) C57 mice
Vogel‘s conflict test Wistar rats (300-350g) Elevated-plus mare Lister rats (250g) Wistar rats (I 50 2OOg) Wistar rats (200&25Og) Light dark tcbt Wlstar rats (I 50 2OOg)
Stress-Induced
Fear-potentiated startle reflex
Light/dark
Vogel‘s conflict test Light/dark test
(S)-RS-56812 (selectwe antagonIst)
<5
maze test
Social interaction Human threat
Elevated-plus Light/dark
Vogel’s conflict test Light/dark test
0.12’”
days)
AP mtce (4-6 days) Female MFI mice (23-358) Swiss mice (25-30%)
I
test Wistar rats (25&27Og) Wistar rats (22&24Og) DPAG-Stimulation Wistar rats (37M50g)
Passive-avoidance
(R)-RS-56812 (selective antagonist)
RS-42359- I97 (S-HT? antagonist)
test
Aggression-provoked Human threat
Four hot-elates Free ob&ation
Stress-induced hyperthermia
Marble burying
Wistar rats (9-I 1989
l99lb
e, al., 1993 <‘I al.. 1993
er al.. 1993 PI al., 1993
Tokuyama
er al.. 1993
Bill CI rrl., 1992
Bill E! rrl., 1992
Fontana Fontana
Fontana Fontana
Costall Pf al.. 1993 Costall P, al.. 1993
Costall Pf al.. 1993
Costall (‘I al.. 1993 Fontana YI al.. 1992
Papp and Przegalinski. 1989 Sanger and Joly, 1989-1990 Jenck CI al.. 1989a
Piper cf al.. 1992
Tyers el nl., 1987 Costall er al.. 1988b Costall er al.. 198%
Jones <‘I al.. 1988 Piper er al.. 1988 Borsini (‘I al.. 1993 Jones rr ul.. 1988
Borsini er al., 1993 Mos CI al., 1989 Tyers et al.. 1987
Lecci el ol.. 1990
Nastiti CI a/.. 1991 Njung’e and Handley.
Mos and Olivier.
Vogel’s test Dunn E, nl.. 1991 File and Johnston. 1989 Kshama CI rrl.. 1990 Dunn <‘I
Modllied
Asymmetric
Asymmetric compartments Asymmetric compartments
Weak effect
Weak effect
Warm condition Cold condition
&f WI
6
”
rz
6 ;: a.
g 4 &.
rr (I/
l9YO: ,‘:‘Wona
(‘I r/i..
IYXY: ‘Lqwn
1993. ‘Takao
<‘r ol
19’) I, “‘Colpacrt
1992. ,‘“K!lpalrlck
(‘I (I/.
(‘I u/
test
maze
= Low
,“‘Millan
I YY2. ~““M~rrenaucr
rats (250
3OOg)
[CR-DUB
doses
(mnikn)
= High
(‘I ul..
(31 ol..
““Mlyauchl
(2, ul..
l9Y3.
(‘I
,.p. 45
1.p.
1.p. 4s
i.p. 45
ElTechvc
and Hartlg. (‘I nl.. ‘“‘Da
VI
Prada
<‘I ol..
Asymmetric
vehicle
<‘I al..
Interval; 1992: “Hoycr
= Variable
compartments
Asymmetru
compartments
Asymmetric
compartments
Asymmetric
compartments
1982.
E, ol.. lY9l; ‘“Maitre. ‘“Brown PI a/
‘“Andcrsson
1989a
l989b
lY92b
Z, ol..
ef al..
1990; and
CI “1.. 1991: “‘Barnes
P, al..
1992: ‘Con”
and Thomas.
1992. “‘Hyttel. 1977; ,“‘Berendsen 1989; .“:Audmot er
1992. “‘Brumvels
1988; “Doble
1989; “Ybema
= Flxed
199la
1991: ‘Peroutka. cc nl.. 1990”: ‘Nelson
and Schoeffter.
199la
1993
FR
l992b
1992
1992a
Interval:
Barnes (‘I al..
Cheng
Barnes L’I al..
1992b
and Johnson. Barnes CI al.,
Young
File and Andrews.
l992b
and Johnson,
PI al..
Barnes er nl..
Young
Barnes
1992b
and Andrew,
CI al.
1989
l9Ylb
I988
1993
1990
et iii , 1991
CI ul..
Barnes er al..
File
Costall
and NelJt.
~‘r II/.. 1992: ,“Hoyer
1985. ‘Ktlpatrlck
Costall Dun”
?I ul.,
1993 and Johnston.
Fl = Fixed
rats (14 days) AsymmetrIc
treated
Chronic
compartments
Asymmetric
compartments
Asymmetric
compartments
days)
vehxle rats (I4
Chronic treated
(21(I/.. 1990: LKllpatrtck
(31 (I/
19910: IYY I. ,‘“Fletcher
‘“Cosl;~ll (,I
+
*Olivicr
gray;
+
+
f
+
0
_
+
0
0
0
+
+
+
File
Kshama
0
Griebel,
1992b
Johnson.
1989b
1992
CI al..
and
e/ al..
and Johnson.
1988a
References PI al..
Bill PI a/..
Barnes
Young
Costall
Young
Costall
0
compartments
Asymmetric
compartments
Asymmetric
compartme”ts
Asymmetric
and rears
compartments
Asymmetric
Comments
+
+
+
+
+ + +
+
Etfccts
6’1 cr/. 198X: “Kenncrl.
IYY3; ‘Yagaloff
. 19Yl:
Dox.
pruaqueductal
198’): “Peroulka
(21 (I/
30 1.p. 60
I p.
1988: ‘VanWlJngaarden
= Lower
1992: ,‘“‘M”Jo~ (11 (I/
1991: ‘llKllpiltrIck
and Hoyer. and van de Kar.
Dorul 1983: ‘Sanders-Bush. 1993: ‘Malgouri, 1992. ,“Schoefftcr
,IRhodcs
=
I
IO
IO
LED
DPAG Unfamiliar. r, II/,
Light 1990. “Gozlan
HLU
Injection,
0.00001-1
0.0001~.
0.000001
0.00001
0.001 ~1
1.p. 45
1.p. 60
0.01&l 0.00001~1
1.p. 4.5
1.p. 45
0.0000 I~-0 01
0.000001~
1-p. 30
S.C. 45
0.001~1
i.p. 30
i p. 45
0 3-l
IO
30
1.p. 60
30
p.0.
S.C. 30
p. 45
p. 30
p. 45
0.0001-n.00l
0.001~10
0.01~1
2
0.001 a.01
1
17x
0.001~1
0.01~0
0.0001
0.001~.05
1.p.
45
p.0.
i.p
(min)
0.0001-17.8
L1ater Td,> (250~3oog) 1.t = mtrathecal
Routes latency
administration.
0.001-100
0.0001~10
001
mice (30.35g)
BKW
Efficient or doses tested
Mice
mice (3&35g)
BKW
mice (I 7-35g)
Female
L1stcr rats (25Og)
Lister
DUB
mice (I 7-358)
ICR
nuce (3&35g)
BKW Femitle
nuce (3Om35g)
rats (25Og)
(35woog)
BKW
Lister
/rw/!lr
Cullithr~ \
rats (2%3OOg)
(225-275g) Marmoset
W1star
rats
rats (25Og)
Sprague-Dawley
Lister
rats (I 5CrZOOg)
Swiss mice (IO weeks)
I YY2: ,“‘Lcvy IYYI:
(‘I ul..
TiO
(3&35g)
mice (22. 308)
1993: ,,“‘Dc Vry vi lr/
‘Moreau
(a( ol..
(2, u/
IYYI.
lY87.
mxe
Female
BKW
mice (I 7v35g)
ICR-DUB
m,ce (2&m30g)
Mwz
mice (30-358)
Ammals
Female
BKW
BKW
Wistar
and Pcroutka.
Familiar:
v, II/..
Light
inJectmn:
SOCl,ll Inler‘icllo”
Light’dark
IYXY: PThom.ir
IYYOb,
test
maze
mteraction
dark
Elevated-plus
Social
Light
Elevated-plus
threat
interaction
Human
Social
Holeboard
Models
IYX2. ‘Schmidt
LLF
IYY?. ‘Hoyer.
PI (I/
ri I//..
19X6: ‘,Schhcker
2.29”
0.33””
5.HT?
= lntracercbroucntricular
Schedule.
I c.1
5-HTx
1992: ~‘“Bolano, v( 111 1990. “‘Blackburn
vi u/,
IIM)
Rcmforcement
19X8. ~Nclson ri II/..
IY86; “Kldd
(KI.
S-HTx
= ‘\“xloge”esls:
19X5. “Engel r’i (I/..
19’) I. d’c’Barrcc~ and Zhdng.
Broekkamo.
P, (I/..
,“Heuring
-
5.HT,u
Affimties
= Continuous
I”acllvc.
5.HT,H
IYX7. .*-Bill (‘I (I/..
(2, (I/
and SandcwBubh.
IYXY: “‘Hoyer
CRF
and I~lclcr.
\chedulc.
IYX6: ‘Lyon
Ratm
0 =
dntagonrsr)
- = d”\lOl),I~.
(selecrlvc
5-HT,a
anraponw)
( + )Zacopridc
(selecwe
( ~ )Zacopride
Compounds
Table I. Continued g
5-HT-interacting of the central 5-HT system in the regulation particular experimental procedures.
2. ANIMAL
MODELS
OF ANXIETY
361
drugs
of anxiety-
or fear-related
DISORDERS:
ATTEMPTS
responses
is only evident
in
AT CLASSIFICATION
A survey of current animal models of anxiety reveals a bewildering diversity of procedures (for reviews, see Treit, 1985; Lister, 1990; Sanger, 1991). There are more than 30 animal behavior paradigms that claim to model anxiety (Fig. 1). Most of them involved exposure of animals to external (e.g. cues previously paired with footshock) or internal (e.g. drug states) stimuli that are assumed to be capable of inducing anxiety in humans. The first category can be grouped into two subclasses: the first includes ethologically based paradigms and involves animals’ spontaneous or natural reactions to stress stimuli that do not explicitly involve pain or discomfort (e.g. exposure to a novel test chamber); the second involves animals’ conditioned responses to stressful and often painful events (e.g. exposure to electric footshock). Some authors have attempted to classify anxiety models more precisely into three, four or more categories. For instance, Treit (1985) further divided the models based on conditioned reactions into two subgroups; models based on traditional learning paradigms (e.g. Geller-Seifter conflict test) and those involving phylogenetically prepared forms of aversive learning (e.g. conditioned taste aversion, conditioned defensive burying). More recently, Handley (1991) proposed a classification based on the nature of the aversive stimulus and on the response elicited, suggesting that the neuronal control of anxiety may differ according to whether the interpretation of a signal as aversive is innate or learned (Gray, 1982) and whether it causes the emission of a response or conversely inhibits an ongoing, rewarded behavior. Hence, Handley distinguished three main types of animal models of aversive behavior, namely, passive avoidance tests, active avoidance tests and conflict tests. For the sake of convenience, anxiety models in the present review are placed into one of the following two categories: (a) tests based on unconditioned responses and (b) models based on conditioned reactions (Fig. 1). The first category can be further divided into four subgroups: (al) models based on exploratory behavior in rodents (e.g. elevated plus-maze; light/dark test); (a2) models based on rodent and monkey social behavior (e.g. social interaction test; human threat in monkeys); (a3) situations based on somatic stress reactions (e.g. stress-induced hyperthermia). and in the last group, we can find some miscellaneous models that do not fit easily into the other subgroups, such as the marble burying test or the anxiety/fear test battery. In the second category, the traditional conflict paradigms (e.g. Geller-Seifter and Vogel conflict tests) are distinguished from a number of other models involving conditioned responses, including the fear-potentiated startle reflex or the conditioned emotional response (CER) test.
3. BEHAVIORAL EFFECTS OF DRUGS MODULATING 5-HYDROXYTRYPTAMINE NEUROTRANSMISSION IN ANIMAL MODELS OF ANXIETY 3.1. Behavioral Actions of Central Application of 5-Hydroxytryptamine and Peripheral Administration of 5-Hydroxytryptamine Indirect Ligands 3.1.1. 5-Hydro.yytryptumine As shown by Fig. 2a, a direct application of 5-HT in brain structures has been found to produce an anxiogenic-like profile in several studies. These results seem consistent with the observation that intraventricularly administered 5-HT is accumulated (with a half-life of about 445 hr) in several brain regions, including the periaqueductal gray area of the midbrain, the septum and the amygdala (Aghajanian and Bloom, 1967) regions frequently associated with punished and aversive behavior (Adams, 1979; Olds and Olds, 1962). Furthermore, they fit well with the 5-HT hypothesis of anxiety, as the increased availability of 5-HT in the brain may have potentiated emotional reactivity in the animals. However, as also illustrated by Fig. 2a, a similar treatment often reduces anxious responses. This inconsistency from one study to another probably is due to a number of factors. For example,
BASED ON ExPLmAlmN
-Elevated plus-maze -Free-exploration lest -H&board - Light/dark lest -Open-field -Staircase test - Zer*ma.ze
MoMLs
Mooas
I
RESPOHSES
-
of the existing
Corticosteron~ response Defecalion/micturation Nociceptio” Thermic response
Fig. 1. Classification
-Social competition - Social interaction test - Ultrasonic Distress vocalization
_Human threat
I
BASED ON UNCONDITIONED RESPONSES
MODELS BASEDON Soc!AL
1
animal
models
-
of anxiety
AnxielyiFear test baltery - cork gnawing - Marble burying
disorders
- Vogel
tests
_ Geller-Seiftet - Pigeons and monkeys wnflid
CONFLICT TEST8
-Active/passive avoidance test - Caditioned emotional response - Condtiioned tale aversion - DPAG-stimulation - Fear-pot&i&d starlle reflex - Hot plate -Shock-probe buying teat
MwxLLAPlsoUS
5-HT-interacting
369
drugs
it is obvious that the target site into which the injection was performed explains, at least in part, this variability. Several authors who found an anxiolytic-like action of 5-HT (Thiebot et ul., 1982. 1984; Higgins ef al., 1991) injected the neurotransmitter directly into the dorsal raphe. Yet, it is clearly established that this area contains a great density of 5-HT,,, receptors, which are localized on the cell bodies. The activation of these binding sites provides an inhibitory control on ascending serotonergic activity. Therefore, the anti-anxiety effect of such injections probably involves reduced 5-HT function. This variability could also be attributed to the use of different experimental paradigms. As is made clear by Fig. 3a, the anxiolytic-like actions of 5-HT have been found more often in conditioned procedures (64%) than in models based on spontaneous responses (20%). Thus, ethologically based tests may provide results more consistent with the classic S-HT hypothesis of anxiety.
5-HT
5-HT
REUPTAKE
0
8or
-
+
PCPA
INHIBITORS
146 y
60 7
8 6
40 kit
a
d)
-
o
+
f)
o
.‘I.‘._. :. I:::. ;. :. kl -
Cl RU
BUSPIRONE
8-OH-DPAl
3
20
+
24969
80
80
r
21 y 5 2 a
60
40
60
I 23
40
5 k.? B
6
6 .. .. . 20 /I 0
.“. .’ ..:
mCPP
Fig. 2. Illustration neurotransmission
23
5
a h)
‘. :.
‘I
-.
20 & o
0
RITANSERIN
+
ONDANSETRON
of the outcomes of the most studied compounds modulating 5-HT after a single acute dose in animal models of anxiety disorders. -. anxiogenic; +. anxiolytic; 0. inactive.
G. Griebel
370 3.1.2. 5Hydro.uytryptamine
Reuptake
Inizibitors
1SRls)
Several lines of evidence indicate that extracellular 5-HT concentration is increased by SRIs (e.g. Auerbach et al., 1989; Rutter and Auerbach, 1993). Various functional measures also indicate that serotonergic function is increased acutely after SRIs are given (Fuller et al., 1991). Consequently, we can expect that the administration of these compounds may modulate fear-related behaviors in animal models of anxiety. Single acute doses of these agents have been investigated largely in animal models of anxiety. More than 70 experiments have been carried out with SRls. Incontestably, the most studied agent in this group is imipramine. The initial work of Cook and Davidson (1973) suggested that imipramine was inactive in the Geller-Seifter conflict procedure. However, more recently, authors using either unconditioned models or learning paradigms demonstrated a modification of the animals’ emotional reactivity after a single acute dose of imipramine. Anxiogenic-like effects have been recorded in the Geller-Seifter (Sanger. 1992) and Vogel’s (McCown rt al.. 1983; Fontana and Commissaris, 1988) conflict tests. but also in the CER (Sanger, 1990). However, contradictory evidence has also been reported. Indeed, imipramine was found to be anxiolytic by a number of groups (Meert and Colpaert, 1986a; Craft et al., 1988 in the shock-probe burying test in rats; Young and Johnson, 1991~ in the light/dark test in mice). Variable effects have also been reported for other SRIs (e.g. amitriptyline, citalopram, fluoxetine). Nearly 38% of the studies failed to detect effects of these compounds. while the same percentage revealed an increase in the anxious responses of the animals (Fig. 2b). Finally, 26% of the investigations found some evidence for an anxiolytic-like action of SRIs. The suggestion that the behavioral effects of these compounds, which are all potential antidepressant drugs, cannot be detected in anxiety models, should be tempered by a number of clinical studies showing a potentiation in anxious symptoms early in the treatment, especially in patients suffering from panic attacks (Gorman et al., 1987; van Praag. 1988; Westenberg and den Boer, 1988; Humble et al., 1989; Giesecke, 1990; Westenberg, 1992). Analysis of the different experimental procedures used provides evidence that some models are more sensitive than others to the behavioral action of SRIs. As summarized in Fig. 3b. tests based on spontaneous responses more often revealed a modification in the behavioral responses of baselines (70%) than did conditioned paradigms (48%). In addition, results from ethologically based models seem more consistent with the ‘classic’ hypothesis of 5-HT function in anxiety, as 45% of the experiments revealed an anxiogenic-like profile of SRIs. whereas only 20% of the investigations using conditioned paradigms showed such an activity. It must be emphasized, however, that several models from the first group revealed anxiolytic-like effects of SRIs. Such an action is notably observed with the marble burying test (Njung’e and Handley, 1991 b) and the ultrasonic distress vocalization model (Mos and Olivier. 1989; Winslow and Insel. 1991 b). Nevertheless, the results from these models must be considered with caution. For example, it is striking that the marble burying test was unable to reveal any anxiogenic-like action of compounds known to possess such an effect, such as yohimbine or P-CCE (Njung’e and Handley. 199 I a). Furthermore, the ultrasonic distress vocalization test could not detect the anxiolytic effect of mcprobamate (Benton and Nastiti. 1988) and revealed an ‘anxiolytic’ profile of morphine (Carden and Hoffer. 1990).
3.1.3. p-Chloropl~en~~lc~lar~irlr (PCPA) Koe and Weissman (1966) and Jequier et al. (1967) were the first to show that the administration of PCPA depletes in a specific manner the synthesis of 5-HT by inhibiting the release of tryptophan-hydroxylase, which is involved in the formation of 5-HTP. More recently, Chaput et al. (1990) reported that 350 mg!‘kg of PCPA (during 2 days, with a daily injection) reduced the dorsal hippocampal 5-HT concentration by about 95%. The evidence that pretreatment (during 3 days, with a daily injection in most cases) with PCPA may modulate animals’ emotional reactivity first arose from the study of Tenen (1967). who demonstrated the efficacy of this 5-HT depletor in counteracting the disruption of drinking induced by stress. Since this initial experiment. more than 30 studies have investigated the behavioral effect of PCPA in anxiety models (Fig. 2~). Seventy per cent of these studies revealed an anxiolytic-like action of PCPA, whereas only 9% showed the opposite effect. Although some learning paradigms
5-HT-interacting
371
drugs
100
80
E 2
4
11
60
d 4
2
80
Y 8
Iu
3
:::,I .:::c ::::. ‘.‘I’.’
-
0
+
4:
C a c
60
z nu f?
40 18 20
d)
6 :.:.:.:.:. 0
-
0
+
Fig. 3. Illustration of the outcomes of the most studied compounds modulating 5-HT neurotransmission after a single acute dose in animal models of anxiety disorders subdivided into unconditioned procedures and conditioned tests.
periaqueductal gray (DPAG) stimulation) showed PCPA potentiation of anxiety, more than 60% of the experiments using such procedures provided evidence for an anti-anxiety action of this compound (Fig. 3~). It appears, therefore, that most anxiety models can reveal an anxiolytic-like profile of PCPA. Such an effect is consistent with the classic hypothesis of 5-HT in anxiety.
(e.g. dorsal
3.2. Behavioral Effects of Direct-acting
5-Hydroxytryptamine
Ligands
The focus on the involvement of 5-HT in modulating anxiety disorders coincided with the identification of various 5-HT binding sites in the brain (Hamon et al.. 1990). Molecular biological data concerning 5-HT receptor subtypes are increasing exponentially. At the present time, the 5-HT receptor family can be split into seven groups: 5-HT,-like, 5-HT,-like, 5-HTj, 5-HT4, 5-HTs, 5-HT6 and 5-HT,. Within the 5-HT, family, five subtypes have been described, i.e. 5-HTIA, 5-HTle, 5-HTlo, 5-HTIE and 5-HTIF. The 5-HT2 group can be further divided into 5-HT2A, 5-HTle and 5-HTrr (Hoyer et al., 1994). Of these, at least the 5-HTIA, 5-HTle, 5-HT?A zc and 5-HT3 receptors have been implicated in anxiety.
G. Griebel
312
5-HTIA receptors are located both presynaptically (somatodendritic autoreceptors) on the 5-HT cell bodies in the raphe nuclei of the brainstem, which innervate the forebrain. and postsynaptically, in particular in limbic structures, such as the hippocampus and the amygdala. Activation of presynaptic S-HT,, receptors results in an inhibition of cell firing and. hence, a decrease in 5-HT neurotransmission. while the activation of postsynaptic S-HT ,,, receptors leads to a neuronal inhibition in some limbic structures (e.g. hippocampus. septum). Both of these actions provide a rationale for studying 5-HT14 receptor ligands in animal models of anxiety. The amount of data that has been accumulated on the effects of 5-HT14 receptor ligands in the various anxiety procedures is vast. The most widely studied agents in this group are the pyrimidiny;p:?erazine partial agonist buspirone and the aminotetralin full agonist &OH-DPAT. Within the past I2 years, the behavioral effects of buspirone have been investigated in about 200 experiments, while more than 100 studies have involved 8-OH-DPAT. Anxiolytic-like properties of buspirone and 8-OH-DPAT have been shown in 71 and 61% of the experiments, respectively (Fig. Zd,e). Reports of an opposite effect have also been found. while several studies could not reveal any modification of baseline levels after the administration of buspirone or 8-OH-DPAT. Numerous previous and recent reviews have discussed extensively the variability in the effects of 5-HT,, ligands, in particular, those observed with the two drugs mentioned above (e.g. de Vry ct al., 1991: Handley. 1991; Treit, 1991: Oakley and Tyers, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a.b.c). Some authors (Treit. 1991; Oakley and Tyers, 1992) have suggested that pharmacological variables. such as the route of administration or the doses used. may account for some of this variation. For example. Treit (1991) suggested that the outcome of an administration of 5-HT14 receptor agonists into the central nervou’: system is more reliable than peripheral application. However. detailed examination of the literature indicates that neither route of administration or drug dose can satisfactorily explain these inconsistencies. For instance, both anxiolytic- and anxiogenic-like properties of X-OH-DPAT have been revealed in a large dose-range (0.001&S mg/kg). To explain this variability. most authors have focused on the procedures used and/or the experimental conditions. A common opinion is that traditional conflict paradigms are less sensitive to the action of 5-HT,, agonists than unconditioned models. However, as is made clear by Fig. 3d,e, both types are equal in revealing anxiolytic-like effects of these compounds. A more reliable explanation involves the experimental and/or the environmental conditions used by each laboratory. For instance. the evidence for both anxiolytic and anxiogenic effects of 5-HT, 4 ligands in the elevated plus-maze is extensive. Handley and McBlane (1993b) recently investigated the possibility of obtaining either effect at will in one laboratory by altering the conditions of the experiments. They showed that increasing illumination from 170 to 785 lux reversed the effect of 8-OH-DPAT from anxiogenic to anxiolytic. Moreover. they demonstrated that these differences cannot be accounted for by any simple differences in strain. maze construction protocol or control baseline. Furthermore, a series of experiments in conflict-type procedures (Costello ct trl.. 19913: Sanger. 1990, 1992; Wojnicki and Barrett. 1993) has shown that there are conditions under which it is possible to obtain increases in suppressed responding of rats or pigeons with buspirone. For example, Sanger (1990) demonstrated that when responding was suppressed in the presence of a stimulus correlated with r.p.spotz.rC-ir7~/~~p~~~~~/~~t~t .r/7ock. buspirone produced a similar behavioral pattern to that seen with benzodiazepines. In contrast, when responding was suppressed by ~c.s~)orl.~c~-c~cp~~~~(~~~ni ,sl7ock. buspirone did not produce an increase in punished responding of rats. It is obvious from these studies that the behavioral effects of 5-HT,,, ligands easily can switch from ‘anxiolytic’ to ‘inactive’ or even ‘anxiogenic’ when small alterations are made in the procedure used. However. further studies with other 5-HT14 ligands are needed in order to establish the generality of the effects of such procedural variations on the behavior change associated with this class of compounds.
3.2.2. 5-H,.~lro.\-?~tr~~~I,tNlllit~~~,~ Rmeptor 5-HTIH sites arc both presynaptic exist as heteroceptors on cholinergic
Agmists
terminal autoreceptors and postsynaptic receptors. They also neurons (Hoyer and Middlemiss, 1989: Middlemiss and Hutson,
SHT-interacting
drugs
373
1990; Palacios et al., 1992). Contrary to recent theories based on species variations in pharmacological measurements (Heuring et al., 1987; Hoyer and Middlemiss, 1989), molecular biological data have demonstrated that 5-HT,, receptors exist in numerous species, including humans (Jin et al., 1992). Owing to the lack of selective ligands, the evidence for the involvement of 5-HT,, sites in anxiety states is limited. A recent preliminary study using mutant mice showed, however, that this receptor plays a determinant role in the modulation of emotional responses (Hen et al., 1993). These authors generated, by homologous recombination, mutant mice lacking the gene encoding 5-HT,, receptor and showed that this binding site is totally absent in the homozygous mutant mice. They further demonstrated a lack of anxiogenic-like responses to RU 24969 (a mixed S-HTIA/5-HTIB agonist) in mice that do not possess the 5-HTIe receptor subtype. Experiments with RU 24969 using normal mice or rats have shown anxiogenic- as well as anxiolytic-like effects; and, in some studies, the drug was found to be inactive (Fig. 2f). A more detailed analysis of the data indicates that in ethologically based procedures, RU 24969 produced an anxiogenic effect in 60% of the experiments, whereas it was inactive or even showed an anxiolytic-like profile in 10 and 30% of the studies, respectively. In contrast, authors using conditioned paradigms reported an anxiolytic-like action of the compound in 60% of the investigations, or could not reveal any effect in 40% of the experiments. In the first category, studies using the ultrasonic distress vocalization paradigm (Gardner, 1985~; Mos and Olivier. 1989) and the marble burying test (Njung’e and Handley, 199la) revealed an opposite effect (anxiolytic) of RU 24969 compared with the other tests of this group (elevated plus-maze and social interaction test). Thus, results of both tests should be approached with caution. Data obtained with RU 24969 in traditional conflict procedures are also inconsistent: it was found anxiolytic in the Vogel’s conflict test in rat (Korneyev and Seredenin, 1993) and in pigeons (Gleeson et al., 1989) and inactive in the Geller-Seifter paradigm in rats (Deacon and Gardner, 1986) and in monkeys (Gleeson and Barrett, 1990). This variability might be due, at least in part, to the use of various types of schedules in conflict procedures or to species differences (particularly in the ‘5-HTle-like’ receptors). 3.2.3. 5-HydroxytryptaminezA
and 5-H>!dro.yytryptamine2(
Receptors
5-HTzA (previous name: 5-HT,) receptors are located postsynaptically in many areas of the cortex, the claustrum, some components of the limbic system and parts of the basal ganglia (Hoyer et al., 1986). 5-HTz, (previous name: 5-HTIc) sites are found predominantly in the choroid plexus, as well as the limbic and basal ganglia areas (Pazos et al.. 1984). In general, compounds claimed to be 5-HTzA receptor selective show similar affinity for 5-HT2(. receptors (Hoyer, 1988, Hoyer et al., 1989), which is not surprising, given the very close structural similarity of these two receptors (Hartig. 1989; Julius et al., 1988). For that reason, the study into their specific roles in anxiety states is limited. 3.2.3.1. 5-Hydro,~?~tr~pta~~~ine2.1,rc. receptor agonists. The most studied drugs of this group are TFMPP and mCPP, two mixed 5-HTzA.,, receptor agonists. The latter has been assessed in more than 30 studies using anxiety models. Most of them described anxiogenic-like effects of mCPP (Fig. 2g). These results are in accordance with clinical data that demonstrated that mCPP had anxiogenic effects in healthy subjects and potentiated anxious reactions in agoraphobic, obsessive-compulsive disorder and panic disorder patients (e.g. Klein et al., 1991; Germine et al., 1992; Pigott et al., 1993). As shown in Fig. 3g, unconditioned paradigms seem particularly sensitive to the anxiogenic effects of mCPP, as 75% of the studies observed a potentiation in the anxious responses in animals. Again, the marble burying test (Njung’e and Handley, 1991 b) and the ultrasonic distress vocalization test (Winslow and Insel, 1991a) revealed an opposite effect. The result of the latter study is surprising, as the same authors found an anxiogenic-like action of TFMPP, a compound pharmacologically closed to mCPP. Only eight studies have investigated the effect of mCPP in conditioned procedures (compared with 24 in unconditioned models). Some of these found an anxiogenic-like effect (Kilts et al., 1982 in the Vogel’s conflict test; Mansbach and Geyer, 1988 in the fear-potentiated startle reflex test; Martin, 1993 in the shuttle box), while others reported an anxiolytic-like profile (Davis et al., 1986 in the fear-potentiated startle reflex test; Jenck ef al., 1989a in the DPAG-stimulation paradigm; Meert, 1989 in the shock-probe burying test) or no effect at all (Davis et al., 1986 in the fear-potentiated startle reflex test; Rocha et al., 1993a in the conditioned taste aversion). Differences in procedures
314
G. Griebel
or methodology might explain some of these discrepancies in the results obtained with these latter tests. Thus, studies using the rat fear-potentiated startle reflex paradigm, in which mCPP was variously found to be anxiolytic, inactive or anxiogenic, used four different administration routes: subcutaneous (anxiogenesis), intrathecal (inactive), intraperitoneal (anxiolysis) and intracerebroventricular (anxiolysis). Results obtained with unconditioned procedures are closer to the clinical results, and this must be taken into account in future investigations of such agents. 3.2.3.2. 5-H~dro.ul’tr?.ptanline~,~.~~ receptor antagonists. As with ligands for other 5-HT receptors, studies with 5-HTZA.2c receptor antagonists have produced equivocal results. Figure 2h shows results obtained with ritanserin, the most studied compound in this category. To date, 50 experiments have investigated the behavioral effects of ritanserin in animal models of anxiety. The drug has been found to produce anxiolytic-like effects in more than 40% of the studies, while 12% of them reported evidence for increasing anxiety. Finally, 44% of the reports indicated a lack of activity of the drug in these tests. There is no evidence for a greater sensitivity for one or the other category of models (Fig. 3h). Thus, ritanserin has been reported to have disinhibitory effects, anxiogenic-like effects and/or even no effect in the traditional conflict procedures (Geller-Seifter and Vogel), as well as in exploration tests, such as the elevated plus-maze, the light/dark test or the open-field. It must be emphasized. however, that in one of the models (pigeon conflict paradigm), ritanserin produced reliable and reproducible anti-conflict activity, although the magnitude of the effects is less than those observed in this particular model with benzodiazepines (Gleeson et al., 1989; Brocco et al., 1990). A similar behavioral profile is seen with other mixed 5-HT2,&..?(receptor antagonists, such as ketanserin, cinanserin, ICI 169369, mianserin or the more recently synthesized compound LY 53857. Clinical studies with ritanserin also reported a variety of effects. Thus, it was found to be effective in generalized anxiety disorders (Ceulemans et al., 1985; Arriaga et ul., 1986; da Roza Davis et al., 1992) agoraphobia (Humble et al., 1986) and aversive classical conditioning in healthy volunteers (Hensman et al.. 1991) but these effects have not been confirmed systematically (Ceulemans, 1985) and do not appear to extend to panic disorder. Indeed, panic may even be exacerbated by ritanserin (Den Boer and Westenberg, 1990). The reasons for this apparent difference in anxiety-modulating action of ritanserin and related compounds remain to be determined. Perhaps the evaluation of the behavioral effects of more selective ligands for either the 5-HT,* or the 5-HT:(. site now available (e.g. SR 46349B for the 5-HTZA subtype) could shed light on the differential involvement of these receptors in the modulation of emotional responses. 3.2.4. 5-H?,dro.~~tr~pturniI~~~ Receptor
Antagonists
The identification and characterization of 5-HTI binding sites in brain tissue, in particular in limbic areas such as the amygdala (Kilpatrick et ul., 1987; Barnes et al., 1988; Peroutka and Hamik, 1988) and the synthesis of highly selective ligands for these receptors, have been the starting point of numerous studies that investigated the behavioral action of 5-HT, receptor antagonists in animal models of anxiety. A number of 5-HTj receptor antagonists has been examined for potential anxiolytic-like activity in animals: anpirtoline, DAU 6215, GR 68755, granisetron (BRL 43694) MDL 72222, ondansetron (CR 38032F), RS-42359-197, tropisetron (ICS 205-930) WAY 100289, Y-25,130 and zacopride. Among these compounds, ondansetron has been the most studied. More than 75 experiments have investigated the modulatory action of ondansetron on anxiety-related responses in animals. As shown in Fig. 2i, 66% of the results provided evidence for an anxiolytic-like action of this compound, while 33% of them did not observe any modification in the animals’ responses. Only one study reported an anxiogenic action of ondansetron (Gleeson et al., 1989). This is surprising in view of the outcomes of the other drugs mentioned in Sections 3.1.1-3.2.3, which all reported clear evidence for both anxiolytic- and anxiogenic-like effects. More precisely, authors using ethologically based tests reported an anxiolytic-like effect in 72% of the cases (Fig. 3i). Interestingly, most of these studies revealed a positive effect over a wide dose range, with minimum dose levels in the nanojpicogram range. Furthermore, ondansetron mimics the anxiolytic activity seen with benzodiazepines. However, they differ from the latter as they lack the sedative and muscle relaxant effects of benzodiazepines and fail to antagonise electric shock and leptazol-induced convulsions (Costa11 et al.,
5-HT-interacting
drugs
375
1988e). In addition, unlike benzodiazepines, ondansetron and 5-HT, receptor antagonists, in general, have been found to enhance performance in tests of cognition (Costa11 et al., 1992b). As shown in Fig. 3i, however, in some studies using these same models (28%), ondansetron has failed to show anxiolytic-like effects. Obviously, some methodological problems with procedures involving spontaneous behavior influence the data obtained. For example, negative results have been observed in the light/dark choice paradigm when rats were the experimental subjects (Morinan, 1989; Kshama et al., 1990). Furthermore, ondansetron was found to be inactive in a few studies using the elevated-plus maze. As mentioned in the Introduction, these differences evidently are produced by a multitude of, perhaps small, methodological differences that do not necessarily become clear, even with the most detailed scrutiny of published reports. In addressing the problem raised by the plus-maze data, Handley and McBlane (1993b) recently questioned whether such differences could involve genetic variability in rats or even investigation, as minor stressors often affect positively motivated behavior. When the reliance has been placed on conditioned procedures, the potential anti-anxiety actions of 5-HT1 receptor antagonists have been observed in only a few studies. For instance, ondansetron was found to be anxiolytic in 44% of the investigations using conditioned procedures, whereas it was ineffective in 50% of such studies (Fig. 3i). Costa11 and Naylor (1991) recently have suggested that the models failing to show anxiolytic-like effects of 5-HT, receptor antagonists may be insensitive to novel pharmacological mechanisms involved in anxiety. Alternatively, Barrett and Vanover (1993) speculated that the specific conditions of the models revealing an anxiolytic-like action of these agents may be sensitive to a behavioral effect other than an anxiolytic effect. No matter what approach is used, only positive effects in clinical trials can help to decide which of the animal models are the best predictors of these effects. Even less is known, from a clinical point of view, about possible anxiolytic effects of 5-HT3 receptor antagonists. Whilst a number of open and placebo-controlled studies have either been carried out or are under way since 1986 (Schweizer and Rickels, 1991), only one has been published so far. Lecrubier et al. (1993) recently reported that tropisetron is efficacious in the treatment of generalized anxiety disorder. However, no data from any other of these studies have been made available yet, apparently because 5-HT3 receptor antagonists do not show significant treatment differences between drugs and placebo. In conclusion, in the case of 5-HT, receptor antagonists, both types of animal models appear to have little problem finding an anxiolytic-like effect. Yet, this does not show up in the clinical tests. Insofar as this is true, it indicates that we can get good agreement (in the published literature at least) regarding a particular effect in animal models, yet not predict good clinical efficacy. This suggests (a very practical outcome) that more favorable attention be given to the publication of nonsignificant effects, and, second (of more scientific interest) that we continue and, in fact, enhance our efforts to understand why animal models sometimes predict and why they sometimes do not.
4. PERSPECTIVES
AND
SUMMARY
It is obvious from the data discussed above and summarized in the table that 5-HT-related drugs have equivocal anxiety-modulating properties in animal models. The reasons for this variability in drug effect remain in great part unknown, but certainly include some factors (such as species differences or sex of the animals), which have been widely assessed in many recent reviews (e.g. Barrett and Gleeson, 1991; Briley et al., 1991; Costa11 and Naylor, 1991; de Vry et al., 1991; Handley, 1991; Treit, 1991; Oakley and Tyers, 1992; Wettstein, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a,b,c; Hughes, 1993; Schreiber and de Vry, 1993). Much of the current interest in this field is focussed on differential responsivity of various animal paradigms after 5-HT drug challenge. As reviewed in the present paper, agents triggering the release or increasing the availability of 5-HT, such as the neurotransmitter itself, 5-HT reuptake inhibitors, RU 24969 or mCPP usually promoted anxiety responses in ethologically based procedures, whereas they were inactive or even decreased emotional reactivity in traditional learning paradigms. Clearly, the results obtained in unconditioned models seem more consistent with the classic 5-HT hypothesis of anxiety, which assumes that 5-HT activity enhances anxiety. Hence, these results question the validity ofconditioned paradigms, in particular conflict tests, in the investigation of the behavioral effects of drugs known
376
G. Griebel
to possess anxiogenic properties, including compounds stimulating 5-HT neurotransmission. As mentioned by Treit (1985), one of the problems with conflict tests is that significant anticonflict effects have been produced by drugs that either produce or potentiate anxious responses in humans. such as amphetamine (Lehman and Ban, 1971; McMillan, 1973; Miczek, 1973; McKearney and Barrett, 1975). LSD (Commissaris and Rech. 1982), caffeine (Beer rt ul., 1972). isoproterenol (Pate1 and Malick. 1980) or the &adrenoceptor antagonists idazoxan and yohimbine (Sanger. 1991). Obviously, the data from these latter studies. as well as some that reported anxiolytic-like action of drugs stimulating the 5-HT system. confirm Treit’s assumption (Treit. 1985) that conflict tests are not totally selective, and strongly suggest that these paradigms are ‘only’ animal models of ‘anxiolytic’ drugs. This is problematic when considering the behavioral studies of newly synthesized drugs, as we do not necessarily expect one or the other effect of these compounds. Thus, to detect false-positive effects in conflict procedures, authors should complete their studies by adding results obtained in models able to reveal both anxiolytic- and anxiogenic-like properties of drugs. This is less likely to happen, however, when it is required that conditioning task researchers should adopt ethological tasks, or vice versa. In contrast, data showing anxiolytic-like effects with compounds interacting seiectively with .5-HTIA receptors. or even with drugs blocking 5-HT2,< 2(.binding sites, did not provide evidence that one particular category of models is involved in one particular effect. As with benzodiazepine receptor agonists, both conditioned and unconditioned tests revealed, in the majority of cases. an anxiolytic-like action of 5-HT,, full or partial agonists. even if these effects were more variable and smaller in magnitude when compared with standard anxiolytics. As it has been assessed in previous reviews (see references above), these phenomena are not discussed in the present paper. Furthermore, Treit’s assertion that only the light/dark choice paradigm. the social interaction test and the fear-potentiated startle model show “good sensitivity to both benzodiazepine and 5-HT,, agonists” is unacceptable, as both 8-OH-DPAT and buspironc were found to have anxiolytic, anxiogenic or null effects in all three models (see Table I). At this time. only the conflict procedure in pigeons revealed invariably an anxiolytic-like action of 5-HT14 compounds, and this effect is comparable to that obtained with benzodiazepines (Barrett and Vanover, 1993). However, these results must be confirmed by laboratories other than that of Barrett’s group. which investigated in great part the effects of these drugs in the pigeon’s conflict test. Anxiolytic-like effects of 5-HT? receptor antagonists have also been established only in selected test procedures. Consideration of the distinction between ethologically based tests. and ‘conventional’ testing procedures indicates that these effects only occur in the first mentioned models. In these, only the lightidark choice paradigm in mice constantly showed an anxiolytic-like action of these agents. Variation in the effects of 5-HT drugs in animal models of anxiety could reflect differences in the degree to which the models themselves represent fear or anxiety (Treit. I991). It is obvious that all models are not equivalent. Thus. models based on reactions to non-painful strcssors or on spontaneous responses, in particular exploration procedures or the social interaction test, may reflect a type of anxiety linked with uncontrollable stress (‘depressive anxiety’), as animals are exposed by force to a novel and/or aversive environment from which they cannot escape. while those based on conditioning and/or reactions to painful stressors, especially the Geller-Seifter and Vogel’s conflict tests, may reflect a type of anxiety associated with controllable aversive events (‘anticipatory anxiety’) (Gardner. 1986; Soubrii and Thikbot. 1986). Thus, 5-HT modulation at 5-HT, target sites might be selectively involved in situations dealing with the so-called ‘depressive anxiety’, whereas 5-HT,,, and perhaps S-HT:% Jc receptors. may be involved in both types of anxiety-related responses. This view is akin to Gardner’s, Handley’s and McBlane’s assumption of the existence of multiple 5-HT mechanisms in anxiety (Gardner, 1986; Handley. 1991; Handley and McBlane, 199 1). To shed light on the complex story concerning the involvement of 5-HT neurotransmission in the regulation of emotional reactivity, clinical investigations more and more hold the key. Several 5-HT-interacting compounds are now in various phases of clinical development, in particular, drugs acting selectively at 5-HT,,% sites (e.g. S20499, MDL 73005EF, WY-50.324). Information from clinical trials should permit future experimental research in this area to focus more precisely on the behavioral paradigms that are particularly sensitive to the effects of 5-HT drugs and on the 5-HT receptor subtypes that are specifically involved in the modulation of fear-related behaviors.
5-HT-interacting
drugs
311
AIknoM,/ed~enlents-The author thanks Prof. R. J. Blanchard (Bekesy Laboratory of Neurobiology and Department of Psychology, University of Hawaii, U.S.A.), Prof. D. C. Blanchard (Btkesy Laboratory of Neurobiology. University of Hawaii, U.S.A.), Prof. R. Misslin (Laboratoire de Psychophysiologie, Universite Louis Pasteur, Strasbourg, France) and Dr H. K. Taukulis (Department of Psychology, University of New Brunswick, Canada) for their kind reviewing of this manuscript.
REFERENCES Adams. D. B. (1979) Brain mechanisms for offense, defense and submission. Behav. Brain Sci. 2: 2Oll241. Aghajanian, G. K. and Bloom, F. E. (1967) Localization of tritiated serotonin in rat brain by electron-microscopic autoradiography. J. Pharn?ac. e.up. Ther. 156: 23-30. Ahlenius, S., Larsson, K. and Wijkstriim, A. (1991) Behavioral and biochemical effects of the 5-HTlh receptor agonists flesinoxan and S-OH-DPAT in the rat. Eur. J. Pharmac. 200: 259-266. Ahlers, S. T.. Weissman. B. A. and Barrett, J. E. (1992) Antagonism studies with BMY-7378 and NAN-190: effects on &hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons. J. Pharmnc~. e_yp. Ther 260: 474-48 I. Akai. T., Takahashi, M., Nakada, Y., Ohnishi, R., Ikoma, Y. and Yamaguchi, M. (1991) Anxiolytic effects of lisuride and its action to central 5-HT,, receptors. Foliu pharmac. ,jap. 90: 209-220. Allen, L. E., Fergusson, H. C. and Cox, R. H. (1974) Pharmacologic effects of MJ 9022-1, a potential tranquilizing agent. Arxeimittel-Forsch. 24: 917-922. Almeida, S. S.. de Oliveira, L. M. and Graeff, F. G. (1991) Early life protein malnutrition changes exploration of the elevated plus-maze and reactivity to anxiolytics. Ps>~chopharmacology 103: 513-518. Amano, M., Goto. A., Sakai, A., Achiba, M., Takahashi. N., Hara. C. and Ogawa, N. (1993) Comparison of the anticonflict effect of buspirone and its major metabolite I-(2-pyrimidyl)-piperazine (1-PP) in rats. Jop. J. Phnrmnc. 61: 311-317. Amrick, C. L. and Bennett. D. A. (1986) A comparison of the anticonflict activity of serotonin agonists and antagonists in rats. Sot. Neurosci. Abstr. 12: 907. Andersson, G.. Christensson. E., Eriksson, E., Fex, T.. Klint, T., Lundstedt, T., Pettersson, G. and Svartengren, J. (1992) Neuropharmacology of FG5893. a new psychotropic drug with high affinity for both the S-HTIA and the S-HT, serotonin receptor. In: 211d ktetvationul Symposium on Serotonin, from Cell Biology ro Pllcrrr?lcrc,olog~, ~rd Thercrpeutics, p. 16, Houston. 15-l 8th September. Andree, T. H., Moyer. J. A., Stack, G.. Muth, E. A. and Haskins, J. T. (1988) Preclinical nemopharmacological profile of WY-48.723. a potent serotonin (S-HT,,,) agonist. Sot. Neurosci. Abstr. 14: 555. Andrews. N. and File, S. E. (1993) Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence. P.s~~c~hopl2rrrniL~~~)log~. 112: 2 1-25. Aprison. M. H. and Ferster. C. B. (1961) Neurochemical correlates of behavior - II. Correlation of brain monoamine oxidase activity with behavioural changes after iproniazid and 5hydroxytryptophan administration. J. Ncurochem. 6: 350-357. Arriaga. F., Leitao. J.. Padua. J., Ruiz, I., Tropa, J., Sousa, M. P., Mills, F. J. and Gelders, Y. (1986) Ritanserin, an original sleep quality improving agent in generalized anxiety disorders. In: C.I.N.P. Congress, Puerto Rico, p. 174. December 14-l 7. Audi. E. A., de Aguiar, J. C. and Graeff. F. G. (1988) Mediation by serotonin of the antiaversive effect of zimelidine and propranolol injected into the dorsal midbrain central grey. J. Psychopharmac. 2: 26-32. Audi. E. A.. de Oliveira. R. M. W. and Graeff, F. G. (1991) Microinjection of propranolol into the dorsal periaqueductal gray causes an anxiolytic effect in the elevated plus-maze antagonized by ritanserin. P.,~~(~llophrrrr,2frc.ol~)g~~ 105: 5533557. Audinot. V.. Canton, H., Jacques. L., Verriele, L. and Millan, M. J. (1993) Receptorial profiles of atypical antipsychotics at cloned human dopamine Dz and D, receptors and at rat D? and 5-HTlc ?receptors in ritro:e.y riro. SW. Neuro.cci. Ahstr. 19: 1 169. Auerbach. S. B., Minsenberg, M. J. and Wilkinson, L. 0. (1989) Extracellular serotonin and 5-hydroxyindoleacetic acid in hypothalamus of the unanesthetized rat measured by in piz%odialysis coupled to high-performance liquid chromatography with electrochemical detection: dialysate serotonin reflects neuronal release. Brain Res. 499: 28 lL290. Baduel, A.. Lemoal, M. and Stinus, L. (1986) Comparison of the effects of buspirone, diazepam, haloperidol and sulpiride on a conflict schedule in rats. Neurosci. Lett. 26 (Suppl.): S278. Barnes, N. M.. Costall, B., Ironside. J. W. and Naylor. R. J. (1988) Identification of 5-HT, recognition sites in human brain tissue using [‘Hlzacopride. J. Pharm. Phurmuc. 40: 668. Barnes, N. M.. Costall. B.. Domeney, A. M., Gerrard, P. A.. Kelly, M. E., Krlhling. H., Naylor, R. J., Tomkins, D. M. and Williams. T. J. (1991) The effects of umespirone as a potential anxiolytic and antipsychotic agent. Phcrrmnc~. Biodlem. Behur 40: 89-96. Barnes, N. M.. Cheng. C. H. K., Costall. B., Ge. J.. Kelly, M. E. and Naylor, R. J. (1992a) Profiles of interaction of R( +):S( -)-zacopride and anxiolytic agents in a mouse model, Eur. J. Pharmnc. 218: 91-100.
378
G. Griebel
Barnes, N. M., Costall, B., Ge, J., Kelly, M. E. and Naylor, R. J. (1992b) The interaction of R( +)- and S( -)-zacopride with PCPA to modify rodent aversive behaviour. Eur. J. Pharmac. 218: 15-25. Barrett, J. E. (1992) Studies on the effects of 5-HT,,A drugs in the pigeon. Drug Dw. Res. 26: 299-317. Barrett, J. E. and Gleeson, S. (1991) Anxiolytic effects of 5-HT,, agonists, 5-HT, antagonists and benzodiazepines: conflict and drug discrimination studies. In: 5-HTI1 Agonists, 5-HTI Antagonists and Benzodiazepines, Their Comparative Beharioural Phrrr~?l~:c,olog~~.pp. 59 105, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley and Sons, Chichester. Barrett, J. E. and Vanover, K. E. (1993) 5-HT receptors as target for the development of novel anxiolytic drugs: models, mechanisms and future directions. Ps.vchr/ppllarnluco/og~, 112: I ~ 12. Barrett, J. E. and Zhang, L. (1991) Anticonflict and discriminative stimulus effects of the S-HTIA compounds WY-47,846 and WY-48,723 and the mixed 5-HT,,, agonist/S-HT1 antagonist WY-50,324 in pigeons. Drug Dec. Res. 24: 179-188. Barrett, J. E., Witkin, J. M. and Mansbach, R. S. (1984) Behavioral and pharmacological analysis of the effects of buspirone. FASEB J. 43: 931. Barrett, J. E., Witkin, J. M., Mansbach, J. M., Skolnick, P. and Weissman, B. A. (1986) Behavioral studies with anxiolytic drugs. III. Antipunishment actions of buspirone in the pigeon do not involve benzodiazepine receptor mechanisms. J. Pharmac. exp. Ther. 238: 1009-1013. Barrett, J. E., Gleeson, S., Nader. M. A. and Hoffmann, S. M. (1989) Anticonflict effects of the 5-HTIA compound flesinoxan. J. Psychopharmac. 3: 64-69. Baudrie, V., de Vry, J., Broqua, P., Schmidt, B., Chaouloff. F. and Glaser. T. (1993) Subchronic treatment with anxiolytic doses of the 5-HT,, receptor agonist ipsapirone does not affect 5-HTz receptor sensitivity in the rat. Eur. J. Pharmac. 231: 395-406. Beckett, S. R. G., Lawrence, A. J., Marsden, C. A. and Marshall. P. W. (1992) Attenuation ofchemically induced defense response of 5-HT, receptor agonists administered into the periaqueductal gray. P.svchophurmacolog~ 108: 110-l 14. Beer, B., Chasin, M., Clody, D. E., Vogel, J. R. and Horovitz. Z. P. (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety. Science 176: 42X-430. Benjamin, D., Lal, H. and Meyerson. L. R. (1990) The effects of 5-HT,, characterizing agents in the elevated plus-maze. Li/k Sci. 47: 195-203. Benjamin, D., Saiff, E. I., Nevins, T. and Lal, H. (1992) Mianserin-induced 5-HT1 receptor downregulation results in anxiolytic effects in the elevated plus-maze test. Drug Der. Rex. 26: 287-297. Benton, D. and Nastiti, K. (1988) The influence of psychotropic drugs on the ultrasonic calling of mouse pups. Psychopharmacology
95: 99-l 02.
Berendsen, H. H. G. and Broekkamp, C. L. E. (1990) Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. Br. J. Pharmac. 101: 667-673. Bickerdike, M. J., Fletcher, A. and Marsden, C. A. (1993) CCK-induced anxiety in rats on the elevated X-maze can be antagonised by (+)WAY100135, a 5HT,, receptor antagonist. Sot. Neurosci. Ahstr. 19: 173. Bill, D. J., Fletcher, A. and Knight, M. (1989) Actions of 5-HT,, ligands and standard anxiolytics on mouse exploratory behaviour in a two-compartment light: dark arena. Br. J. Pharmac. 98 (Suppl.): 679P. Bill, D. J., Fletcher, A., Glenn, B. D. and Knight. M. (1991) Behavioural effects of WAY 100289, a novel 5-HT3 receptor antagonist, in two animal models of anxiety. In: SEROTONIN 1991, 5-Hydrayytryptamine-CNS Receptors and Brain Function, p. 143. Birmingham, 14-17th July. Bill, D. J., Fletcher, A.. Glenn, B. D. and Knight, M. (1992) Behavioural studies on WAY 100289, a novel 5-HT? receptor antagonist, in two animal models of anxiety. E‘ur. J. Pharmac. 218: 327-334. Blackburn, T. P., Baxter. G. S., Kennett, G. A., King. F. D.. Piper. D. C., Sanger, G. J.. Thomas. D. R., Upton, N. and Wood, M. D. (1993) BRL 46470A: a highly potent, selective and long acting 5-HT? receptor antagonist with anxiolytic-like properties. Pslchopharf?luccllog~ 110: 257-264. Blakely. T. A. and Parker, L. F. (1973) The effects of parachlorophenylalanine on experimentally induced conflict behavior. Pharmuc. Biochem. Behar. 1: 609-613. Blanchard, D. C., Hori, K., Rodgers, R. J.. Hendrie. C. A. and Blanchard, R. J. (1989) Differential effects of benzodiazepines and 5-HT,A agonists on defensive patterns in wild rattus. In: Behaz,ioura/ Pharmacology of 5-HT, pp. 145-147, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Blanchard, D. C., Shepherd, J. K., Rodgers, R. J. and Blanchard. R. J. (1992) Evidence for differential effects of 8-OH-DPAT on male and female rats in the Anxiety;Defense Test Battery. P.s~~ckopharmacolog~ 106: 53 l-539.
Blanchard, R. J., Shepherd, J. K., Rodgers, R. J., Magee. L. and Blanchard. D. C. (1993) Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine. P,~~~cl~opharmac,o/og~~ 110: 245-253. Boaventura, A. M., Blaquiere, B., Palou, A. M. and Oberlander, C. (1986) Possible involvement of 5-HT,& sites in the anxiolytic response to diazepam. Neurosci. Let?. 26 (Suppl.): S278. Bodnoff, S. R., Suranyi-Cadotte, B., Aitken. D. H., Quirion, R. and Meaney. M. J. (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Ps,c,/zopllronltrco/(~g~. 95: 298-302. Bodnoff, S. R., Suranyi-Cadotte, B.. Quirion, R. and Meaney, M. J. (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacolog_v
Bolanos,
97: 277-279.
F. J., Schechter.
L. E., Miquel.
M. C., Emerit.
M. B.. Rutnigny,
J. F.. Hamon.
M. and Gozlan,
H.
5-HT-interacting
drugs
379
(1990) Common pharmacological and physicochemical properties of 5-HT, binding sites in the rat cerebral cortex and NG 108-15 clonal cells. Biochem. Pharmac. 40: 1541-1550. Borsini, F., Brambilla, A., Cesana, R. and Donetti, A. (1993) The effects of DAU 6215, a novel 5HT-3 antagonist, in animal models of anxiety. Pharmacol. Res. 27: 151-164. Bouws, G. A. H., Korte, S. M. and Bohus, B. (1991) Plasma catecholamine and corticosterone levels during active and passive coping in the conditioned defensive burying paradigm in rats; effects of ipsapirone. In: SEROTONIN 1991, 5-Hydro.yJtryptamine-CNS Receptors andBrain Function, p. 168, Birmingham, 14-17th July. Brady, L. S. and Barrett, J. E. (1985) Effects of serotonin receptor antagonists on punished responding maintained by stimulussshock termination or food presentation in squirrel monkeys. J. Pharmac. esp. Ther. 234: 106-l 12. Briley, M., Chopin, P. and Moret, C. (1990) Effects of serotonergic lesion on ‘anxious’ behaviour measured in the elevated plus-maze test in the rat. Psychopharmacology 101: 187-189. Briley, M., Chopin, P. and Moret, C. (1991) The role of serotonin in anxiety: behavioural approaches. In: Ne)b Concepts in Anxiety,. pp. 56-73, Briley, M. and File, S. E. (eds) MacMillan Press, London. Brocco, M. J., Koek, W.. Degryse, A.-D. and Colpaert, F. C. (1990) Comparative studies on the anti-punishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller-Seifter and Vogel conflict procedures. Behac. Pharmac. 1: 40334 18. Broekkamp, C. L. and Jenck, F. (1989) The relationship between various animal models of anxiety, fear-related psychiatric symptoms and response to serotonergic drugs. In: Behacioural Pharmacology of‘ 5-HT, pp. 321-335, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Brown, C. M., Kilpatrick, A. T., MacKinnon, A. C., Kenny, B. A., Broudiscou, A., Clague, R. U., Clark, R. D., Weinhardt, K. K. and Spedding, M. (1989) RS-30199. an azepine with affinity for the 5-HT,, site. Br. J. Pharmac. 98 (Suppl.): 681P. Bruinvels, A. T., Landwehrmeyer, B., Waeber, C., Palacios, J. M. and Hoyer, D. (1991) Homogeneous 5-HT,,, recognition sites in the human subtantia nigra identified with a new iodinated radioligand. Eur. J. Pharmac. 202: 89-9 1. Budhram, P., Deacon, R. and Gardner, C. R. (1986) Some putative non-sedating anxiolytics in a conditioned licking conflict. Br. J. Pharmac. 88 (Suppl.): 331P. Cadogan, A. K., Wright, 1. K.. Coombs, I., Marsden, C. A., Kendall, D. A. and Tulloch, I. (1992) Repeated paroxetine administration in the rat produces an anxiolytic profile in the elevated X-maze and decreased “H-ketanserin binding. Neurosci. Lert. 42 (Suppl.): S8. Carden, S. E. and Hoffer, M. A. (1990) Independence of benzodiazepine and opiate action in the suppression of isolation distress in rat pups. Behaz). Neurosci. 104: 160-166. Carli. M. and Samanin, R. (1988) Potential anxiolytic properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin IA receptor agonist. Ps~c,kopharn?acolog?? 94: 84-91. Carli, M., Prontera, C. and Samanin. R. (1989a) Effect of S-HTIA agonists on stress-induced deficit in open field locomotor activity of rats: evidence that this model identifies anxiolytic-like activity. Neuropharmacolog~~ 28: 47 l-476. Carli, M., Prontera, C. and Samanin, R. (1989b) Evidence that central 5-hydroxytryptaminergic neurons are involved in the anxiolytic activity of buspirone. Br. J. Pharmuc. 96: 829-836. Carli, M., Tatarczunska. E., Cervo, L. and Samanin, R. (1993) Stimulation of hippocampal 5-HT,+,-receptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat. Eur. J. Pharmac. 234: 215-221. Carlton, P. L. and Advokat, C. (1973) Attenuated habituation due to parachlorophenylalanine. Pharmacy. Biochem. Behar. 1: 6577663. Carter, R. B. and Smith, H. L. (1992) Loss of ipsapirone efficacy in the rat social interaction paradigm during diazepam withdrawal is attribuable to formation of the metabolite I-(2-pyrimidinyl)-piperazine (1-PP). In: The Role af’Serotonin in Pqchiatric Disorders. p. 44. Castres, 24-26th June. Cassella, J. V. and Davis. M. (1985) Fear-enhanced acoustic startle is not attenuated by acute or chronic imipramine treatment in rats. Ps~chopharmacolg~~ 87: 2788282. Ceulemans, D. L. S. (1985) The antagonism of serotonin receptors in the treatment of anxiety disorders. In: Proceedings of the 5th European Winter Conference on Brain Research, Vars-Les-Claux, France. Ceulemans, D. L. S., Hoppenbrouwers, M.-L. J. A., Gelders, Y. G. and Reyntjens, A. J. M. (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharnlcrcop.s~chiatr?. 18: 303-305. Chaput, Y., Lesieur, P. and de Montigny. C. (1990) Effects of short-term serotonin depletion on the efficacy of serotonin neurotransmission: electrophysiological studies in the rat central nervous system. Synapse 6: 328-337. Cheng, C. H. K., Costall, B., Kelly, M. E. and Naylor, R. J. (1992) 5-Hydroxytryptophan as an anxiogenic agent in a mouse model. In: 2nd International S_vmposium on Serotonin, ,from Cell Biologra to Pharmacologic crntl Therapeutics, p. 59, Houston, 15518th September. Chojnacka-Wojcik, E. and Przegalinski. E. (1991) Evidence for the involvement of 5-HT,* receptors in the anticonflict effect of ipsapirone in rats. N~~Ltrop/7arn7acolog~,30: 7033709. Chopin, P. and Briley, M. (1987) Animal models of anxiety: the effect of compounds that modify serotonergic function. TIPS 8: 383-388.
380
G. Griebel
Clarke, A. and File, S. E. (1982) Effects of ACTH. benzodiazepines and 5-HT antagonists on escape from periaqueductal grey stimulation in the rat. f’rog. N[,rtro-P.rr~r.hop/~rrr-nlnc,. hiol. P.s~~chirr/. 6: 27-35. Colpaert, F. C., Meert. T. F., Niemegeers. C. J. E. and Janssen. P. A. J. (1985) Behavioural and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rats. P.s~~c~/70~~~/7~7’~7~7~7~.~7/0~~~ 86: 45-54. Colpaert, F. C., Koek, W., Lehmann, J.. Rivand. J.-M., Lejeune. F., Canton. H.. Bervoets. K., Millan, M. J.. Laubie, M. and Lavielle, G. (1992) S 14506: a novel, potent. high-efficacy 5-HT I4 agonist and potential anxiolytic agent. Drug DEP. Rrs. 26: 21-48. Commissaris. R. L. and Rech, R. H. (1982) Interactions of metergoline with diazepam, quipaLine. and hallucinogenic drugs on a conflict behavior in the rat. P.s~~c~hr~~7/7n~7r7trc~o/og~~ 76: 2X2 285. Conn, P. J. and Sanders-Bush. E. (1986) Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HTz binding site. J. Nrurmci. 6: 3669%3675. Conner, R. L., Stalk, J. M.. Barchas, J. D. and Levine, S. (1970) Parachlorophenylalanine and habituation to repetitive auditory startle stimuli in rats. Phyriol. RCIINI.. 5: I7 I5 I21 9. Cook. L. and Davidson, A. B. (1973) Effects ot behaviorally active drugs in a conflict punishment procedure in rats. In: Tl7~ Benzodia~~~pirws. pp. 379-404. Garattini. S., Mussini, E. and Randall, L. 0. (eds) Raven Press. New York. Cook, L. and Sepinwall. J. (1975a) Psychopharmacological parameters of emotion. In: E771otiom Tlwir Paramrtm~ md Meusuremmt, pp. 379-404, Levi, L. (ed.) Raven Press. New York. Cook. L. and Sepinwall, J. (1975b) Behavloural analysis of the effects and mechanisms of action ol benzodiazepines. In: Mrchanisn7s of’f’A~~tio77sof Bc77loditr_cpir7c~.s.pp. I-28. Costa. E. and Greengard. P. (eds) Raven Press, New York. Costall, B. and Naylor, R. J. (1991) Anxiolytic effects of S-HT; antagonists in animals. In: 5.HT, , Agotri.sr.s, 5-HT, Antagoni.stsand Benzodiazcpines, Tlwir Cornpclrrrtirc Brlrtrr~iourc~l Pl7r7rt~7~7r~oln~~~. pp. I 33 I 5X, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Costall, B., Domeney, A. M., Hendrie. C. A., Kelly. M. E.. Naylor, R. J. and Tyers. M. B. ( IY87a) The anxiolytic activity of GR38032F in the mouse and marmoset. BK .J. P/INI.I~~u~~. 90 (Suppl.): 257P. Costall, B., Domeney. A. M., Kelly, M. E.. Naylor. R. J. and Tyers. M. B. (1987b) The behavioural consequences of treatment with selective 5-HT? receptor antagonists. Br. J. Pl7crrr77rrc.92 (SuppI.): 657P. Costall, B., Domeney, A. M., Gerrard, P. A., Kelly. M. E. and Naylor. R. J. ( 19XXa)Zacopride: anxiolytic profile in rodent and primate models of anxiety. J. Phm. P/7crm7trc~. 40: 302 305. Costall, B.. Domeney, A. M.. Gerrard, P. A.. Kelly. M. E., Naylor. R. J. md Tyers. M. B. (19XXb) Effect> ol the 5-HT receptor antagonists GR38032F. ICS205-930 and BRL43694 in tests for anxiolytic activity. Br. .J. Plxfrffxx. 93 (Suppl.): 195P. Costall. B., Domeney, A. M., Gerrard. P. A. and Naylor, R. J. (19XXc) A primate model for the assessment of anxiolytic drug action. Br. J. Phormac~. 95 (Suppl.): 475P. Costall, B.. Kelly, M. E.. Naylor. R. J. and Onaivi. E. S. (198Xd) Actions of buspirone in a putative model 01 anxiety in the mouse. J. Pharrt7. Pharmrrc. 40: 4944500. Costall. B., Naylor. R. J. and Tyers, M. B. ( 19XXe) Recent advances in the neuropharmacology of5-HT,agonists and antagonists. Rev. ;Veurosci. 2: 41 65. Costall. B., Domeney. A. M., Gerrard. P. A.. Jones. B. J.. Kelly, M. E.. Oakley. N. R. and Tyers. M. B. ( I9X9a) The anxiolytic activities of the S-HT, receptor antagonists GR38032F. ICS 305-930 and BRL 43694. In: Bchriowtrl Phrrrrwucolog~~of 5-HT. pp. 3X3--3X7. Beban. P.. Cools. A. R. and Ai-chcr. T. (eds) Erlbaum. Hillsdale. Costall. B.. Jones, B. 3.. Kelly. M. E.. Naylor. R. J. and Tomkins, D. M. (lOX9b) Exploration of mice in a black and white test box: validation as a model of anxiety. Pi7ur777nc. Biwi7tv7~. Bchw. 32: 777 7X5. Costall. B., Kelly, M. E.. Naylor. R. J.. Onaivi. E. S. and Tyers. M. B. (lYX9c) Neuroanatomical sites of action of 5-HT, receptor agonist and antagonists for alteration of aversive behaviour in the mouse. By. .J. Plrrrrn7ur 96: 325-332. Costall. B., Domeney, A. M., Kelly. M. E.. Martinez. L.. Naylor. R. J. and Farre. A. J. (l99la) Anxiolytic-like activity in the rat. mouse and monkey of E-4413. a new 5-HT IA receptor ligand. In: SEROTOh’/N /WI, 5-H!~dro.x!~tr!~ptan~ine-CNS Receptors m7d Bruit7 Fw7c~ttot7. Birmingham. p. 141. 14-17th July. Costall. B.. Kelly. M. E.. Naylor, R. J. and Tyer\, M. B. (1991 b) The profile of action of GR68755: a novel 5-HT, receptor antagonist in a mouse model of anxiety. In: SERO7‘0,YIS /WI. 5-H., (/1.o\l./lll.l)7l/)77;)7(,-~‘~~.S Rrwptor.s md Brain Function. Birmingham. p. 144. 14 17th July. Costall. B.. Domeney. A. M., Farre. A. J., Kelly. M. E.. Martine/. L. and Naklor. R. J. (199%) Profile ofaction IAreceptor ligand E-4424 to inhibit aversive behavior in the mouse. rat and of a novel 5-hydroxytryptamine marmoset. 1. Phurmnc. c.up. T/w. 262: 90 9X. Costall, B., Domeney, A. M.. Kelly, M. E. and Naylor. R. J. (l992b) Intlucnce of 5-HT on cognitive performance. In: Serotonin. CNS Rewptor.~ n77d Brnir7 F7o7ctio77. pp. 147 104. Bradley. P. B.. Handlcy, S. J., Cooper. S. J., Key, B. J.. Barnes. N. M. and Coote. J. H. (eds) Pergamon Presa. Oxford. Costall, B., Domeney, A. M., Kelly, M. E.. Tomkins, D. M.. Naylor. R. J., Wong, E. H. F., Smith. W. L., Whiting, R. L. and Eglen, R. M. (1993) The effect ofthe 5-HT: receptor antagonist. RS-4235X-197. in animal models of anxiety. Eur. .J. Pharmu. 234: 91-99. Costello, N. L., Carlson. J. N. and Glick. S. D. (199la) Acute ~ldministration of d~axpam and busplrone in
5-HT-interacting
drugs
381
rats trained on conflict schedules having different degrees of predictability. Plinmznc. Biochenz. Behm. 40: 787-794. Costello, N. L.. Carlson, J. N., Glick, S. D. and Bryda, M. ( 199 I b) The effects of acute administration of gepirone in rats trained on conflict schedules having different degrees of predictability. Pharmac. Biochem. Behm. 40: 795-800.
Craft, R. M., Howard, J. L. and Pollard, G. T. (1988) Conditioned defensive burying as a model for identifying anxiolytics. Pharrmc. Biocirem. Behat>. 30: 775-780. Critchley, M. A. E. and Handley. S. L. (1986) Anxiogenic-like effects of three 5-HT agonists. Ps~~~i~ophamlcrcolog~~ 89: S56.
Critchley. M. A. E and Handley, S. L. (1987) Effects in the X-maze model of agents acting at 5-HT, and 5-HT, receptors. P.s~‘c~hopilcrrnzn~ol~)g~93: 502-506. Critchley, M. A. E.. Njung’e, K. and Handley, S. L. (1987) 5-HT ligand effects in the social interaction test of anxiety. Br. J. Phrwnz~~c. 92 (Suppl.): 660P. Critchley, M. A. E.. Njung’e. K. and Handley, S. L. (1988) Prevention of 8-OH-DPAT anxiogenic effect by ipsapirone and by 5-HT, antagonist b-adrenoceptor antagonists. Br. .I. Phrrrtncrc. 94 (Suppl.): 389P. Critchley, M. A. E., Njung’e, K. and Handley. S. L. (1992) Actions and some interactions of 5-HT,, ligands in the elevated X-maze and effects of dorsal raphe lesions. P.s~~~ilopiznmlacolog? 106: 484-490. Crow, T. J. and Deakin. J. F. W. (1981) Affective change and the mechanism of reward and punishment: a neuro-hormonal hypothesis. In: Der~elopments in P.yhiatry, Vol. 5, pp. 536-541, Perris. G., Struwe, G. and Jansson. B. (eds) Amsterdam. Elsevier. Curle. P. F., Guardiola. B.. Renard, P. and Vitte, P.-A. (1991) Anxiolytic-like activity of (+-) S 20244 in the elevated plus maze test in rat. In: SEROTONIN 1991, 5-h~drosytr~~ptarnine-CNS Receptors ad Bruin Fuwtiotl. p. 139, Birmingham. l4-17th July. Cutler. M. G. (1990) Behavioural effects in gerbils of the 5-HT, receptor antagonists, BRL 43694 and ICS 205-930, under circumstances of high and low light intensity. Neuropiznrnlncok,g~, 29: 5 15520. Cutler, M. G. (199la) An ethological study of the effects of buspirone and the 5-HT, receptor antagonist. BRL 43694 (granisetron) on behaviour during social interactions in female and male mice. NeuropilLlnllaco/og~, 30: 2999306. Cutler, M. G. (1991 b) Effects of social environment on the behavioural responses by mice to the 5-HT, receptor antagonist, granisetron (BRL 43694). Br. J. Phnrwm~. 102 (Suppl.): 254P. Cutler, M. G. and Dixon, A. K. (1989) Effects ofthe 5-HT, antagonist. ICS 205-930, on behaviour ofmice during social encounters. Br. J. Pharnmc~. 96 (Suppl.): 12P. Cutler, M. G. and Piper, D. C. (1990) Chronic administration of the 5-HT, receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil. P.s~~izopizrrmzu~o/og~.101: 2446249. Da Prada. M.. Keller. H. H., Burkard, W. P., Schaffner, R., Bonetti. E. P., Launay, J. M. and Haefely, W. (19X2) Some neuropharmacological effects of Ro 1l-2465 - A novel tricyclic antidepressant with potent inhibitory activity on the uptake of 5-HT. In: T~~picularui At.vpicni Allti~~~prc.sJ(1nt.r:Moleculcu Mcdzmi.snzs. pp. 235.-248. Costa, E. and Racagni, G. (eds) Raven Press, New York. Da Roza Davis, J. M.. Sharpley. A. L. and Cowen, P. J. (1992) Slow wave sleep and 5-HT? receptor sensitivity in generalized anxiety disorder: a pilot study with ritanserin. P.s~‘(.i~opiz~lrt)~n~.oio,~~, 108: 387-389. Davis. M. (1988) The potentiated startle response as a measure of conditioned fear and its relevance to the neurobiology of anxiety. In: Atlirmi Models irz P.s~~c~hiatric~ Di.sor&r.s, Vol. I, pp. 61 ~89. Simon, P.. Soubrie. P. and Wiedlocher. D. (eds) Karger, Basel. Davis. M. (1993) Pharmacological analysis of fear-potentiated startle. Brrrr. .I. Med. hiol. Rcs. 26: 735mm260. Davis. M. and Sheard. M. H. (1976) p-Chloroamphetamine (PCA): acute and chronic effects on habituation and sensitization of the acoustic startle response in rats. Eur. J. Phtrvmnc. 35: 261-273. Davis, M.. Redmond. D. E. and Baraban, J. M. (1979) Noradrenergic agonists and antagonists: effects on conditioned fear as measured by the potentiated startle paradigm. P~s~.(.izopii”r”?~~~,~~/~~~~~, 65: I I Ill 18. Davis. M., Astrachan, D. I.. Gendelman, P. M. and Gendelman. D. S. (1980a) 5-Methoxy-N.IY-dimethyltryptamine: spinal cord and brainstem mediation ofexcitatory effects on acoustic startle. P.s~,c,hophcrrr,7rrl~oio,~~, 70: 123-l 30.
Davis. M.. Astrachan. D. I. and Kass, E. (1980b) Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle. .%ierzc,r 209: 521-523. Davis. M.. Cassella. J. V., Wrean, W. H. and Kehne, J. H. (1986) Serotonin receptor subtype agonists: differential reactivity measured with acoustic startle. P.s~.c.ilopirclr~l2cr(.. Bull. 22: 837-843. Davis. M., Cassella. J. V. and Kehne. J. H. (1988a) Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone. P.s~~c~i~~/li~~~~~~~t~.~~i~~g~~ 94: 14-20.
Davis. M.. Hitchcock. J. M. and Rosen, J. B. (1988b) Anxiety and the amygdala: pharmacological and anatomical analysis of the fear-potentiated startle paradigm. In: The P.s~~cho/og~~ o/‘Lenrr?iug md Motirwtiou. Vol. 21. pp. 263-305. Bower. G. H. (ed.) Academic Press, New York. Deacon. R. and Gardner. C. R. (1986) Benzodiazepines and 5-HT ligands in a rat conflict test. Br. ,I. Phclrwrrc. 88 (SuppI.): 33OP. De Angelis. L. (1992) The nootropic drugs piracetam and oxiracetam do not reduce anxiety in mice during elevated-X-maze testing. C‘rrrr. Ther. Res. 52: 230-237.
382
G. Griebel
Den Boer, J. A. and Westenberg, H. G. M. (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Ps,rchopharmacolog~ 102: 85594. De Vry, J.. Glaser, T., Schuurman, T.. Schreiber, R. and Traber, J. (1991) S-HTIA receptors in anxiety. In: Near Conceprs in An.uief~~, pp. 94-129, Briley, M. and File, S. E. (eds) MacMillan Press, London. Doble, A., Allam, D., Blanchard, J. C., Boireau, A., Comte, M. T., Farges, G., Ferris, O., Gueremy, C., Laduron, P. M., Malleron, J. L., Perrier, M. L. and Zundel, J. L. (1990) RP 62203, a novel naphtosultam derivative with potent and selective 5-HTz antagonist properties: I. Binding and second messenger studies. Eur. J. Pharmac. 183: 1744. Dunn, R. W., Corbett. R. and Fielding, S. (1989) Effects of 5-HTI,b receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur. J. Pharmuc. 169: I-10. Dunn, R. W., Corbett, R., Hubbard, J. W., Tobiasz, P., Nordstrom, L. C., Carlezon, W. A., Cornfield. M. L. and Fielding, S. (1990) The preclinical anxiolytic profiles of the 5-HT, antagonists ondansetron, zacopride and MDL-72222. FASEB J. 4: A812. Dunn, R. W., Carlezon, W. A. and Corbett, R. (1991) Preclinical anxiolytic versus antipsychotic profiles of the 5-HTI antagonists ondansetron, zacopride, 3a-tropanyl-lH-indole-3-carboxylic acid ester, and IcrH. 3a, 5?H-tropan-3-yl-3,5-dichlorobenzoate. Drug Dev. Res. 23: 289-300. Durel, L. A., Krantz, D. S. and Barrett, J. E. (1986) The antianxiety effect of beta-blockers on punished responding. Pharmac. Biochem. Behac. 25: 371-374. Dwyer, K. D. and Roy. E. J. (1993) Juvenile desipramine reduces adult sensitivity to imipramine in two behavioral test. Phurmac. B&hem Behar 45: 20 I-207. Egawa, M., Abe, M., Tabata, R., Saito, K.-I., Tobe, A.. Matsuda, T. and Baba, A. (1993) Pharmacological effects of MKC-242: a novel potential anxiolytic and antidepressant compound with selective 5-HT,, agonistic profile. Sot,. Neurosci. Ahstr. 19: 1243. Eison. A. S., Eison, M. S., Stanley, M. and Ribland. S. A. (1986) Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmnc. Biochem. Behav. 24: 7OlL707. Ellison, G. D. (1977) Animal models of psychopathology. The low-norepinephrine and low-serotonin rat. Am. Pswhol.
32: 1036-1045.
Engel. G.. Gothert, M.. Hoyer, D.. Schhcker. E. and Hillenbrand, K. (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT,u binding sites. Naun~n-S~,hnlierb~,rg’s Arch. Pharmac. 332: l-7. Engel. J. A., Hjorth, S.. Svensson. K., Carlsson, A. and Liljequist, S. (1984) Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetrahn (X-OH-DPAT). Eur. J. Pharmac. 105: 3655368. Erwin, G. N.. Soroko, F. S. and Cooper, B. R. (1987) Buspirone antagonizes the expression of conditioned taste aversion in rats. Drug Der. Res. 11: 87-95. Fechter, L. D. (1974) Central serotonin involvement in the elaboration of the startle reaction in rats. Phnrmnc. Biochem. Behar. 2: 161&171. Fernindez-Guasti. A. and Hong. E. (1989) Antianxiety effect of various putative 5-HT, receptor agonists on the conditioned defensive burying paradigm. In: Behdourul Phnrmacolog_v qf’5-HT. pp. 3777382, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Fernandez-Guasti, A. and Lopez-Rubalcava, C. (1990) Evidence for the involvement of the 5-HT14 receptor in the anxiolytic action of indorenate and ipsapirone. Ps~ehop/zarmac,o/og~’ 101: 354-358. Fernandez-Guasti, A. and Lopez-Rubalcava, C. (1992) Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics. In: The Role of Serotonin in Ps>,chiurrk Disorders. p. 49. Castres. 24-26th June. Fernandez-Guasti. A.. Hong, E. and Lopez-Rubalcava, C. (1992a) Speciesdifferences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action. P.s~~c~hophcrrnzac~)l~~g~~ 107: 6 l-67.
Fernandez-Guasti, A., Lopez-Rubalcava, C., Perez-Urizar, J. and Castaiieda-Hernindez. G. (1992b) Evidence for a postsynaptic action of the serotonergic anxiolytics: ipsapirone, indorenate and buspirone. Brain Rex. Bull. 28: 497 -501. File, S. E. (1981) Behavioural effects of serotonin depletion. In: Metabolic, Disorders qf the Nerwus SJ’.stem. pp. 429-445, Rose. F. C. (ed.) Pitman. London. File, S. E. (1984a) The validation of animal tests of anxiety-pharmacological implications. PO/. J. Phrrrmnc. Phnrm.
36: 505-5
12.
File, S. E. (1984b) The neurochemistry of anxiety. In: Drugs in Psychiatry,. Norman. T. and Davies, B. (eds) Elsevier, Amsterdam. File, S. E. (1985) Animal models for predicting clinical efficacy
Vol. 2, pp. I3 -30, Burrows, of
anxiolytic:
social
G. D..
behaviour.
Neurop.s!~chobiolog~~ 13: 55-62.
File. S. E. (1990) Preclinical studies of the mechanisms of anxiety and its treatment. In: Neurobio/og>, qf’Puni( Di.sorder, pp. 31 --48, Ballenger, J. C. (ed.) Liss, New York. File, S. E. and Andrews. N. (1991) Low but not high doses of buspirone reduce the anxiogenic effects ofdiazepam withdrawal. P~~,‘,lzc’~/?crrnl~~~~~/(~g~, 105: 578-582. File, S. E. and Andrews. N. (I 993) Enhanced anxiolytic effect of zacopride enantiomers in diazepam-withdrawn rats. Eur. J. Phurmac. 237: 127-l 30.
5-HT-interacting
drugs
383
File, S. E. and Hyde, J. R. G. (1977) The effects of p-chlorophenylalanine and ethanolamine-o-sulphate in an animal test of anxiety. J. Pharm. Pharmac. 29: 7355738. File, S. E. and Johnston, A. L. (1989) Lack of effects of 5-HT, receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat. Psvchopharmacology 99: 24825 1. File. S. E. and Mabbutt, P. S. (1991) Effects of tianeptine in animal models of anxiety and on learning and memory. Drug Det’. Res. 23: 47-56. File, S. E., Hyde, J. R. G. and McLeod, N. K. (1979) 5,7_Dihydroxytryptamine lesions of dorsal and median raphe nuclei and performance in the social interaction test of anxiety and in a home-cage aggression test. J. &j%ct. Dis. 1: 115-122. File, S. E., Johnston, A. L. and Pellow. S. (1987) Effects of compounds acting at CNS 5-hydroxytryptamine systems on anxiety in the rat. Br. J. Pharmac. 90 (Suppl.): 265P. Fletcher, A., Bill, D. J., Bill, S. J., Brammer, N. T., Cliffe, I. A., Forster, E. A., Reily, Y. and Lloyd. G. K. (1991) WAY 100135: a novel and highly selective 5-HT,, receptor antagonist. Sot. Neurosci. Abrtr. 17: 92. Fletcher, A., Bill, D. J., Cliffe, I. A.. Forster, E. A., Hartley, J. and Dourish, C. T. (1992) Behavioral profile of the enantiomers of the selective 5-HT,, antagonist WAY 100135. In: 2nd International Symposium on SEROTONIN, from Cell Biolog,v to Pharmacology and Therapeutics, p. 30, Houston, 1S-1 8th September. Fletcher, P. J. and Davies, M. (1990) Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142. Psvchopharmacologv 102: 301-308. Fontana, D. J. and Commissaris, R. L. (1988) Effects of acute and chronic imipramine administration on conflict behavior in the rat: a potential ‘animal model’ for study of panic disorder? Ps.v~hopllarnla~f~/og~, 95: 147-l 50. Fontana, D. J., Carbary, T. J. and Commissaris, R. L. (1989) Effects of acute and chronic anti-panic drug administration on conflict behavior in the rat. Psychopharmacofogv 98: 157- 162. Fontana. D. J., Wong, E. H. F., Kilfoil, T. and Eglen, R. M. (1992) A behavioral analysis of RS-42358-197, a novel 5-HTI receptor antagonist, suggests a selective anxiolytic action. In: 2nd Interna/iona/ Symposium on SEROTONIN,,from Cell Biology to Pharmacology and Therapeutics. p. 59, Houston, 15-18th September. Fontana, D. J., Henderson, C. A., Daniels, S., Nunes, J., Wong, E. H. F., Whiting. R. L. and Eglen. R. M. (1993) Behavioral profile of(R) and (S) RS-56812, novel 5-HT, receptor antagonists with cognition-enhancing properties. Sot. Neurosci. Abstr. 19: 1234. Foreman, M. M., Fuller, R. W., Leander, J. D., Benvenga, M. J., Wong, D. T.. Nelson. D. L.. Calligaro. D. 0.. Swanson, S. P., Lucot, J. B. and Flaugh, M. E. (1993) Preclinical studies on LY228729 - a potent and selective serotonin,, agonist. 1. Pharmac. e.up. Ther. 267: 58-71. Fuller, R. W., Wong, D. T. and Robertson, D. W. (1991) Fluoxetine, a selective inhibitor of serotonin uptake. Med. Res. Rer. 11: 17-34. Gacsalyi, I., Gyertyin, I., Kapolnai, L.. Somogyi, 8. and Gigler, G. (1991) Serotonin antagonistic activity of a novel putative anxiolytic agent EGIS-3886. In: SEROTONIN 1991, 5-H~~dro.u!~trvptamine-CNS Receptors and Brain Function, p. 142, Birmingham, 14-17th July. Galizio, M., Journey, J. W., Royal, S. A. and Welker, J. A. (1990) Variable-interval schedules of timeout from avoidance: effects of anxiolytic and antipsychotic drugs in rats. Pharmac. Biochem. Behar. 37: 2355238. Galizio, M., Hale, K. L., Liborio, M. 0. and Miller, M. (1993) Variable-ratio schedules of timeout from avoidance: effects of anxiolytic drugs. Behat>. Pharmac. 4: 487-494. Gao, B. and Cutler, M. G. (1992a) Effects of sub-chronic treatment with chlordiazepoxide, buspirone and the 5-HT, receptor antagonist, BRL 46470, on the social behaviour of mice. Neuropllrcrrnaccl/og~ 31: 2077213. Gao, B. and Cutler, M. G. (1992b) Effects of acute administration of the 5-HT, receptor antagonist, BRL 46470A, on the behaviour of mice in a two compartment light-dark box and during social interactions in their home cage and an unfamiliar neutral cage. Neuropharmacologv 31: 7433748. Gao, B. and Cutler, M. G. (1992~) Effects of acute and subchronic administration of propranolol on the social behaviour of mice; an ethopharmacological study. Neuropharmacologl~ 31: 749-756. Gao, B. and Cutler, M. G. (1993a) Effects of acute and subchronic administration of ritanserin on the social behaviour of mice. Neuropharmacoiog~~ 32: 2655272. Gao, B. and Cutler, M. G. (1993b) Effects of chlordiazepoxide, buspirone and the 5-HT, receptor antagonist. BRL 46470, on the behaviour of oestrous and dioestrous female mice when encountering male partners, Neuropharmacolog_v 32: 969-975. Gardner, C. R. (1985a) Distress vocalisations in rat pups: a simple screening method for anxiolytic drugs, J. Pharmac. Meth. 14: 181-187. Gardner, C. R. (1985b) Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxide and diazepam. Drug. Der. Res. 5: 1855193. Gardner, C. R. (1985~) Pharmacological studies of the role of serotonin in animal models of anxiety. In: Neuropharnzacolog~ of Serotonin, pp. 281-325. Green, A. R. (ed.) Oxford University Press, Oxford. Gardner, C. R. (1986) Recent developments in SHT-related pharmacology of animal models of anxiety, Pharmac. Biochem. Behar. 24: 147991485. Geller, I. and Blum. K. (1970) The effects of 5-HTP on parachlorophenylalanine (P-CPA) attenuation ofconflict behavior. Eur. J. Pharmac,. 9: 319-324. Geller, I. and Hartmann, R. J. (1982) Effects of buspirone on operant behaviour of laboratory rats and cynomolgus monkeys. J. c/in. Psvchiar. 43: 25-32. Geller, I.. Hartmann, R. J. and Croy, D. J. (1974) Attenuation ofconflict behaviour with cinanserin. a serotonin
384
G. Griebel
antagonist: reversal of the effect with 5hydroxytryptophan and -methyltryptamine. Res. Conumu~. C’/ICW. Par/ml. Pharmacy. 7: 165-l 74. Germine. M.. Goddard, A. W., Woods. S. W.. Charney. D. S. and Heninger. G. R. (1992) Anger and anxiety responses to r)t-chlorophenylpiperazine in generalized anxiety disorder. Biol. Ps)diur. 32: 457~ 461. Geyer, M. A.. Warbritton, J. D., Menkes. D. B., Zook. J. A. and Mandell, A. J. (1975) Opposite effects o! intraventricular serotonin and bufotenin on rat startle responses. Plzarmac~. Biodwm. Be/m. 3: 687.~691. Geyer. M. A., Petersen. L. R. and Rose, G. J. (1980) Effects of serotonergic lesions on investigatory responding by rats in a holeboard. Behcw. Nwral Bid. 30: 16OGl77. Gibson, L., Barnfield, A. and Curzon. G. ( 1991) Erect of chronic diaLepatn on hippocampal dialysate 5-HT and subsequent anxiogenic response to mCPP. In: SEROTONIN IY9l. 5-H1,dro.ul.t~~pfrlrnir7e-C’.Y.S R~wpto~s cd Braitz Furzc~fior~,p. 134, Birmingham. 14--l 7th July. Giesecke. M. E. (1990) Overcoming hypersensitivity to fluoxetine in a patient wtth panic disorder. ,4rtt. /. P.s,dIiar. 147: 532-533. Gleeson. S. and Barrett. J. E. (1990) S-HT,,, agonist effects on punished responding of squirrel monkeys. P/~riwm~. Biod1~w7. Be/w. 37: 335 337. Gleeson. S.. Ahlers. S. T.. Mansbach, R. S.. Faust. J. M. and Barrett, J. E. (IYXY) Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes. J. Plwnmc~. c.~p. T/w. 250: 809 -8 I I. Glenn. B. and Green. S. (1989) Anxiolytic profile of GR 3X032F in the potentiated startle paradigm. Bclttrr,. P/tarntrrc,. I: 9 l&94. Goldberg. M. E., Manian. A. A. and Efron. D. H. (1967) .4 comparative study of certain pharmacological responses following acute and chronic administration of chlordiazepoxide. Life Gi. 6: 48 I 49 I. Goldberg. M. E.. Salama, A. I.. Patel. J. B. and Malick. J. B. (19X3) Novel non-benzodiaLepine anxiolytics. Nt~ltrop/lril~,~lfl~~~~/~J~~~~ 22: 1499 I 504. Gorman. A. L. and Dunn. A. J. (1993) Beta-adrencrgic receptors are involved in stress-related behavioral changes. P/I~I~~ILI~.Bioc~het~~.BcJ/Ju~..45: I 7. Gortnan, J. M., Liebowitz. M. R., Fyer. A. J.. Goetz. D., Campeas. R. B.. Fyer. M. R.. Davies. S. 0. and Klein, D. F. (1987) An open trial of fluoxetine in the treatment of panic attacks. .l. c,/ir~. P.,~,c,ho~~hcrr-r~~~~(,. 7: 329-333. Gower. A. J. and Tricklebank, M. D. (19X8) Alpha?-adrenoceptor antagonist activity may account for the efccccts of buspirone in an anticonflict test in rat. Gdr. J. Phrrrtnc~c~. 155: I29 137. Go7lan. H.. El Mestikawy. S.. Pichat. A., Glowinski, J. and Hatnon. M. (1983) Identification of presynaptic serotonin autoreceptors using a new ligand [‘HI-PAT. Ncrttrrc, 305: l40& 142. Graeff. F. G. (1974) Tryptatninergic antagonists and punished behavior. J. Pl7trrnuc~. CY/J. T/w. 189: 344- 350. Grael’C F. G. (1988) Anitnal models ofaversion. In: ~I/til~t(~/;\4orl~~/.sof P.\:l,c/~iu/ric,Disorr/c~r.c.Vol. I. pp. I I5 I4 I. Simon. P.. Soubrik. P. and Wiedlocher. D. (eds) Karger, Base]. GraelT. F. G. and Schoenfeld, R. I. (1970) Tryptatninergic mechanisms in punished and nonpunished behaviour. J. Phrtwc. o.Y/~. Thu. 173: 777 2X3. Grae& F. G.. Brandzo, M. L.. Audi. E. A. and Schlitz. M. T. B. (1986) Modulation ofthe brain aversive system by GABAergic and serotonergic mechanisms. Bclrur. Bruin Rev. 21: 65-72. Graeff. F. G., Audi. E. A., Almeida. S. S.. Graeff, E. 0. and HunLiker, H. L. (1990) Behavioral effects of 5-HT receptor ligatnds in the aversive brain stimulation, elevated plus-maze and learned helplessness tests. ,Vc,uro.,c,i. Biohch~. Rcr 14: SOlm~506. Graeff. F. G.. Russo. A. S., Guitnliraes. F. S. and Audi. E. A. (IY91) Effect of anxiolytics tnicroinjecled tnto the periaqueductal grey in (he elevated plus-mare. In: SEROTONIN 199 I. 5-lf~~~/ro.\-~,tr~~/~/~/~~~~~~~~-~’,~’~~ Rcwptor,\ md Barrio Fur~c~tim, p. I 17. Birmingham. I4 17th July. Gray, J. A. ( 1982) Prkcis of T/w ,V~,~rr-op.r!,c~/~r~/~~~~~, 0/‘.417\-icr.r: an enquiry into the functions ofseplo-hippocampal system. Bch. Bruh Sd. 5: 469- 534. Grewal. S. S.. Shepherd. J. K.. Fletcher. A., Bill. D. and Dourish. C. T. (1993) Effect of serotonergic agents in the Lero-maLe lesl of anxiety. In: Brifid~ ~-l.s.\oc~itrrio~tfor P.\:1~c~/to/~/trr,.~~7~/(~~~/~~~~~~. A 19. Cambridge. 15m2Xth July. Griebel. G. (1993) Systt;me s&otoninergiquc ct r&acti\iti &iotionnclle chez le rat et che7 la sour,>. Approche phartn~tcologiquc. Ph.D. thesis. UniversitP Louis Pasteur. Strasbourg. France. Griebel. G., Saffroy-Spittler. M., Missltn, R.. Vofcl. E. and Martin, J. R. (1990) Serenics fluprazine (DU 77716) and eltopra/ine (DU 28853) enhance neophobtc and ernolional behnviour in mice. P.,~~c~/lo/~/~trr,)~t/~~~~/~~~.~~ 102: 498-502. Griebel. Cr.. Missltn. R.. Pawlowjski. M. and Vogel. E. ( IYYI) /It-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice. NcuroReport 2: 617 62Y. Griebel. G., Misslin. R., Pawlowski. M.. Guardlola-Lemaitrc. B.. Guillaumc~. G. and Bizot-Espiard. J. (1992) Anxiolytic-like efTects of a selective 5-HT,, agonist, S20244. and its enantiomers in mice. ,VeuroRcport 3: 84_~Xh. Griebel. G.. Moreau. J.-L.. Jenck. F.. Martin. J. R. and Misslin. R. (1903) Some critical dctcrminants of the behaviour of rats in the elevated plu\-maze. Bdw. Proc~c,.s.\,29: 37 4X. Griebel. G., Moreau. J.-L.. Jenck, F.. Martin, R. and Misslin. J. R. (1994) Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate etnottonal responses in anxiety models in rodents. Ps,.c,hoplltrrnzr/~,~~/(~,~~, 1 13: 463 -470.
5-HT-interacting
drugs
385
G&, M., Alary, C., Del Rio-Lacheze, C.. Junien, J. and Buino, L. (1993) Comparative involvement of 5-HT,, 5-HT2 and 5-HT, receptors in stress-induced colonic motor alterations in rats. Eur. J. Piwrn~crc. 233: 193-199. Guy, A. P. and Gardner, C. R. (1985) Pharmacological characterization of a modified social interaction model of anxiety in the rat. N~uvop.s?,~hohiolog~, 13: 194-200. Hagan, R. M.. Oakley. N. R., Burrldge, J.. Kilpatrick, G. J. and Tyers. M. B. (1991) Effects of the 5-HT1 receptor antagonist. GR68755. in models of anxiety and raised mesolimbic dopaminergic activity in the rat. In: SEROTOiVIN 1991. 5-H~~~o.\-?,tr?~tnn?Dw-CNS Rrwptors md Bra& Function. p. 145. Birmingham. 14-l 7th July. Hamon, M., Lanfumey, L., El Mestikawy. S.. Boni. C.. Miquel, M.-M., Bolanos, F.. Schechter. L. and Gozlan. H. (1990) The main features of central 5-HT, receptors. Ps?,ci2opharnzaco/~/g~~ 103: 349~-360. Handley, S. L. (1991) Serotonin in animal models of anxiety: the importance of stimulus and response. In: Serotonirz, S/wp and Merttul Disor&r.s. pp. 89--l 15, Idzikowski, C. and Cowen, P. J. (eds) Wrightson Biomedical Publishing, Petersfield. Handley, S. L. and McBlane. J. W. (1991) 5-HT ~ the disengaging transmitter’?J. P.s~~c~hop/~rrt.r~~~(.. 5: 322 326. Handley, S. L. and McBlane. J. W. (1992) Opposite effects of Auoxetine in two animal models of anxiety. Br. J. Phrmm. 107 (Suppl.): 446P. Handley, S. L. and McBlane, J. W. (1993a) 5HT drugs in animal models of anxiety. Ps~~~~l~o~/7~11.1~1~1~~010,~~~ 112: 13 -20. Handley, S. L. and McBlane, J. W. (1993b) An assessment of the elevated X-maze for studying anxiety and anxiety-modulating drugs. J. Phnrnmc. Touir. Met/z. 29: 129-138. Handley. S. L. and McBlane. J. W. (1993~) Serotonin mechanisms in animal models of anxiety. Brrr:. J. Mu/. Bid. Rex. 26: l-13. Hird, E. and Engel, J. (1988) EfTects of 8-OH-DPAT on ultrasonic vocalization and audiogenic immobility reaction in pre-weaning rats. Nrlrrop/lnrr,lncolg.~ 27: 981-986. Hfird, E.. Engel. J. and Musi. B. (1982) The ontogeny of defensive reactions in the rat: influence of the monoamine transmission systems. Scatztl. J. P.syho/. 1 (Suppl.): 90-96. Hartig, P. (1989) Molecular biology of 5-HT receptors. TIPS 10: 64-69. Hartmann. R. J. and Geller, I. (198 1) Effects of buspirone on conflict behaviour of laboratory rats and monkeys. Ptw. b’e.ct Phurrnac. Sot. 24: 179- 18 1. Hascott. M.. Bourin. M. and Bradwejn, J. (1992) The anti-conflict effect of drugs acting on serotonin system. J. Ps,~c~ltopita~n~(~r,.6: 129. Haskins, J. T.. Moyer. J. A., Andree, T. H.. Muth, E. A. and Abou-Gharbia, M. (1989) Preclinical profile of the pyrimidinylpiperazinyl imide compound WY-47,846: a potential anxiolytic. Drug Dec.. Rc,.s. 18: Z-45. Heaton. J. C. P., Njung’e. K. and Handley. S L. (1988) Behavioural profile of I-(2.5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) a selective 5-HT, agonist. Br. J. Phcvtnw. 91 (Suppl.): 388P. Hen. R.. Boschert, U.. Lemeur. M., Dierich. A.. Ait Amora. D., Buhot, M. C., Segu L., Misslin, R. and Saudou. F. (1993) 5-HT,,, receptor ‘knock out’: pharmacological and behavioral consequences. SOC,.Ncuro.rci. Ahtr.. 19: 632. Hensman. R.. Guimaraes, F. S., Wang, M. and Deakin. J. F. W. (I 991) Effects of ritanserin on aversive classical conditioning in humans. P.s~.L./~o~/Iu~~~IL~~~~~/~~~~~. 104: 220-224. Heuring. R. E., Schlegel. R. J. and Peroutka. S. J. (1987) Species variations in RU 24969 interactions with non-5-HT,, binding sites. Eur. J. Pi~arrmc. 122: X%282. Heym. J.. Mena. E. E. and Seymour, P. A. (1987) SM-3997: a non-benzodiazepine anxiolytic with potent and selective effects on neurotransmission. Sot. Ncrtro.sc,i. Ahstr-. 13: 455. Hibert. M. and Moser. P. (1990) MDL 77837 and MDL 73005EF: novel, potent and selective 5-HT,, receptor ligands with different pharmacological properties. Drugs Fur. 15: 159- 170. Higgins. G. A., Jones. N. R. and Oakley, N. R. (1987) Compounds selective for the j-HT,* receptors have anxiolytic effects when injected into the dorsal raphe nucleus of the rat. Br. J. Pi7nrn~u~. 90 (Suppl.): 65XP. Higgins. G. A.. Bradbury. A. J., Jones. B. J. and Oakley, N. R. (1988) Behavioural and biochemical consequences following activation of 5-HT,-like and GABA receptors in the dorsal raphi nucleus of the rat. Nrrr~o~/~i?r/r-r,lr[,~~~~~,~,~. 27: 993-l 00 1. Higgins. G. A., Jones. B. J., Oakley. N. R. and Tyers. M. B. (1991) Evidence that the amygdala is incoILed in the disinhibitory effects of 5-HT; receptor antagonists. P.s~~c~izopilc~r-r~lcrc~olog~~ 104: 545-55 1. Higgins. G. A.. Jones. B. J. and Oakley. N. R. (1992) Effects of 5-HT,, receptor agonists in two models ofanxiety after dorsal raphe injection. P.s~.c.ito~pi7~t,./?,ac~(~/~~g~~ 106: X-267. Hijzen, T. H., Rijnders. H. J. and Slangen. J. L. (1991) Effects ofanxiety drugs on the modification ofthe acoustic startle reflex by noise gaps. Pi~crr-nrac,. fhhf~?. Beiw. 38: 769-773. Hitchcock. J. M.. McCloskey. T. C.. Padich. R. A.. McCarty. D. R.. Dudley. M. W.. Sprouse, J. S., Freedman. J. and Kehne. J. H. (1991) Potential anxiolytic activity of 5-HT,,, partial agonists MDL 102.181 and MDL 73,005EF in animal models of anxiety sensitive to buspirone. SOC,. Nc~rrosci. Ah.str. 17: 78 1. Hjorth. S.. Stiderpalm. B. and Engel. J. A. (1987) Biphasic effect of L-5-HTP in the Vogel conflict model. ~.S~‘~~i7~JiJilfJ~JJl~l~‘O/~J~~’ 92: 96-99. Hodges. H.. Green. S. and Glenn. B. (19X7) Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination. P~?.c,hopilcr,.,lt~I(.OIOX1.92: 49lL504. HorvLith. K., Andrasi. F., Botka, P. and Hhmori. T. (1992) Anxiolytic profile of girisopam and GYKI 52 322 (EGIS 6775). Comparison with chlordiazepoxide and buspirone. Acttr pi~~~.siol. ixmg. 79: I53 161.
G. Griebel
386
Howard. J. L. and Pollard, G. T. (1990) Effects of buspirone in the GellerSeifter conflict test with incremental shock. Drug Del?. Re.s. 19: 37-49. Hoyer. D. (1988) Molecular pharmacology and biology of 5-HT,, receptors. TIPS 9: 89-94. Hoyer, D. (1991) The 5-HT receptor family. In: 5-HT, , Agonists. 5-HT, Antagonistsand Benzodkeppines, Their Con7purutir~e Bei7a7~iourui Pi7nmmcolog~. pp. 31-58, Rodgers, R. J. and Cooper. S. J. (eds) John Wiley, Chichester. Hoyer. D. and Middlemiss. D. N. (I 989) Species differences in the pharmacology of terminal 5-HT autoreceptors in mammalian brain. TIPS IO: 130~132. Hoyer. D. and Neijt, H. C. (1988) Identification of 5-HT1 recognition sites in membranes of NIE-I I5 neuroblastoma cells by radioligand binding. MO/W. Phurmuc. 33: 303-309. Hoyer, D. and Schoeffter. P. (1991) 5-HT receptors: subtypes and second messengers. J. Receptor Res. 11: 197-214. Hoyer. D.. Engel. G. and Kalkman, H. 0. (1985) Molecular pharmacology of 5-HT, and 5-HT, recognition sites in rat and pig brain membranes: radioligand binding studies with [‘HIS-HT. [‘H]X-OH-DPAT, [“‘I]iodocyanopindolol, [‘Hlmesulergine and (‘Hlketanserin. Eur. J. Pizurmuc. 118: 13-23. Hoyer, D., Pazos, A.. Probst. A. and Palacios. J. M. (1986) Serotonin receptors in the human brain II. Characterization and autoradiographic localization of 5-HT,, and S-HT, recognition sites. Brtrit7 Res. 376: 97FlO7.
Hoyer, D.. Schoeffter. P.. Waeber. stimulation of inositol phosphate Naun?‘77-S[,i7777icdehergp’.r Arch
C.. Palacios, J. M. and Dravid. A. (1989) 5-HT,, receptors-mediated production in pig choroid plexus; a pharmacological characterization.
Phurrnac,.
339: 252-258.
Hoyer, D., Clarke, D. E.. Fozard. J. R.. Hartig, P. R., Martin, G. R., Mylecharane. E. J.. Saxena, P. R. and Humphrey, P. P. A. (1994) VII. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharnzuc~. Rer. 46: 157-204. Hughes, R. N. ( 1993) Effects on open-field behavior of diazepam and buspirone alone and in combination with chronic caffeine. Lifi~ SC,;. 53: 1217 1225. Humble, M., Asberg-Wistedt. A.. Wistedt. B. and Bertilsson. L. (1986) A pilot study of ritanserin (a selective serotonin-2 receptor antagonist) in panic disorder and agoraphobia. Clinical and biochemical effects. In: C.I.N.P. Cor7gr~~x.s.p. 165. Puerto Rico. December 14-17. Humble. M.. Koczkas, C. and Widstedt, B. (1989) Serotonin and anxiety: an open study ofcitalopram in panic disorder. In: Ps~~f7icr/r>, Toduy: 1’111 World C‘ongrrxs of’Pswi7iutr~., p. I5 I. Stefanis. C. N., Soldatos, C. R. and Rabavilas. A. D. (eds) Elsevier, New York. Hyttel, J. (1977) Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu IO- I7 I P.s~~c~i7oJ~iiur7~7~7~01og~~ 51: 2255233. Jenck, F.. Broekkamp. C. L. E. and van Delft, A. M. L. (1989a) Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5-HT,, 5-HT: and 5-HT, receptors. P.s~~~hophurn7c7c~ol~~g~~ 97: 489%495.
Jenck. F., van Delft. A. M. L. and Broekkamp, C. L. E. (1989b) Serotonergic control of dorsal periaqueductal grey (PAG) induced aversion: a functional role for the brain 5-HT,, receptors. In: Scrofor7i7z,,fi.o777 CeUBiolog~~ to Pi7urn7ucolog~~ und Ti7cwpc~uric~s, Florence, April. Jequier, E.. Lovenburg. W. and Sjoerdsma, A. (1967) Tryptophan hydroxylase inhibition: the mechanism by which p-CPA depletes rat brain serotonin. Mo/c,r,. Pizurn7uc~. 3: 2744278. Jin. H.. Oksenberg. O., Ashkenazi, A.. Peroutka, S. J., Rozmahel. R.. Yang, Y., Palacios. J. M. and O’Dowd. ,” receptor. .I. ho/. Ciw77. B. E. (1992) Identification and characterization of the human 5-hydroxytryptamine 267: 573555738. Johnston. A. L. and File. S. E. (1988) Effects of 5-HT, antagonists in two animal tests of anxiety. Nrurosci. Left. 32 (Suppl.): S44. Joly, D. and Sanger, D. J. (1991) Social competition in rats: a test sensitive to acutely administered anxiolytics. Bei7m.. Pi7urn7uc. 2: 205 ~213.
Jones. B. J.. Oakley, N. R. and Tyers, M. B. (1987) The anxiolytic activity of GR38032F. a 5-HTl receptor antagonist, in the rat and cynomolgus monkey. Br. /. Phurn7uc. 90 (Suppl.): 88P. Jones. B. J.. Costall, B., Domeney, A. M., Kelly, M. E.. Naylor. R. J.. Oakley, N. R. and Tyers. M. B. (1988) The potential anxiolytic activity of CR 38032F, a 5-HT; receptor antagonist. Br. .J. Pi7urn7uc. 93: 9X5-993. Julius, D.. McDermott, A. B.. Axel. R. and Jessel. L. (1988) Molecular characterization of a functional cDNA encoding the serotonin IC receptor. Sciorw 241: 558 564. Kaltwasser, M. T. (1991) Acoustic startle induced ultrasonic vocalization in the rat: a novel animal model of anxiety‘? Bci7trr.. Bruir7. Rc.s. 43: 133 137. Kehne. J. H.. Cassella. J. V. and Davis. M. (1988) Anxiolytic effects of buspirone and gepirone in the fear-potentiated startlc paradigm. P.s~~c.ho~pi7trrnrrrc~olog~~ 94: 8- 13. Kennett. G. A. ( 1992) 5-HT,, receptor antagonists have anxiolytic-likeactions in the rat social interaction model. P.s~~c~i7opi7trrn7cic~olog~~ 107: 379-384.
Kennett, G. A.. Whitton, I’., Shah. K. and Curzon. G. (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT,, receptor antagonists. Eur. J. Pi7trrnruc~. 164: 445 454. Kidd. E. J., Haj-Dahmane. S., Jolas. T.. Lanfumey. L., Fattaccini. C.-M.. Guardiola-Lemaitre. B., Gozlan. H. and Hamon, M. (1993) New methoxy-chroman derivatives. 4[N-(5.methoxy-chroman-3-yl)N-propylaminolbutyl-%araspiro-(4,5)-decane-7.9-dione [O-S 202441 and its enantiomers, ( + )-S 20499 and (-)-S
5-HT-interacting
drugs
387
iAreceptors. J. Pharmac. e-up. Ther. 264: 20500, with potent agonist properties at central 5-hydroxytryptamine 863-872. Kilfoil, T., Michel, A., Montgomery, D. and Whiting, R. L. (1989) Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety in mice. Neuropharmacology 28: 901-905. Kilpatrick, G. J., Jones, B. J. and Tyers, M. B. (1987) The identification and distribution of 5-HT, receptors in rat brain using radioligand binding. Nature 330: 746-748. Kilpatrick, G. J.. Jones, B. J. and Tyers, M. B. (1989) Binding of the 5-HTi ligand, [?H]GR 65630, to rat area postrema, vague nerve and the brains of several species. Eur. J. Pharmac. 159: 1577164. Kilpatrick, G. J., Butler, A., Hagan, R. M., Jones, B. J. and Tyers, M. B. (1990a) [‘H]GR 65630, a very high ligand for 5-HT? receptors. Naunyr-Schmiedeberg’s Arch. Pharmac. 342: 22-30. Kilpatrick, G. J., Butler, A. and Oxford, A. W. (1990b) M chlorophenylbiguanide is a potent high affinity 5-HT-3 receptor agonist. Br. J. Pharmac. 99 (Suppl.): 32P. Kilpatrick, G. J., Hagan, R. M., Butler, A., Burridge, J., North, P. C., Oxford, A. W. and Tyers, M. B. (1991) GR68755, a potent and selective antagonist of 5-HT3 receptors. In: SEROTONIN 1991, 5-Hydroxytryptamine-CNS Receptors and Brain Function, p. 50, Birmingham, 14-17th July. Kilts, C. D., Commissaris, R. L. and Rech, R. H. (1981) Comparison of anti-conflict drug effects in three experimental animal models of anxiety. Psychopharmacology 74: 290-296. Kilts, C. D., Commissaris, R. L., Cordon, J. J. and Rech, R. H. (1982) Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam. Psychopharmacology 78: 156-164. Kiser, R. S. and Lebovitz, R. M. (1975) Monoaminergic mechanisms in aversive brain stimulation. Physiol. Behue.
15: 47753.
Kiser, R. S., German, D. C. and Lebowitz, R. M. (1978) Serotonergic reduction of dorsal central gray area stimulation-produced aversion. Pharmac. Biochem. Behav. 9: 27-3 1. Klein, E., Zohar, J., Gerazi, M. F., Murphy, D. L. and Uhde, T. W. (1991) Anxiogenic effects of m-CPP in patients with panic disorder: comparison to caffeine’s anxiogenic effects. Biol. Pswhiat. 30: 973-984. Klint, T. (1991) Effects of 8-OH-DPAT and buspirone in a passive avoidance test andin the elevated plus-maze test in rats. Behat). Pharmac. 2: 481-489. Klodzinska, A., Jaros, T., Chojnacka-Wojcik, E. and Maj, J. (1989) Exploratory hypoactivity induced by m-trifluoromethylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP). J. Neural Transm. 1: 207-218.
Knapp, D. J., Benjamin, D. and Pohorecky, L. A. (1992) Effects of gepirone on ethanol consumption, exploratory behavior, and motor performance in rats. Drug Der. Res. 26: 319-341. Koe, B. K. and Weissman, A. (1966) p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmac. e.yp. Ther.
154: 4999516.
Korneyev, A. Y. and Seredenin, S. B. (1993) Effects of 5-HT-IA receptor agonists on paw licking reaction on hot plate and unpunished drinking in rat. L$ Sci. 52: 997-1004. Korte, S. and Bohus, B. (1990) The effects of ipsapirone on behavioural and cardiac responses in the shock-probe/defensive burying test in male rats. Eur. J. Pharmac. 181: 307-310. Korte, S. M., Bouws, G. A. H., Koolhaas, J. M. and Bohus, B. (1992) Neuroendocrine and behavioral responses during conditioned active and passive behavior in the defensive/probe avoidance paradigm: effects of ipsapirone. PhJviol. Behac. 52: 355-361. Kostowski, W., Plaznik, A. and Stefanski, R. (1989) Intra-hippocampal buspirone in animal models of anxiety. Eur. J. Pharmac.
168: 3933396.
Kostowski, W., Dyr, W. and Krzascik, P. (1990) The effects of 5-HTIA receptor agonists in animal models of anxiety and depression. Psychopharmacology 101: S3 1. Kostowski, W., Dyr, W., Krzascik, P., Jarbe, T. and Archer, T. (1992) 5-HydroxytryptaminelA receptor agonists in animal models of depression and anxiety. Pharmac. To.uic. 71: 24-30. Kshama, D., Hrishikeshavan, H. J., Shanbhoge, R. and Munonyedi, U. S. (1990) Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms. Behar. Neural Biol. 54: 234-253.
Lahti, R. A.. Evans, D. L., Nichols, N. F. and Figur, L. M. (1993) Anxiolytic activity of the 5-HTlA agonist U-93385. attenuation of stress-induced increases in rat corticosterone levels. Sot. Neurosci. Absrr. 19: 1867. Lal, H., Prather, P. L. and Mehdi Rezazadeh, S. (1991) Anxiogenic behavior in rats during acute and protracted ethanol withdrawal: reversal by buspirone. Alcohol 8: 467-471. Lecci, A., Borsini, F., Mancinelli, A., D’Aranno, V., Stasi, M. A., Volterra, G. and Meli, A. (1990) Effects of serotonergic drugs on stress-induced hyperthermia (SIH) in mice. J. Neural Transm. 82: 219-230. Lecrubier, Y., Puech, A. J., Azcona, A., Bailey, P. E. and Lataste, X. (1993) A randomized double-blind placebo-controlled study of tropisetron in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology 112: 129-133. Lee, C. and Rodgers, R. J. (1991) Effects of buspirone on antinociceptive and behavioural responses to the elevated plus-maze in mice. Behac. Pharmac. 2: 491-496. Lehman, H. E. and Ban, T. A. (1971) Effects of psychoactive drugs on conflict avoidance behavior in human subjects. Acta New. Sup. 13: 82-85. Leone, C. M. L., de Aguiar, J. C. and Graeff, F. G. (1983) Role of 5-hydroxytryptamine in amphetamine effects on punished and unpunished behavior. Psychopharmacology 80: 78-82. Lesourd, M., Curie, P. F., File, S., Hamon, M. and Chouvet, G. (1993) S-20499 - a new selective 5-HT,, agonist:
388
G. Griebel
mechanistn of its anxiolytic activity. In: Atz.uier>,~ Ncurohio/ogic,tr/. Clinical ta7d T/7cvtrprutic~.s ,4.s/w~~7.~,p. 18 (Suppl.). Dinard. 20-2lsl September. Levy. A. D. and van de Kar, L. D. (1992) Endocrine and receptor pharmacology of serotonerglc anxiolytics. antipsychotics and antidepressants. Lif? Sci. 51: 83-94. Leysen. J. E.. Niemegeers. C. J. E.. van Nueten. .I. M. and Laduron. P. M. (1982) [‘HlKetanserin (R41 46X). a selective ‘H ligand for serotonin 2 receptor binding sites. Molcc,. Phrrvn7uc. 21: 3Ol--314. Lightowler, S.. Williamson, I. J. R., Hegarty. J.. Kennett. G. A.. Fears. R. B. and Tulloch. I. F. ( 1992) Anxiolytic effect of paroxetine in the rat social interaction model of anxiety. By. J. PAcrrr?~rrc~. 106 (Suppl.): 44P. Lister. R. G. (1990) Ethologically-based animal models of anxiety disorders. P/M~-~KK. T/w. 46: 321 340. Lbpcz-Rubalcava. C., Saldivar, A. and Fernlindez-Guasti. A. (1992) Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolyttcs. Phovn7c7c. Bioc,/7et77. Beh7~. 43: 433-440. Lorens. S. A.. Mitsushio. H. and Van de Kar. L. D. (1989) Effects of the 5-HT,,, agonist ipsapirone on the behavioural. endocrine and neurochemical responses to conditioned fear. In: Beha7+~u~tr/ Phtrr777nc,o/o~~,of 5-HT. pp. 1:~7~369. Bevan, P.. Cools. A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Lucki. I., Ward. H. R. and Frazer. A. (1989) Effect of I-(r77-chlorophenyl)piperazine and I-(777-trifluoromethylphenyl)piperazine on locomotor activity. J. Pl7rrr771trc..(‘\-/7. 7%cr. 249: 155-164. Luscotnbe. G. P.. Mazurkiewicz. S. E and Buckett. W. R. (1990) Evaluation of tricyclic antidepressants in the elevated plus-maze in rats: anxiolytic effect of dothiepin and doxepin. Br. J. Pl7crrr77crc. 100 (Suppl.): 356P. Luscombc, G. P.. Mazurkiewicz. S. E. and Heal, D. J. (1992) The 5-HT,, l&and BP 554 mimics the anxiolytic activity of buspirone. gepirone and ipsapirone in the elevated plus-maze in rats. Br. J. Pl7rrrrntrc~.106 (Suppl.): l3OP. Lyon, R. A. and Titeler. M. (1988) Pharmacology and biochetnistry of the 5-HT, receptor. in: T/w .Sr,ro707ti77 Rct.(~p/7t07..(.. pp. 59-88. Sanders-Bush. E. (ed.) Humana Press. Clifton. Maisonnette. S., Morato, S. and Brandao, M. L. (1993) Role ofresocialiration and of5-HT,a receptor activation on the anxiogenic effects induced by isolation in the elevated plus-maze test. Ph~~.sio/. Bchrw. 54: 753 758. Maitre. L. ( 1997) Antidkpresseurs et lithium. In: P/7tr,r77crc,ok~gi(, l&s C‘O~~CV~/~IS Fot7t/r/t77~t7ttru.\- c/LI.\’ App/icutio77.\ P/7c;rtrllcu/icluc.r. pp. 335-371, Schorderet, M. (ed.) Frison-Roche and Slarkine. Paris and Geneva. Major. J. S.. Le Count. D., Pearce, R. J.. Thornber. C. W., Walters, M. and Cox, B. (1991) ICI 169369 and related cotnpounds have high affinity for 5-HT,, and 5-HT: receptors. In: SERC~TO:VI,Y 1991. ~-H~~t/ro\-1~tr.1~/7rtrt71it7r-cn!s Rcc~c~ptor.s cm/ Bruit7 Fw7c~riotr. p. 40. Birtninehatn. I4 17th July. Malgouris. c... Flamand. F. and Doble. A. (1993) Autoradiographic studies of RP 62203. a potent 5-HT1 receptor antagonist. 177rim and P.\- riw selectivity profile. EIU.. J. Phtr~77nc.. 233: 29~ 35. Mansbach. R. S. and Geyer. M. A. (1988) Blockade of potentiated startle responding in rat> by 5-hy’lroxytrqp(amine IA receptor ligands. E7rr. J. Pl7co771rrc..156: 375 -383. Mansbach. R. S.. Harrod. C.. Hoffmann, S. M.. Nader, M. A.. Lei. Z.. Witkin. J. M. and Barrett. J. E. (19x8) Behavioral studies wjith anxiolytic drugs. V. Behavioral and it7riro neurochemical analyses in pigeons ofdrugs that increase punished responding. J. P/7rrrr77trc,.c-\-p. T/7(,,. 246: I 14~120. Martin, P. (1993) Efects of anxiolytic and antidepressant drugs in an animal tnodel of panic. In: AtI vic/.~‘ ~~ .Yr,7rr_ohio/oXit,[7/~ C’lirzic~dcrr7riT/7cwpcwric~.s A.spw/v. p. 203. Hamon. M.. Ollat. H. and Thit-bot. M.-H. (eds) Les iditions INSERM. Paris. Mason. P.. Skinner. J. and Luttinger. D. (1987) Two tests in rats for antianxiety effect of clinically anxiety attenuating antidepressants. P,s~~~~hophn~rr7r~~~~/~t~~~ 92: 30 34. McBlane. J. W.. Critchley. M. A. E. and Handley. S. L. (1992) Light intensity influences the response to X-OH-DPAT in the elevated X-maze tnodel of anxiety. Br. .J. P/wt~77rrt 105 (Suppl.): 22 I P. McCloskcy. T. C‘.. Paul. B. K. and Cotnmissaris. R. L. ( 1987) Buspirone effects in an animal contlict procedure: comparison with diazepam and phenobarbital. P/7rrrr77c7c~. Bid7cm. Behcrr. 27: I7 I 175. McCown, T. .I.. Vogel. R. A. and Breese. G. R. (1983) An efficient chronic conflict paradigm: lick suppression by incremental footshock. P/7rrrr77rrc,.Bioc,/7c,n7.Brhrw. 18: 277 279. McKearney. J. W. and Barrett. J. E. (1975) Punished behavior: increases in responding after t,-amphetamine. P.s~~(./7o/~ll~/l.t77(1~ ologitr 4 1: 23-m26. McMillan. 1). E. (1973) Drugs and punished responding I: rate-dependent efrects under tnultiple schedules. .J. c~,I. .3/7tr/. Bcl7rrr. 19: 133m145. Meer1. T. F. (19X6) A comparative study of the effects of ritanserin (R55667) and chlordiazepoxide on rat open lield behal-iour. /)~rg l)c,r.. Rc.s. 8: 197-204. Meert. T. F. (1’989)Ritanserin and risperidone in comparison with other 5-HT agonist:antagonists in different animal models in the rat. In: S~,rofor7;77.,f~ot77 C’P// Biolo,qv lo P/7urt77~(,0/(~~~’ crt7d T/~wL~J~~u~~~~J, Florence, April. Meert. T. F. (lY92) Ritanserin overcomes exploratory inhibition induced by cocaine withdrawal. Brl7trr. P/lc7,_r?lr7c~. 3: 149 154. Mecrt. T. F. and Colpaerr, F. C. (l986a) The shock probe conflict procedure. A new assay responsive to bcnzodiazepines. barbiturates and related compounds. P\~,c,/7o)/~/7rrrt77~7[,~~/~)~~. 88: 445~-450. Meert. T. F. and Colpaert. F. C. (1986b) Effects of S, antagonists in two conflict procedures that involve exploratory behaviour. P.s~~c~hophnr-777~~~~~~/~~~~~ 89: S23. Mecrt. T. F. and Colpaert. F. C. (1986~) A pharmacological evaluation of the selected emotional defecation and micturation test. P.s~,c,hophc7~777r~~~/~~~, 89: S23. Melia. K. R. and Davis. M. (1991) Effects of septal lesions on fear-potentiated startle. and on the anxiolytic effects of huspirone and diazepam. P/:,~~.sio/. Bel7m. 49: 603-61 I.
5-HT-interacting
drugs
389
Meneses. A. and Hong, E. (1993) Modification of the anxiolytic effects of 5-HT,, agonists by shock intensity. Pharmac. Biochem. Behar. 46: 5699573. Metzenauer. P., Barnes, N. M., Costall. B.. Gozlan, H., Hamon, M., Kelly M. E., Murphy, D. A. and Naylor, R. J. (1992) Anxiolytic-like actions of anpirtoline in a mouse light/dark aversion paradigm. NemoReport 3: 527-529. Miczek, K. A. (1973) Effects of scopolamine, amphetamine and benzodiazepines on conditioned suppression. Pharmac. Biochem. Behac. 1: 401-411. Middlemiss, D. N. and Hutson. P. H. (1990) The 5-HTle receptors. Ann. N. Y. Acad. Sci. 600: 132-148. Millan, M. J. and Brocco, M. (1993) Serotonin and anxiety: mixed 5-HTt4 agonists ~ 5-HTlc ?antagonists as potential anxiolytic agents. In: Anxiety - Neurohiological, Clinicaland Therapeutics Aspects, p. 153, Hamon, M., Ollat. H. and Thiebot, M.-H. (eds) Les editions INSERM, Paris. Millan. M. J., Canton, H., Rivet, J.-M., Lejeune, F., Laubie, M. and Lavielle, G. (1991) S 14671: a novel naphthylpiperazine S-HTIA agonist of high efficacy and exceptional in riro potency. Eur. /. Pharmuc. 203: 319-322. Misslin. R.. Griebel. G., Saffroy-Spittler, M. and Vogel, E. (1990) Anxiolytic and sedative effects of 5-HT,, ligands, 8-OH-DPAT and MDL 73005EF, in mice. NemoReport 1: 2677270. Miyauchi, T., Inagawa, K.. Uchida, H., Tameda, C. and Sakakibara, M. (1993) Pharmacological profile of HT-YOB, a putative anxiolytic with potent antidepressive activity. Sot. Neurosci. Ahstr. 19: 1867. Molewijk, H. E., van der Poel. A. M.. Vedder, A. W. and Olivier, B. (1993) Ultrasonic distress vocalisations in adult rats as a model for panic disorder. In: British Association far Ps?,chap,pharnlacol~~g~,,25528th July, Cambridge, A12. Moreau, J.-L.. Griebel, G.. Jenck, F., Martin, J. R., Widmer, U. and Haefely, W. E. (1992) Behavioral profile of the 5HT,, receptor antagonist (S)-UH-301 in rodents and monkeys. Bruin Res. Bull. 29: 901-904. Morinan. A. (1989) Effects of the 5-HTI receptor antagonists, GR 38032F and BRL 24924, on anxiety in socially isolated rats. Br. J. Pharmac. 97 (Suppl.): 457P. Morris, H., White, S. M., Shropshire. A. T., Abou-Gharbia, M., Boast, C. A. and Moyer. J. A. (1989) Behavioral characterization of the novel anxiolyticiantidepressant agent WY-50,324. Sot. Neurosci. ilhstr. 15: 852. Mos. J. and Olivier, B. (1989) Ultrasonic vocalizations by rat pups as an animal model for anxiolytic activity: effects of serotonergic drugs. In: Beharioural Pharmacology of 5-HT. pp. 361-366, Bevan, P.. Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Mos, J., van der Heyden, J. and Olivier, B. (1989) Behavioural effects of 5-HT, antagonists in animal models for aggression, anxiety and psychosis. In: Beharioural Pharmacology qf‘5-HT, pp. 389-395, Bevan. P.. Cools, A. R. and Archer, T. (eds) Erlbaum. Hillsdale. Moser, P. C. (1989a) An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Ps~chophurn~acolog~~ 99: 48853. Moser, P. C. (1989b) Buspirone, ipsapirone and 5-HT,.,-receptor agonists show an anxiogenic-like profile in the elevated plus-maze. In: Beharioural Pharmacologic af5-HT, pp. 371-375. Bevan, P., Cools, A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Moser, P. C.. Hibert, M., Middlemiss, D. N., Mir, A. K., Tricklebank, M. D. and Fozard. J. R. (1988) Effects of MDL 73005EF in animal models predictive of anxiolytic activity. Br. J. Pharmuc. 93 (Suppl.): 3P. Moser, P. C., Tricklebank, M. D., Middlemiss, D. N.. Mir, A. K., Hibert, M. F. and Fozard, J. R. (1990) Characterization of MDL 73005EF as a 5-HT,, selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam. Br. J. Phurmac. 99: 3433349. Motta, V., Maisonnette, S.. Morato, S., Castrechini. P. and Brandao, M. L. (1992) Effects of blockade of 5-HT, receptors and activation of 5-HT,,& receptors on the exploratory activity of rats in the elevated plus-maze. P.s~chopl~arr~~at~olog~107: 135- 139. Moulton, B. and Morinan, A. (1990) The effect of RS-30199 on anxiety and hippocampal monoamine oxidase activity in the rat. Br. J. Pharmac. 101 (Suppl.): 516P. Munonyedi, U. S.. Hrishikeshavan. H. J., Shanbhogue, R. S. and Devi, K. (1991) Potentiation of poststartle activity by conditioned fear: effects of anxiolytic and anxiogenic drugs. Biol. Psychiat. 29: 6833686. Nader, M. A. (1991) Behavioral effects of chronic buspirone administration in the pigeon: comparison to midazolam. Pharmac. Biochem. Be/tar. 38: 61 l-61 6. Nagatani. T., Yamamoto, T., Takao. K.. Hashimoto, S.. Kasahara, K.. Sugihara. T. and Ueki, S. (1991) Pharmacological profile of a potential anxiolytic: API 59, a new benzothieno-pyridine derivative, P.~~‘cllopharrn~~col~)g~~ 104: 432-438. Nanry. K. P. and Tilson. H. A. (1989) The role of SHTIA receptors in the modulation of the acoustic startle reflex in rats. P.~~chopharn~acolog~~ 97: 507-5 13. Nanry. K. P.. Howard. J. L. and Pollard, G. T. (1991) Effects of buspirone and other anxiolytics on punished key-pecking in the pigeon. Drug Der. Res. 24: 2699276. Nastiti. K., Benton. D., Brain, P. F. and Haug. M. (1991) The effects of 5-HT receptor ligands on ultrasonic calling in mouse pups. Neurosci. Biobehar. Ret.. 15: 4833487. Nelson, D. R. and Thomas, D. R. (1989) [‘H]BRL 43694 (granisetron), a specific ligand for 5-HT? binding sites in rat brain cortical membranes. Biochem. Pharmac. 38: 1693-1695. Nelson, D. R.. Thomas, D. R. and Johnson, A. M. (1989) Pharmacological effects of paroxetine after repeated administration to animals. Acta psjchiat. stand. 80 (Suppl.): 21-23. Nishimura. H., Tanaka, M.. Tsuda. A. and Gondoh, Y. (1993) Atypical anxiolytic profile of buspirone and a
390
G. Griebel
related drug, SM-3997. in a modified forced swim test employing 46: 647-65
straw suspension.
Pharmac.
B&hem.
Behar.
1.
Njung’e, K. (1990) Effects of some 5-hydroxytryptamine and related ligands in anxiety models. Ph.D. Thesis, Aston University, Birmingham, U.K. Njung’e, K. and Handley, S. L. (1991 a) Evaluation of marble-burying behavior as a model of anxiety. Pharmac. Biochem.
Behar.
38: 63-67.
Njung’e, K. and Handley, S. L. (199lb) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br. .I. Pharmac. 104: 105-l 12. Nogueira, R. L. and Graeff, F. G. (1991) 5-HT mediation of the antiaversive effect of isamoltane injected into the dorsal periaqueductal grey. Behav. Pharmac. 2: 73377. Oakley, N. R. and Jones, B. J. (1983) Buspirone enhances [ZH]flunitrazepam binding in riro. Eur. J. Pharmac. 87: 4999500.
types and anxiety. In: Target Receptorsfor Anxiolytics and Hypnotics: From Molecular Pharmacology to Therapeutics. International Academy of Biomedical Drug Research. Vol. 3, pp. 1 l-23, Mendlewicz, J. and Racagni, G. (eds) Karger, Basel.
Oakley, N. R. and Tyers, M. B. (1992) 5-HT receptor
Ogawa, N., Hara, C. and Takaki, S. (1993) Anxiolytic activity of SC-48274 compared with those of buspirone and diazepam in experimental anxiety models. Jap. J. Pharmac. 61: 1155121. Olds, M. E. and Olds, J. (1962) Approach-escape interactions in rat brain. Am. .I. Physiol. 203: 8033810. Olivier, B., Mos, J., van der Heyden, J. and Hartog, J. (1989) Serotonergic modulation of social interactions in isolated male mice. PsychopharmacoIogy 97: 154-l 56. Olivier. B., Mos, J., Tulp, M. T. M. and van der Poel, A. M. (1992) Animal models of anxiety and aggression in the study of serotonergic agents. In: Serotonin Subtypes: Pharmacological Signtficance und Clinical Implications, Vol. 1, pp. 67-79, Langer, S. Z.. Brunello, N. and Mendlewicz, J. (eds) Karger, Basel. Onaivi. E. S. (1993) The anxiolytic profile of buspirone can be detected in the elevated plus-maze test following r,-stimulation by dexmedethomidine. Sot. Neurosci. Abstr. 19: 755. Onaivi, E. S. and Martin, B. R. (1989) Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety. Prog. Nemo-Psy~chopharmac.
biol. Psychiat.
13: 9633976.
Palacios. J. M., Mengod, G., Hoyer, D., Waeber, C., Pompeiano, M., Niclou, S. and Bruinvels, A. (1992) Autoradiographic localization of 5-HT receptor subtypes. In: Serotonin. CNS Receptors and Brain Function. pp. 61-72, Bradley, P. B., Handley, S. L., Cooper, S. J., Key, B. J., Barnes, N. M. and Coote. J. H. (eds) Pergamon Press, Oxford. Panickar, K. S. and McNaughton, N. (1991) Doseeresponse analysis of the effects of buspirone on rearing in rats. J. Psychopharmuc. 5: 72276. Papp, M. (1988) Similar effects of diazepam and the 5-HTI receptor antagonist ICS 205-930 on place aversion conditioning. Eur. .I. Pharmac. 151:321-324. Papp, M. and Przegalinski, E. (1989) The 5-HT, receptor antagonist ICS 205-930 and GR38032F, putative anxiolytic drugs, differ from diazepam in their pharmacological profile. J. Psychopharmac. 3: 14-20. Patel, J. B. and Malick, J. B. (1980) Effects of isoproterenol and chlordiazepoxide on drinking and conflict behaviors in rats. Pharmac. Biochem. Behao. 12: 819-821. Pazos, A., Hoyer, D. and Palacios, J. M. (1984) The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur. J. Pharmac. 106: 5399546. Pellow, S. and File, S. E. (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmac. Biochem. Behar. 24: 5255529. Pellow, S., Chopin. P., File, S. E. and Briley, M. (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Meth. 14: 1499167. Pellow, S.. Johnston, A. L. and File, S. E. (1987) Selective agonists and antagonists for 5-hydroxytryptamine receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plus-maze test in the rat. J. Phnrm.
Pharmac.
39: 917-928.
Peroutka, S. J. (1986) Pharmacological differentiation and characterization of 5-HT,,, 5-HT,,, 5-HTic binding sites in rat frontal cortex. J. Neurochem. 47: 5299540. Peroutka. S. J. and Hamik, A. (1988) [‘H]Quipazine labels 5-HT1 recognition sites in rat cortical membranes. Erlr. J. Phurmuc~. 148: 297-299. Peroutka. S. J., Hamik, A., Harrington, M. A., Hoffman, A. J., Mathis, C. A., Pierce, P. A. and Wang, S. S. H. ( 1988) (R)-( ~ )-[“Br]4-Bromo-2,5-dimethoxy-amphetamine labels a novel 5-hydroxytryptamine binding site in brain membranes. Molec. Pharmac. 34: 5377542. Petersen, E. N. and Lassen, J. B. (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmncology
75: 236-239.
Pith, E. M. and Samanin, R. ( 1986) Disinhibitory, effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: possible role of dopamine. PsychopharmacoIogy~ 89: 125-130. Pigott, T. A., Hill, J. L., Grady, T. A., L’Heureux, F., Bernstein, S., Rubenstein, C. S. and Murphy, D. L. (1993) A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to IV mCPP. Biol. Psych&. 33: 3-14. Piper, D. C., Upton, N., Thomas, D. and Nicholson, J. (1988) The effects of 5-HTI receptor antagonists BRL 43694 and GR 38032F in animal behavioural models of anxiety. Br. .I. Pharmac. 94 (Suppl.): 314P. Piper, D. C., Kenney. C. A., Jenkins, E., Blackburn, T. P. and Hughes, H. C. (1992) A comparison of the
5-HT-interacting anxiolytic
activity
international
of BRL46470A,
Symposium
ondansetron
on SEROTONIN,
.from
and
drugs
391
diazepam
Cell Biology
in the cynomolgus
to Pharmacology
monkey.
and Therapeutics,
In: 2nd p. 16,
Houston, 15-1&h September. Plaznik, A., Stefanski, R. and Kostowski, W. (1991) The role of 5-HTIA- and 5-HT1-receptors within the nucleus accumbens and the hippocampus in the rat emotional behavior. In: SEROTONIN 1991, 5-Hydroxytryptamine-CNS Receptors and Brain Function, p. 190, Birmingham, 14-17th July. Pollard, G. T. and Howard, J. L. (1991) Cork gnawing in the rats as a screening method for buspirone-like anxiolytics. Drug Dev. Res. 22: 179-187. Pollard, G. T., Nanry, K. P. and Howard, J. L. (1992) Effects of tandospirone in three behavioral tests for anxiolytics. Eur. J. Pharmac. 221: 297-305. Porsolt, R. D., Lenegre. A., Caignard, D. H., Pfeiffer, B., Mocaer, E. and Guardiola-Lemaitre, B. (1992) Psychopharmacological profile of a new chroman derivative with 5-hydroxytryptaminelA agonist properties: S 20499 (+). Drug Dev. Res. 27: 389-402. Prather, P. L., Rezazaden, S. M., Lane, J. D., Rowan, G. A., Hooper, M. L., Lytle, D. A., Emmettoglesby, M. W. and Lal, H. (1993) Conflicting evidence regarding the efficacy of ondansetron in benzodiazepine withdrawal. J. Pharmac. exp. Ther. 264: 622-630. Przegalinski, E., Chojnacka-Wojcik, E. and Filip, M. (1992) Stimulation of postsynaptic 5-HTIA receptors is responsible for the anticonflict effect of ipsapirone in rats. J. Pharm. Pharmac. 44: 780-782. Redfern, W. S. and Williams, A. (1989) Acute of centrally-acting drugs on the behaviour of rats in an elevated X-maze and a partially-shaded holeboard. Br. J. Pharmac. 98 (Suppl.): 683P. Redfern, W. S., Clague, R. U. and Spedding, M. (1989) Anxiogenic-like properties of RS-30199 in the rat. Br. J. Pharmac. 98 (Suppl.): 682P. Rex, A., Fink, H., Ott, T. and Stephens, D. N. (1991) A sensitive and simple screen for anxiolytic drugs. In: SEROTONIN 1991,5-Hvdroxytryptamine-CNS Receptorsand Brain Function, p. 147, Birmingham, 14-17th July. Rezazadeh, S. M., Prather, P. L. and Lal, H. (1993) Sensitization to 5-HTlc receptor agonist in rats observed following withdrawal from chronic ethanol. Alcohol 10: 281-283. Rhodes, K. F., Middlefell, V. C., Lattimer, N., Brammer, N. T., Coleman, J., Taylor, A. P., Saville, L. and Ward, T. J. (1993) WAY 100289: pharmacological profile of a new .5-HTz receptor antagonist. Drug. Der. Res. 28: 128-140.
Richards, S-HT,
G., Schoch, P. and Jenck, F. (1991) Benzodiazepine Antagonists
and Benzodiazepines,
Their Comparative
receptors
and their ligands. In: 5-HTla Agonists, Pharmacology, pp. l-30, Rodgers,
Behavioural
R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Robichaud, R. C. and Sledge, K. L. (1969) The effects of p-chlorophenylalanine on experimentally induced conflict in the rat. L@ Sci. 8: 965-969. Rocha, B., Di Scala, G. and Sandner, G. (1992) Differential effect of 5,7_dihydroxytryptamine lesions on conditioned place aversions produced by FG-7 142 or mianserin in rats. In: The Role of Serotonin in Psychiatric Disorders, Castres, 24-26th June. Rocha, B., Di Scala, G., Jenck, F., Moreau, J.-L. and Sandner, G. (1993a) Conditioned place aversion induced by S-HTlc receptor antagonists. Behav. Pharmac. 4: 101-106. Rocha, B., Di Scala, G., Rigo, M., Hoyer, D. and Sandner, G. (1993b) Effect of 5,7_dihydroxytryptamine lesion on mianserin-induced conditioned place aversion and on 5hydroxytryptamine,c receptors in the rat brain. Neuroscience
56: 687-693.
Rodgers, R. J., Cole, J. C., Cobain, M. R., Daly, P., Doran, P. J., Eells, J. R. and Wallis, P. (1992) Anxiogenic-like effects of fluprazine and eltoprazine in the mouse elevated plus-maze: profile comparisons with 8-OH-DPAT, CGS 12066B, TFMPP and mCPP. Behav. Pharmac. 3: 621-634. Rodgers, R. J., Cole, J. C. and Davies, A. (1993) Anxiolytic and motoric effects of buspirone and flexinoxan in the murine elevated plus-maze. Sot. Neurosci. Abstr. 19: 756. Rutter, J. J. and Auerbach, S. B. (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J. Pharmac. exp. Ther. 265: 1319-1324. Saldivar, A., Rios, C. and Fernandez-Guasti, A. (1991) Differential role of serotonin and noradrenaline on anxiety reduction after ejaculation in the rat. Pharmac. Biochem. Behav. 38: 807-812. Sanders-Bush, E. (1988) 5-HT receptors coupled to phosphoinositide hydrolysis. In: The Serotonin Receptors, pp. 181-198, Sanders-Bush, E. (ed.) Humana Press, Clifton. Sanger, D. J. (1990) Effects of buspirone and related compounds on suppressed operant responding in rats. J. Pharmac.
exp.
Ther.
254: 420-426.
Sanger, D. J. (1991) Animal models of anxiety and the screening and development of novel anxiolytic drugs. In: Neuromethods, Vol. 19: Animal Models in Psychiatry, Vol. II, pp. 147-198, Boulton, A., Baker, G. and Martin-Iverson, M. (eds) The Humana Press, Clifton. Sanger, D. J. (1992) Increased rates of punished responding produced by buspirone-like compounds in rats. J. Pharmac.
exp.
Ther.
261: 513-517.
Sanger, D. J. and Joly, D. (1989-1990) Performance of a passive avoidance response is disrupted by compounds acting at 5-HT,, receptors. Behac. Pharmac. 1: 235-240. Sanger, D. J., Joly, D. and Zivkovic, B. (1985) Behavioural effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. J. Pharmac. e.yp, Ther. 232: 831-837.
392
G. Griebel
Sanger, D. J., Joly, D. and LePichon, M. (1989) Buspirone, gepirone and ipsapirone disrupt both active and passive avoidance responding in rats. Behaz,. Pharmac. I: 1533160. Schefke, D. M., Fontana, D. J. and Commissaris, R. L. (I 989) Anti-conflict efficacy of buspirone following acute versus chronic treatment. Psychopharmacology 99: 4277429. Schipper. J., van der Poel, A. M., Mos, J., van der Heyden, J. A. M. and Olivier, B. (1991) Flesinoxan: anxiolytic activity in animal models. In: SEROTONIN 1991, 5-H!,dro.u?,tr!,ptamine-CNS Receptors and Brain Function, p. 138, Birmingham, l4-17th July. Schlicker. E.. Finck, K., Gothert, M., Hoyer. D.. Molderings, G., Roschke, I. and Schoeffter, P. (1989) The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT,,, receptor subtype. NaunJn-Schmiedeberg’s Arch. Pharmuc. 340: 45551. Schmidt, A. W. and Peroutka, S. J. (1990) Quantitative molecular analysis predicts 5-HT1 receptor binding affinity. Molec. Phnrmac. 38: 51 l-516. Schoeffter. P. and Hoyer, D. (1989) 5-Hydroxytryptamine 5-HT,, and 5-HT,, receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine. rauwolscine and some beta-adrenoceptor antagonists. Nnuny-Schmiedeberg’s Arch. Phurmuc. 340: 285.-292. Schoenfeld, R. I. (1976) Lysergic acid diethylamideand mescaline-induced attenuation of the effect of punishment in the rat. Science 192: 8Oll803. Schreiber. R. and de Vry, J. (1993) 5-HTlh receptor ligands in animal models of anxiety, impulsivity and depression: multiple mechanisms of action? Prog. Neuro-Ps.l’~hopharmac. biol. Psychint. 17: 877104. Schreur, P. J. K. D. (1988) The face to face test for anxiolytics: a social interaction test in mice. Sot,. Neurosci. Ab.s/r. 14: 520. Schreur. P. J. K. D., Stone. M. P., Nichols, N. F., Lin. C.-H. and Haadsma Svensson, S. R. (1993) U-93385: an orally active anxiolytic with selective 5-HT,, agonist activity. Sot,. Neurosci. Ahstr. 19: 1867. Schiitz. M. T. B.. de Aguiar. J. C. and Graeff, F. G. (1985) Anti-aversive role of serotonin in the dorsal periaqueductal grey matter. P.s~~cl~ophurnluc~~)l~~g~ 85: 340--345. Schuurman. T., Spencer. D. G. and Traber, J. (1986) Behavioural effects of the 5-HT,, receptor l&and ipsapirone (TVXQ 7821): a comparison with X-OH-DPAT and diazepam. P.s~~c~hophurmacolog~~ 89: S54. Schweizer, E. and Rickels, K. (1991) Serotonergic anxiolytics: a review of their clinical efficacy. In: 5-HT,,, Agonists, 5-HT, Antagonists and Benzodiuzepines, Their Compnrutice Behurioural Phurmuc~ology, pp. 365-376, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Sepinwall, J. and Cook, L. (1978) Behavioral pharmacology of anti-anxiety drugs. In: Handbook of Ps~c~hophurn~crcolog~, Vol. 13. pp. 3455393, Iversen. L. L., Iversen, S. D. and Snyder. S. H. (eds) Plenum Press. New York. Sepinwall, J. and Cook. L. (1980) Mechanisms of action of the benzodiazepines: behavioral aspect. Fedn Proc. 39: 30244303 I. Shephard, R. A., Buxton, D. A. and Broadhurst. P. L. (1982) Drug interactions do not support reduction in serotonin turnover as the mechanism of action of benzodiazepines. N~,uropizclnnuco/~~g~ 21: 102771032. Shepherd, J. K.. Flores, T.. Rodgers, R. J., Blanchard, R. J. and Blanchard, D. C. (1992) The anxiety/defense test battery: influence of gender and ritanserin treatment on antipredator defensive behavior. Ph~xiol. Behac. 51: 277m285. Shepherd, J. K., Rodgers, R. J., Blanchard, R. J., Magee, L. K. and Blanchard, D. C. (1993) Ondansetron, gender and antidepredor defensive behaviour. J. Ps~ehophurmnc. 7: 72-8 1. Shimizu, H.. Hirose. A., Tatsuno. T., Nakamura. M. and Katsube, J. (1987) Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate. Jup. J. Phurmuc. 45: 493. 500. Shimizu. H.. Kumasaka, Y., Tanaka, H., Hirose. A. and Nakamura, M. (1992a) Anticonllict action of tandospirone in a modified Geller-Seifter conflict test in rats. Jup. J. Phurma~~. 58: 2833289. Shimizu. H., Tatsuno, T.. Tanaka, H., Hirose, A.. Araki, A. and Nakamura. M. (1992b) Serotonergic mechanisms in anxiolytic effect of tandospirone in the Vogel conflict test. Jup. J. Pharmuc~. 59: 1055112. Siiderpalm. B. and Engel, J. A. (1989) Does PCPA induced anticonflict effect involve activation of the GABA,‘benzodiazepine chloride ionophore receptor complex? J. Neural Trunsm. 76: 1455153. Soderpalm, B. and Engel, J. A. (1991) Involvement of the GABA,!benzodiazepine chloride ionophore receptor complex in the 5,7-DHT induced anticonflict effect. L@ Sci. 49: 139-I 53. Soderpalm. B. and Engel. J. A. (1992) The 5,7-DHT-Induced anticonflict effect is dependent on intact adrenocortical function. Li/e Sci. 51: 3 15- 326. Siiderpalm. B.. Hjorth. S. and Engel. J. A. (1989) Effects of 5-HT li\ receptor agonists and L-5-HTP in Montgomery’s conflict test. Phurmnc. Biochem. Behrn. 32: 2599265. Shderpalm. B., Lundin, B. and Hjorth, S. (1993) Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HTIA receptor agonist, buspirone. after prolonged chronic administration. Eur. J. Phurmuc. 239: 69%73. Sommermeyer. H., Schreiber, R., Greuel. J. M., de Vry. J. and Glaser, T. (1993) Anxiolytic effects of the 5-HT,, receptor agonist ipsapirone in the rat: neurobiological correlates. Eur. J. Pharmtrc. 240: 29937. Soubrie. P. (1989) 5-HT,, receptors: a bridge between anxiety and depression. In: Behuriourul Phurmuc~olog~ of’5-HT. pp. 3377352. Bevan, P., Cools, A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Soubrie. P. and Thiebot, M. H. (1986) Some pre-clinical observations with buspirone: its effects ofanimal models of anxiety, depression and impulse control. In: Proc,. 151l7 C.I.N.P. Congress. p. 153. Puerto Rico. Stefanski. R.. Palejko. W.. Kostowski, W. and Plaznik, A. (1992a) The comparison of benzodiazepine
S-HT-interacting
drugs
393
derivatives and serotonergic agonists and antagonists in two animal models of anxiety. NeuropharmacologJ 31: 1251-1258. Stefanski, R., Plaznik, A., Palejko, W. and Kostowski, W. (1992b) The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. Pharmac. Res. 25 (Suppl.): 79980. Stefanski, R., Palejko. W., Bidzinski A., Kostowski, W. and Plaznik, A. (1993a) Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of midazolam and S-HT,, receptor agonists. Neuropharmacology 32: 9777985. Stefanski, R., Palejko, W.. Bidzinski A., Kostowski, W. and Plaznik, A. (1993b) Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of the S-HTI receptor antagonists. Neuropharmacology 32: 9877993. Stein, L., Wise. C. D. and Berger, B. D. (1973) Anti-anxiety action of benzodiazepines: decrease in activity of serotonin neurons in the punishment system. In: The Benzodiusepines, pp. 299-326, Costa, E. and Greengard, P. (eds) Raven Press. New York. Stein, L., Wise C. D., and Belluzzi, J. D. (1975) Effects of benzodiazepines on central serotonergic mechanisms. In: Mechanisms ofAction ofBenzodiazepines, pp. 29-44, Costa, E. and Greengard, P. (eds) Raven Press, New York. Stutzmann, J. M., Eon, B., Darche, F., Lucas, M., Rataud, J., Blanchard, J. C. and Laduron, P. M. (1991) Are S-HTz antagonists endowed with anxiolytic properties in rodents? Neurosci. Lett. 128: 4-8. Sudak, H. S. and Maas. J. W. (1964) Central nervous system serotonin and norepinephrine localization in emotional and non-emotional strains in mice. Nature 203: 1254-1256. Sullivan, J. W., Keim, K. L. and Sepinwall, J. (1983) A preclinical evaluation of buspirone in neuropharmacologic, EEG and anticonflict test procedures. Sot. Neurosci. Abstr. 9: 434. Sullivan, J. W., Gold, L. and Sepinwall, J. (1985) Anticonflict effects ofthree compounds having antiserotonergic activity: metergoline, mianserin, and clozapine. Sot. Neurosci. Abstr. 11: 1187. Svensson. L. (198.5) Effects of 8-OH-DPAT, lisuride and some ergot-related compounds on the acoustic startle response in the rat. Psychopharmacology 85: 469-475. Svensson, L. and Ahlenius, S. (1983) Enhancement by the putative S-HT receptor agonist 8-OH-2-(di-n-propylamino)tetralin of the acoustic startle response in the rat. Psychopharmacology 7% 104-107.
Takao. K., Nagatani, T., Kasahara, K.-I. and Hashimoto, S. (1992) Role of the central serotonergic system in the anticonflict effects of d-AP159. Pharmac. Biochem. Behav. 43: 503-508. Taylor. D. P., Eison, M. S., Riblet, L. A. and van der Maelen, C. P. (1985) Pharmacological and clinical effects of buspirone. Pharmac. Biochem. Behar:. 23: 687-694. Tenen, S. S. (1967) The effects of p-chlorophenylalanine. a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychophurmacologiu 10: 2044219. Thiebot. M.-H., Hamon. M. and Soubrie, P. (1982) Attenuation of induced-anxiety in rats by chlordiazepoxide: role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons. Neuroscience 7: 2287-2294.
Thiebot, M.-H., Hamon. M. and Soubrie. P. (1983) The involvement of nigral serotonin innervation in the control of punishment-induced behavioral inhibition in rats. Phurmac. Biochem. Behau. 19: 225-229. Thiebot. M.-H., Soubrie. P., Hamon, M. and Simon, P. (1984) Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat. Psychopharmacology 82: 355-359. Thiebot, M.-H., Dangoumau, L., Charrier. D. and Puech, A. J. (1990) Interaction ofbuspirone with ‘anxiogenic’ drugs in a safety signal withdrawal paradigm of conflict. Psychopharmacology 101:S57. Thiebot, M.-H.. Dangoumau, L., Richard, G. and Puech. A. J. (1991) Safety signal withdrawal: a behavioural paradigm sensitive to both ‘anxiolytic’ and ‘anxiogenic’ drugs under identical experimental conditions. Ps~~cllopilrrrnlucolog~ 103: 4 1S-424. Thomas. D. R., Nelson. D. R. and Johnson, A. M. (1987) Biochemical effects of the antidepressant paroxetine, a specific S-hydroxytryptamine uptake inhibitor. Psychopharmacology 93: 193-200. Tokuyama. S.. Takahashi, M. and Kaneto, H. (1993) Involvement of serotonergic receptor subtypes in the production of antinociception by psychological stress in mice. Jup. J. Pharmac. 61: 237-242. Tomkins, D. M.. Costall. B. and Kelly, M. E. (1990) Action of ritanserin and DO1 on the elevated X-maze. P~~~~~12opharnlrccolog~101:S57. Traber, J., Davies. M. A., Dompert, W. U., Glaser, T., Shuurman, T. and Seidel, P.-R. (1984) Brain serotonin receptors as a target for the putative anxiolytic TVXQ 7821. Bruin Res. Bull. 12: 741-744. Treit. D. (1985) Animal models for the study of anti-anxiety agents: a review. Neurosci. Biobehnr. Rer. 9: 2033222.
and 5-HTIA agonists: animal models. In: 5-HT,,, Agonists, Behurioural Pharmacology, pp. 107-I 32, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Treit, D. and Fundytus. M. (1988) A comparison of buspirone and chlordiazepoxide in the shock-probe/burying test for anxiolytics. Pharmuc. Biochem. Behar. 30: 1071~1075. Treit, D.. Robinson, A., Rotzinger, S. and Pesold, C. (1993) Anxiolytic effects of serotonergic interventions in the shock-probe burying test and the elevated plus-maze test. Behar. Bruin Res. 54: 23-34. Tye, N. C., Everitt, B. J. and Iversen, S. D. (1977) 5-Hydroxytryptamine and punishment. Nature 268: 741-743. Treit, D. (1991) Anxiolytic 5-HT,
Antngonistsnnd
effects of benzodiazepines
Ben~odiuzepines,
Their Comparative
G. Griebel
394
Tye, N. C., Iversen, S. D. and Green, A. R. (1979) The effects of benzodiazepines and serotonergic manipulations on punished responding. Neuropharmacology 18: 689-695. Tyers, M. B. (1989) A review of the evidence supporting the anxiolytic potential of 5-HT, receptor antagonists. In: Behavioural Pharmacology of5-HT, pp. 3533359, Bevan, P.. Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Tyers, M. B., Costall, B., Domeney, A., Jones, B. J., Kelly, M. E., Naylor, R. J. and Oakley, N. R. (1987) The anxiolytic activities of 5HTI antagonists in laboratory animals. Neurosci. Left. 29 (Suppl.): S68. Upton, N. and Blackburn, T. P. (1991) Anxiolytic-like activity of the selective 5-HT, receptor antagonist, BRL 46470A, in the rat elevated X-maze test. Br. J. Pharmac. 102 (Suppl.): 253P. Van Dijken, H. H., Tilders, F. J. H., Olivier, B. and Mos, J. (1992) Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats. Ps_ychopharmacology
109: 395-402.
Van Praag, H. M. (1988) Serotonin disturbances in psychiatric disorders: functional versus nosological interpretation. Ado. Biol. Psychiat. 17: 52-57. Van Riezen, H., Pinder, R. M., Nickolson, V. J., Hobbelen, P., Zayed, I. and Van der Veen, F. (198 1) Mianserin. In: Pharmacological and Biochemical Properties of Drug Substances, Vol. 3, pp. 56-93, Goldberg, M. E. (ed.) American Pharmaceutical Association, Washington. Van Wijngaarden, I., Tulp, M. T. and Soudijn, W. (1990) The concept of selectivity in 5-HT receptor research. Eur. J. Pharmac.
188: 301-312.
Vasar, E., Peuranen, E., &pik, T., Harro, J. and Minnistii, P. T. (1993) Ondansetron, an antagonist of 5-HT, receptors, antagonizes the anti-exploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze. Psychopharmacology 110:2 13-2 18. Vivian, J. A. and Miczek, K. A. (1993) Antagonism ofdiazepam withdrawal by gepirone startle and ultrasounds. Sot. Neurosci. Abstr. 19: 756. Wada, T. and Fukada, N. (1991) Effects of DN-2327; a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze. Psychopharmacology 104: 4444450. Walters, J. K., Davis, M. and Sheard, M. H. (1979) Tryptophan-free diet: effects on the acoustic startle reflex in rats. Psychopharmacology 62: 103-l 09. Weissman, B. A., Barrett, J. E., Brady, L. S., Witkin, J. M., Mendelson, W. B., Paul, S. M. and Skolnick, P. (1984) Behavioural and neurochemical studies on the anticonflict actions of buspirone. Drug Dec. Res. 4: 83-93.
in anxiety and related disorders. In: 2nd International Symposium on and Therapeutics, p. 24, Houston, 15-18th September. Westenberg, H. G. M. and den Boer, J. A. (1988) Clinical and biochemical effects of selective serotonin-uptake inhibitors in anxiety disorders. Adv. Biol. Psychiat. 17: 84-99. Wettstein, J. G. (1988) Behavioral effects of acute and chronic buspirone. Eur. J. Pharmac. 151: 341-344. Wettstein, J. G. (1992) 5-HT, receptor ligands as potential anxiolytics. In: Central and Peripheral 5-HTj Receptors, pp. 257-274, Hamon, M. (ed.) Academic Press, London. Whitton, P. and Curzon, G. (1990) Anxiogenic-like effect ofinfusing I-(3-chlorophenyl) piperazine (mCPP) into the hippocampus. Psychopharmacology 100: 1388140. Wiley, J. L., Compton, A. D. and Porter, J. H. (1993) Effects of four antipsychotics on punished responding in rats. Pharmac. Biochem. Behav. 45: 263-267. Williams, J. H., Meara, J. R. and Azmitia, E. C. (1990) Effects of 5,7_dihydroxytryptamine injections in the fornix-fimbria on locomotor activity in photocell cages and the open field. Behac. Brain Res. 40: 37-44. Winslow, J. T. and Insel, T. R. (1991a) Infant rat separation is a sensitive test for novel anxiolytics. Prog. Neuro-Psychopharmac. biol. Psychiat. 15: 745-757. Winslow, J. T. and Insel, T. R. (1991b) Serotonergic modulation, of the rat pup ultrasonic isolation call: studies with 5HT, and 5HT2 subtype-selective agonists and antagonists. Psychopharmacology 105: 513-520. Winter, J. C. (1972) Comparison of chlordiazepoxide, methysergide, and cinanserin as modifiers of punished behavior and as antagonists of N,N-dimethyltryptamine. Arch. Int. Pharmacodyn. 197: 1477159. Wise, C. D., Berger, B. D. and Stein, L. (1972) Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177: 180-183. Witkin, J. M. and Barrett, J. E. (1986) Interaction of buspirone and dopaminergic agents on punished behavior of pigeons. Pharmac. Biochem. Behao. 24: 751-756. Witkin, J. M. and Perez, L. A. (1989-1990) Comparison of effects of buspirone and gepirone with benzodiazepines and antagonists of dopamine and serotonin receptors on punished behavior of rats. Behav. Pharmac. 1: 247-254. Witkin, J. M., Mansbach, R. S., Barrett, J. E., Bolger. G. T., Skolnick, P. and Weissman, B. (1987) Behavioral studies with anxiolytic drugs. IV. Serotonergic involvement in the effects of buspirone on punished behavior of pigeons. J. Pharmac. exp. Ther. 243: 970-977. Wojnicki, F. H. E. and Barrett, J. E. (1993) Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response. Psychopharmacology 112: 26633. Wong, E. H. F., Wu, I., Eglen, R. M. and Whiting, R. L. (1992) Labelling of species variants of 5-hydroxytryptaminez (5-HT,) receptors by a novel 5-HTI receptor ligand [ZH]RS-42358197. Br. J. Pharmac. 105 (Suppl.): 33P. Wright, I. K., Heaton, M., Upton, N. and Marsden, C. A. (1992a) Comparison of acute and chronic treatment Westenberg,
Serotonin,
H. G. M. (1992) Serotonin
from
Cell Biology
to Pharmacology
5-HT-interacting of
various
serotonergic
Psychopharmacology
agents
with
those
of
drugs
diazepam
395 and
idazoxan
in
the
elevated
X-maze.
107: 405-414.
Wright, I. K., Upton, N. and Marsden, C. A. (1992b) Effects of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. Psychopharmacology
109: 338-346.
Yagaloff, K. A. and Hartig, P. R. (1985) [“‘I]LSD binds to a novel serotonergic site on rat choroid plexus epithelial cells. J. Neurosci. 5: 3 178-3 183. Ybema, C. E., Slangen, J. L., Olivier, B. and Mos, J. (1992) Discriminative stimulus of the serotonergic compound eltoprazine. J. Pharmac. exp. Ther. 260: 1045-1051. Young, R. and Johnson, D. N. (1988) Comparative effects of zacopride, GR 38032F. buspirone and diazepam in the mouse light/dark exploratory model. Sot. Neurosci. Abstr. 14: 207. Young, R. and Johnson, D. N. (1991a) Anxiolytic-like activity of R( +)- and S( -)-zacopride in mice. Eur. J. Pharmac.
201:
151-155.
Young, R. and Johnson, D. N. (1991b) Comparison of routes of administration and time course effects of zacopride and buspirone in mice using and automated light/dark test. Pharmac. Biochem. Behat>. 40: 733-737. Young, R. and Johnson, D. N. (1991~) A fully automated light/dark apparatus useful for comparing anxiolytic agents. Pharmac. Biochem. Behac. 40: 739-743. Young, R., Urbancic, A.. Emrey, T. A., Hall, P. C. and Metcalf. G. (1987) Behavioral effects of several new anxiolytics and putative anxiolytics. Eur. J. Pharmac. 143: 361-371. Zhang, H. T. and Luo, Z. P. (1993) Potentiating effect of clonidine on anxiolytic action of buspirone in rats. Acta pharmac.
sin. 14: 354-357.
Associate
Pharmac. T/w. Vol. 65, pp. 319-395, 1995 Copyright (0 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0163-725X/95 $29.00
01617258(94)00065-4
Editor: B. E. LEONARD
5-HYDROXYTRYPTAMINE-INTERACTING DRUGS IN ANIMAL MODELS OF ANXIETY DISORDERS: MORE THAN 30 YEARS OF RESEARCH GUY GRIEBEL* Laboratoire
de Psychophysiologie,
7 rue de I’iJnicersiti,
67000 Strasbourg,
France
Abstract-An overview of the behavioral data arising from the vast literature concerning the involvement of 5hydroxytryptamine (5-HT) neurotransmission in the regulation of anxiety is presented. More than 1300 experiments were carried out in this area and they provide evidence that: (1) results obtained in ethologically based animal models of anxiety with drugs stimulating S-HT transmission are most consistent with the classic 5-HT hypothesis of anxiety in that they show an increase in animals’ emotional reactivity; (2) no category of anti-anxiety models are selectively sensitive to the anxiolytic-like effects of drugs targetting 5-HT,,, 5-HTzA or 5-HTZc receptor subtypes; (3) anxiolytic-like effects of 5-HT1 receptor antagonists, in the great part, are revealed by models based on spontaneous behaviors. Taken together, these observations lead to the conclusion that different 5-HT mechanisms, mediated by different receptor subtypes. are involved in the genesis of anxiety. Keywords-5-HT (serotonin), 5-HT conditioned paradigms, unconditioned
ligands, 5-HT paradigms.
receptors,
animal
models
of anxiety,
CONTENTS 1. Introduction 2. Animal Models of Anxiety Disorders: Attempts at Classification 3. Behavioral Effects of Drugs Modulating 5-Hydroxytryptamine Neurotransmission Animal Models of Anxiety 3.1. Behavioral actions of central application of 5-hydroxytryptamine and peripheral administration of 5-hydroxytryptamine indirect hgands 3.1.1. 5-Hydroxytryptamine 3.1.2. 5-Hydroxytryptamine reuptake inhibitors (SRls) 3.1.3. p-Chlorophenylalanine 3.2. Behavioral effects of direct-acting 5-hydroxytryptamine hgands 3.2.1. 5-HydroxytryptaminelA receptor ligands 3.2.2. 5-HydroxytryptaminelH receptor agonists 3.2.3. 5-HydroxytryptaminezA and 5-hydroxytryptamine2c receptors 3.2.4. 5-Hydroxytryptaminei receptor antagonists 4. Perspectives and Summary Acknowledgements References
320 367 in 367 367 367 370 370 371 372 372 373 374 374 377 377
Abbreviations-CER, conditioned emotional response; DPAG, dorsal periaqueductal gray: 5-HT. 5-hydroxytryptamine; S-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; mCPP. I-(3-chlorophenyl)piperazine; PCPA, p-chlorophenylalanine; SRI, 5-hydroxytryptamine reuptake inhibitor; TFMPP, l-(3-trifluoromethylphenyl)piperazine. *Present address-Synthhlabo Recherche (L.E. R.S.), CNS Pharmacologic Group, 31. ~IIYVIUOPaul Vaillant-Couturier, B.P. 110. 92225 Bagneux Cede.u, France.
320
G. Griebel 1. INTRODUCTION
It has been suggested on the basis of previous behavioral studies that 5hydroxytryptamine (5HT) could be considered as a central neurotransmitter involved in the modulation of emotional behavior (Sudak and Maas, 1964; Geller and Blum, 1970; Wise rr al., 1972; Stein et 01.. 1973; Crow and Deakin, 1981). This view mainly arose from some observed activity of 5-HT antagonists in operant conflict paradigms (Robichaud and Sledge, 1969) as well as from an association between reduction in turnover of 5-HT and the anxiolytic effects of benzodiazepines (Goldberg et al., 1967). It is now acknowledged that a reduction of the function of brain 5-HT pathways often leads to an anxiolytic-like effect, whereas increased activity of ascending 5-HT pathways usually results in an anxiogenic-like effect (Gardner, 1986; Chopin and Briley, 1987). However, the picture is nowhere near as clear. The behavioral effects of drugs decreasing the activity of the central 5-HT system are often more variable than the effects of standard anxiolytics, and not all findings are accounted for by the classic hypothesis. There are a few instances in which these compounds produce effects opposite to those of standard anxiolytics, suggesting an anxiogenic-like action. Moreover, in some studies, drugs known to possess a 5-HT-stimulating action displayed anxiolytic-like properties, while in others they potentiated animals’ emotional reactivity. Finally, a great number of studies found no evidence for an anxiolyticor anxiogenic-like effect of drugs modulating central 5-HT neurotransmission. This is exemplified by Fig. 2, which illustrates the variability in behavioral effect of some of the most studied compounds interacting with the 5-HT neurotransmission. As an illustration, the central application of 5-HT results in an anxiogenic-like action in half of the studies. whereas in the other half, authors obtained the opposite effect. This variability is probably due to a number of factors, including administration routes (Treit. 1991). doses used (Soderpalm et al., 1989), species differences (Barrett and Gleeson, 1991). the sex of the animals (Hughes, 1993) or the environment in which a test is conducted (Wettstein, 1992; Griebel et al., 1993). Certain authors point to a determining role of the experimental paradigms used when studying 5-HT agents in animal models of anxiety disorders. Variation in the effects might reflect differences in the degree to which the models themselves represent fear or anxiety (Handley, 1991; Treit, 1991; Wettstein, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a,b,c). These behavioral tests have been useful in the preclinical testing of benzodiazepine-type anxiolytics, in studying the functional relevance of the benzodiazepine receptor system, and in characterizing the effects of benzodiazepine antagonists, partial agonists, and inverse agonists (for recent reviews, see Barrett and Gleeson, 199 1; Treit, 199 1). However, the validation of these paradigms has depended primarily on their sensitivity to benzodiazepines only, and the recent introduction to clinical practice of non-benzodiazepine anxiolytics such as buspirone has challenged the validity of these tests as general models of anxiety disorders. The possibility that these tests may be less sensitive to agents not acting at benzodiazepine receptors has been advanced to explain these inconsistencies (Richards PI ul.. 1991). The main objective of this review is to provide an overview of the developments in research involving the 5-HT system and anxiety. The emphasis will be on a review of the results of animal models used to evaluate these drugs with the help of a synoptic table that summarizes the studies investigating the behavioral effects of 5-HT compounds in this area from 1961 to November 1993 (Table 1). This table is composed of following sections: (I) name of drug (starting with 5-HT. p-chlorophenylalanine (PCPA), 5-HT reuptake inhibitors, and ending with 5-HT, receptor antagonists); (2) its affinity for 5-HT receptors; (3) animal models of anxiety used; (4) animals and strains used and their weight or age; (5) efficient doses or doses tested; (6) administration route and latency period; (7) effect observed; (8) comments; and finally, in column 9 the pertinent references are indicated. In Section 2, we will briefly review some aspects of the literature concerning the animal models of anxiety disorders used in investigations of the behavioral actions of psychotropic drugs. Section 3 will focus on the studies evaluating the behavioral actions of 5-HT compounds in animal models of anxiety. The results obtained with these agents will be considered and discussed for the most important 5-HT receptors. Outcomes of some of the most studied compounds, such as 5-HT. 8-OH-DPAT, buspirone, mCPP or ondansetron, will be illustrated graphically with attention to the types of behavioral procedures used. This will allow examination of the possibility that involvement
5-HTP (5-HT precursor)
5-HT
Compounds
3.1
5.HT,A
3.4
5-HT,e
2.8
5.HT,n
2500
5-HTu
Affimt~es (Ki, no)
3.1
5-HTx
22’
5.HT,
test
Modified Vogel’s test FR50
_ + _
40 40
25-100
Wistar rats (I 5CL2OOg)
Mice
i.p. 60 S.C. 60 i.p. 30
25 2.5-160 5-50
30
t.p.
30
30
p. 30
Fear-potentlated Ltster rats (375415g) startle reflex Shock-probe Wtstar rats (25&280g) burying test Marble burymg test Female MFI mice
pmol
40
28448
i. p. 30
10&400 50 50
i.m.
p. 30
I8
+
0
_
Locomotion reduced
ef al.. 1990
er al., 1990
el al., 1989
Njung’e
199lb
1986a
Continued
and Handley,
Meert and Colpaert,
1989
er al., 1990 Glenn and Green,
Kshama
Cheng e, al.. 1992
Kshama
Kshama
_
Saderpahn
and Ferster,
er al.. 1987
_
Aprison
Hjorth
_ In combination with tranylcypromine In combination with tranylcypromine and asymmetric compartments Asymmetric compartments In combination with tranylcypromine
Kilts et al., 1982
VI21
_
i.p. 120
er al., 1984
Davis er al., 1980b
1961
Geller and Blum, 1970
_
15
SpragueeDawley rats (2OOg) Sprague-Dawley rats (180-2500) White Carneau Pigeons (6 months) Sprague-Dawley rats (25s35Og) Wistar rats (15&2OOg)
rats
10 IO
Schiitz et al., 1985 Graeff er al., 1986
DPAG, DPAG,
+ +
5-20 nmol 5-20 nmol
Wistar rats (25s300g) Rats
Thiibot
+ +
et al., 1991
1993
et ol., 1988d
al., 1973 e, ol., 1987 al., 1972 er al., 1982
Geyer er al., 1975
Higgins
Griebel,
Costall
Stein el Hodges Wise er ThiCbot
i.c.v., 8 days i.t. Dorsal raphe
IO nmol
Sprague-Dawley
References Wise er ol.. I972
200 /Jg
LLF HLU
Asymmetric compartments
CRF
VI20
Comments
_ + +
_
+ +
_
_
Effects
Amygdala, 5 Dorsal mph&, 5 i.c.v.
i.c.v., 30
Dorsal raphC
i.c.v., 0 Amygdala, 0 i.c.v., > 20 Dorsal raphe
i.c.v., IO-20
100-10000 ng 20-100 ng I-15.625 fig
2.5-5 pg
Rats
Swiss mice (10 weeks) Lister rats @l&280 g) Sprague-Dawley rats (320-400 g) Rats (30&4OOg)
20 pg l-5 pg I-10 pg l&100 nmol
Rats Rats (382446 g) Rats Wtstar rats ( 195-205 g) Mice (25-35 g) IO ng
I-10 /lg
Rats
Animals
Routes administration, latency (min)
in Animal Models of Anxiety.
Efficient doses or doses tested (mgikg)
5-HT Neurotransmission
Wistar rats (IS&ZOOg)
test
maze
test
Holeboard
Light/dark
Elevated-plus
Conflict
Vogel’s conflict test
Geller-Seifter
Conditioned emotional response DPAG-stimulation
Fear-potentiated startle reflex
Social interaction
Light/dark
GellervSeifter conflict test
Models
Table 1: EJJects of Drugs Modulating
322
G. Griebel
t
+
+Gs++
i.p. 14 days i.p. during 3 days i.p. during 2 days i.p. during
100 32&900 300 75-150 316
Rats (25Og)
+
i.p. I5 1.p. I5
5 5
Geller-Seifter conflict tet
5.7-DHT (5.HT neurotoxin)
1 Pg 2 vg 1 KS 2 Fz
Dorsal raphe, I5 days Ventromedian tegmentum, 12 days Dorsal raphe, I5 days Substantia nigra. I5 days
3 fig
Wistar rats (195-2058) Wistar rats Sprague-Da&y rats (25&3OOg) Wistar rats
Dorsal raphe, 21 days
100 vg
Rats
I.C.“., 2
0
i.p. 2-15 hr
5
Sprague-Dawley rats (250-3008) Sprague-Dawley rats (300-400g) Sprague~Dawley rats (25&3OOg)
Fear-potentiated startle reflex
+
+
+
0
0
+
0
i.p. 9 and 8 days
0
+
0
IO
i.p. 30
i.p. 60
+
VI21
CRF/FR7
CRFIFR7
CRF
Modified Vogel’s test Modified Vogel’s test
199lb
1975
1973
cf ul.. 1982
ThiCbot <‘I ol., 1983
1976
1976
Thiebot P, al., 1984 Tye CI rrl., 1977
Thiebot
Stein PI al., 1975
Davis and Sheard.
Davis et al., l988a
Davis and Shard,
Chojnacka-Wbjcik and Przegalinski, 1991 Przegalinski PI al., 1992
Njung’e and Handley,
Kilts er al., 1982
Ogawa PI rrl., 1993
Ogawa rr al.. 1993
Kiser and Lebovitz,
_
+
Lecci er al.. 1990
Wistar rats (lSG22Og)
l-10
0.25-I
and Advokat.
Fechter, 1974 Davis cf al.. 1988a
Carlton
0
0
0
i.p. 9 and 8 days
SpragueeDawley rats (2009) Female MFI mice (23s35g)
Wistar rats (7-S weeks)
p.“. 60 p.“. (7-8 weeks) p.“. 60
,.p. 3-18 days
3 days
Hard PI al.. 1982 Hard E, al.. 1982
+ +
_
Tenen, 1967
+
Conner r, al., 1970
Trelt et al., 1993
+
IO
GellervScifter conflict text
190r
S.C. 14 days
300
Long-Evans rats (70 days) Sprague-Dawley rats (175-2008) Rats Sprague~Dawley rats (3WWg) Swiss mice (25-306)
25-50 5-50 25
1.p. during 4 days 1.p. during 3 days
300 100
Rats (15-25 days) Rats (416 days)
ICR mice (7-8 weeks)
p.“. dung
100
rats 3 days
i.p. during 4 days
130
rats
Sprague-Dawley (25G35Og) Sprague-Dawley (3OOg)
Vogel’s conflict test Wistar rats (lSt%22Og)
5.6.DHT (5-HT “eurotoxin)
PCA (5-HT neurotoxin)
test
Vogel’s conflict test
Fenfluramine (5-HT stimulant) Marble burying
Unavoidable stress (gastric lesion) Passive-avoidance test
SC-48274 (S-HT stimulant)
Stress-induced hyperthermia DPAG-Stimulation
Shock-probe burying test Disruption of drinking induced by stress Freezing Ultrasonic ‘distress’ vocalization Fear-potentiated startle reflex
6
E:
s. fi z 2 5’ 09
3
r
324
G. Griebel
21000 inhibitor)
Fluoxetme (5.HT rcuptake inhibitor II500 (ICr, = 27 n~)ll’
Clomipramine (5-HT reuptake
Citalopram > 10000 (5.HT reuptake inhlbitor) (ICr, = 3.8 “MY”
Cianopramine (5-HT reuptake inhibitor) (ICw = 1.5 “M).1”’
6170
4266
> IOOOP
1820
180
269
r::
II220 *,u
test
Swiss mice (I 0 weeks)
Wistar rats (15&22Og)
test
Rats Wistar rats (15&2OOg)
Holeboard Wistar rats (15&2OOg) Ultrasonic ‘distress’ Wtstar rats (9-l I days) vocalization Wistar rats (9-l I days) Novelty-suppressed Long-Evans rats (30&325g) feeding
Light/dark
0
+
,.p. 30-120
30 30 30 i.p. 60 during 21 days (xl)
20 IO
i.p. 30 30
+
+ _
0
_
+ _
+
i.p. 30 30
+ 1-p.
0
0
+
+
_
_
+
0
_
+
_
+
S.C.
IO 5m20
1.25~10 10
5-10 IO
5 LED = IO 15
Rats Adult rats Rats (25Og)
Ultrasonic ‘distress’ vocalization DPAG-Stimulation
30 i.p. 30
S.C.
I
l-50 3-10
S.C. 45 i.p. 30 i.p. 30 i.p. 30 i.p. 30
Rats Rats
Vogel’s conflict test Rats Elevated-plus maze Wistar rats (15&2OOg)
i.p. 30 i.p. 21 days (xl)
i.p. 30 i.p. during 21 days (xl) i.p. 30
dung
10 l&30 l-30 30 l-20
4
l-10 IO IO
I-IO IO
IO
Cold condltlon
Warm condition
Asymmetric compartments
Chronic and acute treatments
FR8, weak effect
Bodnoff er al., 1989
_
i.p. 60 21 days (xl) 60 during 21 days (xl)
IO +
0
i.p. 30
I-8
during
Gardner.
0
S.C. 60
I986a
1976
Mos and Olivier, 1989 Bodnoff er al., 1989
Kshama PI rrl.. 1990 Mos and Olivier, 1989
Handley and McBlane. Kshama er ul.. 1990
Handley and McBlane, Kshama Ed ul.. 1990
1992
1992
Winslow and Insel, l99lb Molewijk PI nl., 1993 Kiser er al.. 1978
Schoenfeld, File, 1985
Winslow and Insel, 199lb
Broekkamp and Jenck, 1989 Griebel 6’1a/ ( 1994 Griebel P, al., 1994 Griebel cf a/., 1994 Njung’e and Handlcy, 199lb
HascoEt er al., 1992
Griebel PI al., 1994
Griebel CI al., 1994
Griebel e, ul.. 1994
Bodnoff et al.. 1988
1985~1
Meert and Colpaert.
Costall CI al., 1989b
0.6340
Asymmetric compartments and sedation (“)
1991
i.p. 45
Klint,
30
0
S.C. 30
0.1~1
Vogel’s conflict test Social interaction
Vogel’s conflict test Rats Elevated-plus maze Wistar rats (15~-2208) Light/dark test Swiss mice (I 0 weeks) Free-exoloration test Swiss mice (IO weeks) Marble’ burying tesi Female M‘FI mice (23-358) Ultrasonic ‘distress’ Rats vocalization
Rats
test Swiss mace (IO weeks)
test
maze
Geller-Seifter conflict test
Free-exploratmn
Light/dark
Elevated-plus
Shock-probe Wistar rats (25&2X0& burying test Ultrasonic ‘distress‘ Wlstar rats (9-12 days) vocalization Novelty-suppressed Long-Evans rats feeding (30&325g) Long-Evans rats (30&325g
Light/dark
Sprague-Dawley rats (200&25og3 BKW mice (20 3Og)
;=: vl
?
g O9
2 3 6
i.
5.HT,,
(5-HT reuptakc
lllllpMlll”~
mhlbltor)
2lOOOh
Fluvoxamme > 10000 (5.HT reuptake Inhlbttor) (ID,, = 5 mg kg)“’
Compounds
5.HT,n
5.HT,,
,lM)
>
260’
I00
5.Hl’x
1000”
5-HTzs
Affimtles (KI.
5708
S-HT?
Animals
j-10 LED = 20 5.-20 0.6340
Wistar rats (400-5OOg) Wlstar rats (25&28Og)
Social competitton Ultrasonic ‘distress’ vocalization Conditioned emotional response Shock-probe burying test
IS
Long-Evans rats (105-117 days) Wistar rats (12Og) Adult rats
3.16
Defense test battery
mice
S.C. 60
i.p. 30
i.p. 30 1-p.
1.p. 60 i.p. during II days (xl) i.p. 60 1.p. durmg 1 I days (xl) i.p. during 3 weeks (xl)
i.p. 30
i.p. 30
i.p. 30 p.o. 60
s-15 l-30 I-4
30
I-30 8 32
20
Female JCR-DUB (l7m35g)
+
t.p. during l-5 weeks (x2)
25
Female Long Evans rat (I2 weeks)
test
Light;dark
Llster rats (2504OOg) SpragwDawley rats (170~2OOg) ICR mxe (20-358)
0
i.p. 30
I - IO
I “I. 15
Modified
_
1.p. IO
7. I-20
0
+
0 +
0 o +
+
0
0
0
T
1973
Vogel‘s test
TransitIons and AsymmetrIc compartments Locomotmn decreaxd and Asymmetw compartments Saline mJectron
Co”l”ll~sarls.
1991~
IYXY
CI N/
1993
1990 Meert and Colpaert.
Sanger,
1986a
Joly and Singer. 1991 Molewijk (1, ol.. 1993
Blanchard
Dwyer and Roy. IYY3
Young and Johnson.
Onaivi and Martm.
Pclloa PI f/l 1985 Luscombe er nl lY90
I088 Nanry PI N/.. lY9l Martin. lY93
Fontanuand
Vogel’s test Fontsna and Commissar~s. IYX8 VI21 Kilts PI ul.. 19x1
L’, ol.. 1983
Sanger. 1992 Cook and Dawdson. Kilts E, nl.. I981 Vogel’\ test McCown
Caffeine-pretreated rats
Modified
Modified
_
i.p 30
VI30 V1301FRIO FR40
Mos and Olivier, 1989 Molewijk E, nl., 1993 Van DiJken ef o/.. IYY?
Cold conditmn
1989
199lb
Mos and Ohwer.
I O&300
0
References Olivier er ul., 1989 Njung‘e and Handley,
Warm condition
mxe
Comments Isolated
i.p. 30 p.0. i.p. 20 0
+ + 0 o
0
+
_
ElT&S
20 0.55-17.7 I-IO
30 1.p. 1-p. 30 I p. during I4 days (xl)
30
5-20 LED=3 3-30
1.p. 30
5 -20
1.p.
Routes administratm”. latency (min)
I I-20
Open-field
maze
Elevated-plus
Wistar rats (180~2OOg) Rats SpragwDawley rats (20&3203) Vogel’s conflict test Sprague -Dawley rats (2% 3oog) Female Sprague-Dawley rats (225-275~) Sprague~Dawley rats (20s32Og) Female Sprague-Dawley rats (225-2753) Conflict test White Carneau pigeons Shuttle box Rats Geller-Seifter confhct test
DAP mice (22-3Og) Female MFI mice (23-358) Ultrasomc ‘distress’ Wistar rats (9-I I days) vocalizatto” Wlstar rats (9-l I days) Adult rats Freezing Wlstar rats (2%3OOg)
Models Social interaction Marble burymg test
Efficient doses or doses rested (@kg)
Table 1. Continued
0 1.
0
Inhibitor)
agonist) 7.1
1698~ agorust)
2-Me-S-HT (non-selective
stimulant)
Y-Me-S-HT (non-selective pKo s
Txaneptme (5-HT reuptake
Zmzlidme (5-HT reuptake inhibitor)
s3344 (5-HT rcuptake
Paroxetine > 10000 (5-HT reuptake inhibitor) (ED>,, = I .9 mg/kg)
724
6.0
Indalpine 9120 4467 (S-HT reuptake inhibitor) (ICV, = 2.x IIMP”
1800’
6.2
3630
>10000”
6.6
489’
7.2
3235
> 3OO@‘V
> IOOOP
794
210‘,?”
maze
‘distress’
Wistar rats (15&2OOg) Wistar rats (150-200g)
Rats
Rats
CD rats
Lister rats (20&25Og)
Wistar rats (220g)
Female MFI mice ,?I ng,
maze
test
Social interactmn
Light/dark
GellervSeifter conflict test Conflict test
Social interaction
Elevated-plus
pigeons
Lister rats (210-2808)
BKW mice (25-30%)
Mice (25-35g)
White Carneau
Female CFN rats
Rats
Lister rats (20&25Og)
Lister rats (200-250g)
Wistar rats (15&2OOg) Female MFI mice (23-358) Ultrasomc ‘distress’ Wistar rats (9-l I days) vocalization Wistar rats (9-I I days) DPAG-Stimulation Wistar rats (25&3OOg) Rats Wistar rats (200-250g) test
maze test
Holeboard Marble burying
Elevated-plus Ltght/dark
Social interaction
Ultrasonic
Social interaction
Elevated-plus
Vogel’s conflict test
1200”1v Marble burymg test
test
Rats Long-Evans (325-500~) Fear-potentiated Sprague-Dawley rats startle reflex (300-4OOg) Passive-avoidance test Wistar rats (22&24Og) Conditioned place Long-Evans rats aversion (8 weeks) Cork gnawing Long-Evans rats (435-64Og)
Marble burying
30
l-10
0.001~.1 0.001~.0025
O.OOOOOOl~.OOOl
0.0000001-0.0001
1-3
0.3-2
IO 2.5-10 2.5-10 5-10 2.5-10
100nmol
100 nmol
IO0nmol
20 days (xl) 20 days (xl) 30
Dorsal raphe Amygdala or median raphi Amygdala. 5 Dorsal raphC
Dorsal raphe
i.m. 0
i.p
i.p. 5 i.p. during 5 i.p. durmg
30 DPAG, IO DPAG, IO DPAG, IO OT 20
30 i.p. 30
40 l-30
3-10
30 30
40 40
2.5-20
I i.p. 15
pa during 3 weeks (xl) pa during 3 weeks (xl) S.C. 3 weeks (xl)
3 3
i.p. 30
5
i.p. 30
0
p.0. 30
4-32
I-20
0
7.5-30 2-24
Modified
u al.. 1990 er al.. 1990
LLF HLU and LLF
_
F15/FR30
V130/FRIO
1972
and File, 1993
1991
1991
Higgins tv ul.. 1991
Costall PI ol.. 1989~
Costall er a/., 1988~
Graeff and Schoenfeld.
Winter.
Andrew
File and Mabbutt,
File and Mabbutt.
Mos and Olivier. 1989 Schiitz cr al., 1985 Graeff ef al.. 1986 Audi PI al.. 1988
Cold condition
Weak effect
Mos and Olwer.
1989
Kshama r, ul.. 1990 NJung‘e and Handley.
Kshama Kshama
1970
l99lb
and Insel, 199lb
ef RI.. 1992
PI al., 1992
File, 1984a
Winslow
Lightowler
Cadogan
l99lb
1991
1981
Warm condition
Asymmetric compartments
Weak effect
Asymmetric compartments Asymmetric compartments
0
Njung’e and Handley,
Pollard and Howard.
Sanger P, al., 1989 Erwin er al.. 1987
Vogel’s test Petersen and Lassen,
_
0
0
+
0
0
+
+
+
+
+
0
+
_
_
+
+
+
0
+
0
Cassella and Davts. 1985
0 o
i.p. 5 i.p. during 3 weeks (xl) .p. 30 .p. 60
5-10
Craft e, al., 1988
+
i.p. 30
416
5 I?”
0.32” agomst)
08 agontst)
antagomst)
antagonist)
7 9D antapomrt)
Lisuride (non-selective
Bromo-LSD (non-selective
DMT (non-selectwe
Metergoline (non-selective
39 8b
199
5.HT,.
5-HT,,
5.CT (non-zelectlvc
Comoounds
0 79”
36 6
2s
S-HT,,,
Aflinitics
Ih
5.01”
633”
0.64”
19.9
630”
~-HT~A 5-H-f.<
(Ki. no)
7400’
5.HT?
Models
test
Animala rats rats rats rats
(210-27Og) (200-25Og) (200 -25Og) (2lO-270~)
rats(200-2508)
pigeona
Female MFI mice (23-358) Ultrasonic ‘distress‘ Wistar rats (Y-12 days) vocalization Fear-potentiated Sprague-Dawley rats startle reflex (32&35Og)
Shock-probe boring test Marble burying test
Social interaction
Sprague-Dawley rats (20&25Og) Rats Wistar rats (18&2OOg) Sprague-Dawley rats (200-2508) Wistar rats (25&28Og)
70
i.p. 30
0.1-10
I p.
i.p. 30
O.IC-I
I
S.C. 60
0.63-10
i.p. 60
0.1&X62
p.0. 30 S.C. 40
1.p. 30 i.p. 40
4 4 0.05-10
5-20 2.5
i.m. 30 i.m.
0
i.p. 60
2-4 0.56 0.03-0.3
0
i.p. 180
0.25-2
0
+
+
+
0
0
0
0
+
+
+
+
0
+
p.0. 1.p. 10
2.5-20 0.25-2
0
_
+
+
+ +
+ +
Effects
Rats Sprague-Dawley rats (20&225g) Sprague-Dawley rats (20% Wistar rats (18&22Og)
0
5 5
5 5
p.o. 25
i.p.
im
i.p. 30 i.p. IO
Dorsal mph&, Dorsal raphe, DPAG, 0 Dorsal raphC, Dorsal raphe,
20
2-7
0.1-3
0.05-O. I 0.05-0.8
0.0001-0.001 0 00002-0.0005 l-10 nmol 0.00002 0.00002-0.0001
Routes administratton. latencv (min)
Rats
Female CFN rats
White Carneau
Wistar rats Sprague-Dawley rats (320-35Og)
L1ster Lister Llster Lister Lister
Pigeons Columbia livia Squirrel monkeys (550-9lwg) maze Rats Ltster rats (2%35Og) Mice (2%35g) test
test
Open-field
Light/dark
Elevated-plus
Conflict
Vogel’s conflict test
Geller-Seifter conflict test
Geller-Seifter conflict test
Conflict
Vogel’s conflict test Fear-potentiated startle reflex
Open-field Social Interaction
Vogel‘s conflict test
Efficient doses or doses tested (mnlkel
Table I. Continued
al., al.. al., al.. al.,
1987 1988 1992 1987 1988
References ef er er tv er
1972
1986
decreased Myorelaxation
Locomotion
HLU
1970
Kilts er al., 1982
Sullivan er al., 1985 Commissaris and Rech, 1982
Deacon and Gardner.
Wmter,
Graeff and Schoenfeld,
Akai PI al.. 1991 Svensson, 1985
Higgins Higgins Beckett Higgins Higgins
Svensson.
Gardner,
1985
l985a
NJung‘e and Handley,
Meert and Colpaert.
199lb
l986b
File, 1981 Guy and Gardner. 19X5 Kennett CI al., 1989
Lucki cf al., 1989
File CI al., 1987 Pellow rr al.. 1987 Costall er al.. 1988~
Vogel’s test Choinacka-W6icik and Przegalinski, 1991 Leone er al., 1983 FR30 Brady and Barrett, 1985
Sedation and asymmetric compartments
Moddied
VI21
VI30/FRIO
VI30
FI5/FR30
HLU
Comments
Methysergide (non-selective
25h antagonist)
1584h
3.Yh
2.Sh
2.5h
Sprague-Dawley rats (20s32Og) Female CFN rats Wistar rats (l98-260%) Rats Rats Rats (3824468)
Open-field
Sprague-Dawley (2ocr25Og) Rats Sprague-Dawley
rats
Stress-induced colonic motor alterations DPAG-Stimulation
VI21 VI21
_ 0 0
i.p. 30 i.p. I i.p. I i.p. 30 im. 0 i.m. i.p. 30 i.p. 40
IO I-IO l-18 0.3-3 2-20 0.1-3 0.1~1 l-10 0.05~10
i.p. 30
It&30
i.p. 30
2-10
Rats
30
0.3-3
i.p. 30
i.p. 30
5-10
0.1
S.C. 60
IO
Wistar rats (250.300g)
S.C. IO
0.3-10
5-10
L
+
0
0
VI21
_
i.p. 30
IO
i.p. 30
VI21
+
Kilts ef al., 1982
Kilts et al., 1981
Kilts e/ al.. 1982
Kilts et al., 1981
Meert and Colpaert,
File, 1981 Mansbach and Geyer,
Lucki PI al., 1989
Costall cf al., 1988~
Kilts CI al., 1981
High level of illumination
Clarke and File, 1982
1991b
1986b
et nl.. 1993
CUP c, al.. I993
1988 l986b
1989
Meert and Colpaert,
Tokuyama
Mos and Oiivier.
decreased Njung’e and Handley. Warm condition Cold conditin
Locomotion
LLF and HLU
Sedation, ataxia and asymmetric compartments
FR40
Vogel’s test Petersen and Lassen, 1981 Gardner, 1985b FIS/FR30 Graeff and Schoenfeld, 1970 FR30 Brady and Barrett. 1985
Modified
Witkin
VI20 FR30/FRIO
+
1975b
1989
and Perez, 19X9-1990
Winter, 1972 Graeff, 1974 Cook and Sepinwall. Stein e/ al.. 1975 Hodges er al., 1987
3 IO I .25-5 IO 0.0005~.0025 0.25-5 0.1-30
V130/FRIO FIl/FR5 FRIO/VI30
Kilts cf al., I981
+ + +
FR40
Schiitz CI al.. 1985 Jenck el al.. l989a Graeff ef al., 1986
Nanry and Tilson, Gardner, l985b
i.p. i.p. 30 1.p. I i.p. 0 Amygdala, i.p. I5 i.p.
0
0
+
0
0
DPAG, IO t.p. 35 DPAG, IO
S.C. I80
1-p. 30
l-18
10 nmol O.l&lO IO nmol
Wlstar rats (250-300g) Wistar rats (37045Og) Rats
Sprague-Dawley rats (330-37083 Vogel’s conflict test SpragueeDawley rats (20&320e) Spra&-Da&y rats (2OOg) SpragueeDawley rats (200&32Og) Sprague-Dawley rats (2OOg) Wistar rats (220g) Rats Conflict test White Carneau pigeons Squirrel monkeys (55&9OOg) Conditioned Sprague-Dawley rats emottonal response (200-32Og) Light/dark test Mtce (25-358)
Geller -Seifter conflict test
0.5-2 IO 20
CD rats (9-13 weeks) Rats
Social interaction Fear-potentiated rats startle reflex Shock-probe Wistar rats (25&28Og) burying test Marble burying test Female MFI mice (23s35g) Ultrasonic ‘distress’ Wistar rats (9-1 I days) vocalization Stress-induced ddY mice (I 8-20g) anttnociception Defecation-micturition Rats
195OOk
Conditioned emotional response DPAGStimulation
:
E1-
z
fi $ g,
6’
5-H-f,,,
antagonist)
5.Y
125”’ antagonist)
19h antagonist)
Compounda
Alprenolol (non-selectwe
Cyanopindolol
lsamoltanc (non-selective
( - )Pmdolol (non-selective
4l@
Il74”J
630qh
112,”
15 80
5-HT,u
17
5-HT,e
5.HTx
5.HTI
PI al.. 1989 1992
Kennett Kennett.
0
0
0
0
0
1.p. 30
S.C. 40 S.C. 30
i.p 30 i.p. 30
5
6 3-6
2.5-20 2.5-20
Swiss Webster mice (20-35s) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (25@-32Og) Wistar rats (292-368) Wistar rats (144-1968)
maze
test
maze
Stress-mduccd antinociception DPAG-Stimulation
Shock-probe burying test
Marble burying
Social interaction
Open-field
Llght)dark
19800h > lOOO+ > 10000” Elevated-plus
DPAG-Stimulation
Elevated-plus
mteraction
0
+
0
0
0
+
1.p. 30 i.p. 30 i.p. 60 S.C. 30
i.p. 30 i.p. 30 i.p. 30 i.p. 30
3.1 IO l-6
S-10 3.1 3.1 l-3
Swiss mice (2&3Og)
Rats
Swiss Webster mice (20-35g) ddY mice (I S-20@
SWISS Webster mxe (20-3Og) Sprague-Dawley rats (ZOO-25Og) Sprague-Dawley rats (25G-3208) Rats Female MFI nnce (23-358) W1s1ar rats (30&35Og)
0
0
+
0
+
i.p. 30
I 0.1l&c.25 2
Rats PVC (20&28Og)
+
DPAG
WI&II rats
nmol
(18&25Og) 4-32
Fernindez-Gust1 PI al., 1992a Fernzindez-Guasti (‘I nl.. 1992a
0
i.p. 30
5
Shock-probe burying test
0
i.p. 30
References
(k)
LLF
increased Kennett,
Locomotion
1989
I993 Jenck ef al.. 1989b
Fernindez-Guasti PI ol., 19Y2a Fernlndez-Guasti P, nl.. l992a Tokuyama er u..
Critchley er al.. 1987 Npmg’e and Handley.
1992
mcreased Lucki rf al,
1987
1991
199 1b
and 1990 i’f ol.. 1992
and Handley.
and Grxff.
FernPndez-Guastl L6pez-Rubalcaw. Lbpez-Rubalcava
Crltchley
Noguelra
IY9l
, Almeida
(‘I rrl
PI
Almeida
Locomotion
Observatmns durmg IO mm
Rats were well-nourished Rats were malnourished
Colpaert PI ol.. 1992 Fernindez-Guastl and L6pez-Rubalcava, 1990 Lbpez-Rubalcava PI ul.. 1992
5
FR30
Swiss Webster mice w3og) Wistar rats (300-350g)
Comments
0
0
Pigeons Swiss mice (20-30g)
Effects
im. 5 i.p. 30
0.63-10 5
Animals
Models Conflict test Lightfdark test
1. Continued Routes administration. latency (min)
Table Efficient doses or doses tested (%/kg)
31622” > 10000’ > lOOO@ SowI
5.HT:4
Afiimt~es (Ki. no)
Eltoprarmc
(non-srlecti\e
hgand)
40
52
540’
(f)
14@
(+)
390
(i)
1700
(?)
XI
(&)
SSX,’
85. I”
(+)
C-J
158”
2490”
IOOOCP 758”
(-)
(-)
(k)
3162h
46.8”’
antagomst)
Propra”olol
(non-selective
I300
(i)
4000
test
mue
test
interaction
reflex
‘diatres\‘
test
stress
dark
a”cr\Io”
Cot~ditwned
place
‘dl\trcsz‘
YoCilliidtiO”
mice (25-328)
CD-I
mice (324Og)
rats (I 50-2OOg)
(200-3OOg)
mxe
CD-I
(9
days) I I days)
II
309)
(250
3OOg)
Evil”% rat\
rat\
(9.
“I!CC (22
I
IO
I 3
0 3-3
I 20
5 I5
IO
( I2 weeks) (I 2 weeks)
nmol
mg: L
I .25%X IO
weeks)
2.2-8.8
2.5
l-10
1040
I
20
IO
12.4-24.9
I .5-6
I6
l&40
IO
I.5
12.4 -24.9 mg/L
IO
0.0001
rats (150-22Og)
mice (6-X
rat,
Long
Wlrtar
Wistar
DAP
32g)
rats (200&25Og)
mice (25
I days)
Swiss n~tcc
Wtrtar
DBA,2
Wlstar
(Y-l
rats
rats (250~2XO&)
Sprague--Dawley
Wistar
Rats
Rate
(200-25og)
rats
(324Og)
Sprague-Dawley
CDI
(?OO-25Og)
rats
rats (ISC-200g)
rats (I 5&2OOg)
Sprague-Dawley
Wistar
Wistar
CD I mice (324Og)
CDI
Wistar
rats
2.5
CD-COBS
CD-I
5-10
mice
CDI
5 nmol
IO nmol
5 nmol
IO nmol
IO nmol
2.5
IO
5-10
I- 5.6
I O-30
(22 24g) mice (25-32g)
RdlS
rats (2OOm25Og)
Female
Wistar
rats (I 5&2OOg)
Rats
rats (250-3508)
pigeons
Ltster
Carneau
rats (22Og)
Wistar
White
Wistar
test Swiss nwc
test
maze
interaction
Ultrasonic
Social
Free-exploratory
Light
Elevated-plus
DPAG-Stimulation
Restraint
vocallratlo”
Ultrasonic
burying
Shock-probe
t’cedmg
Novelty-suppressed
startle
Fear-potentiated
Open-field
Social
Holeboard
Ltghtidark
Elevated-plu\
test
conflict
conflict
Vogel’s
5
IO
30
durmg
30
30 30
IO or 20
1P-
30
30
p.o. 60
,.p, 30
,,p. 30
1.p.
I p.
DPAG.
i.p. 30
SC
S.C. 60
i.p. 60
--IS days (xl)
pa.
i.p. 30
S.C. 40
30
i.p. 30
days (xl)
p.0.
12-15
p.o. during
30
ICV.
1.p. 30
t.p.30
DPAG
DPAG,
DPAG
1.p 30
30
I. p. 30
I m.
p. 30
C-J
FR30
Vogel’s
D.L L
L
Asymmetric
AsymmetrIc
+ _
0
_
+
+
0
+
+
+
+
Asymmetric
L
Cold
Wartn
mice
mcreased
condition
conditwn
Isolated
Locomotion
compartments
or ol.,
(‘I ol..
<‘I ol..
CI II/..
I993
1989
cr (I/..
C0,lr;lrrretl
1984, lYY3a
and Olivw.
I993
199la
IYSY
1990
I990
PI rrl.. 1992
and Oliwer.
Rocha
Mos
Mos
Olivia
Griebel
Griebel
Griebel.
1988
and Dunn, PI I!/.. Rodgers
Audi
German
and Insel.
l986b
1992~
and Colpaert. Winslow
Meert
1991
1979
rr rrl.. 1989
and Cutler.
1989
1985
1992~
nl . 1990 rr al..
1993
1993
I981
1992~
1990
and Gardner,
er
Rex PI al,.
Davis
Lucki
Gao
cl ol..
and Cutler,
Kennett DL,
and Dunn,
1992
1991
and Cutler.
Guy
Gao
Gao
Kshama
0
+
cf al.,
Car11 er nl , l989b
German
0
+
1990
CI cl/.. 1991
Kshama
compartments
DL.
co”1partme”ts
Asymmetric
compartments
DL,
only
1990
I987
and Dunn, 0, ul..
De Angelis.
Graeff
Audi
Graeff
German
er al..
c, al.,
1986
and Lassen,
r, al..
Kshama
Pellow
Durel
test Petersen
0
+
0
0
Stressed Transitions
0
mtce
IO tmn
D.L
(k)
durmg
Observations
Modified
+
+
+
+
+
+
+
0
0
+
O
ti
&I,
Ei-
Gz
g.
z
5’ iD”
?
332
G. Griebel
from
Timeout
rats (IS&220g)
Wistar
Carneau Carneau
White Whtte
Elevated-plus
emottonal maze
response
days)
free
pigeons
pigeons
pigeons
pigeons
Wtstar
rats
rats
(150~2OOg)
(200-3OOg)
SpragueeDawley
(250-3OOg)
rats
PVC
Sprague-Dawley
rats (2%3508) rats (20&26Og)
Ltster
(200&28Og)
rats
PVG
(ZSO-280s)
rats (40&5OOg)
(SO-120
Rats
rats Wistar
specific-pathogen
Holtzman
Pigeons
Carneau
(48%5288)
Carneau
(80&105Og)
White
White
monkeys
rats (20&25Og)
Squirrel
rats (2OC-280~)
rats
Lister
Wistar
Rats
rats (l8&22Og)
Rats
rats (21&27Og)
(20&3Oog)
rats
Wistar
Wistar
Lister
rats
rats (20&25Og)
CDCOBS
Lister
(190-2lOg)
Sprague-Dawley
(200-3oog)
rats rats
SpragueeDawley
rats
SpragueeDawley
( I ?o-2lOg)
SpragueeDawley
procedure
test
Conditioned
avoidance
test
conflict
Conflict
Vogel’s
Ra1s
rats
(382-446~)
Wtstar
Rats
rats
rats (186200g) Wistar
Wistar
(2%350g)
rats
Wistar
I5
I5
I5
I
I25
I
I5
15
30
raphe,
60
raphe,
IO
0.25
0.2
0.012550.
0.05~~. I
0.25
0.015~1
0.01w.03
0.1-I
0. l-l
0.005~.81
0.0331
0.3-3
0.1-3
0.03-3
0.001~.3
0.001-0.0025
I
Nucleus
IO
IO
15
30
I5
5
IS
0
0
30
S.C. I5
s.c. I5
i.p.
t.p,
i.p.
i.p.
i.p.
i.m.
i.m.0
i.m.
i.m.
i.m.
i.m.
accumbens,
Htppocampus,
0.00054.001
30
raphe,
30
I5
i.p.
Dorsal
i.p.
i.p.
Hippocampus
Dorsal
i.p.
Dorsal
i.p.
S.C. 30
S.C.
S.C. I5
i.p.
i.p.
i.p.
t.p,
S.C. 60
0.25
0.OooO2~.005
0.5
0.025~.05
0.0254.
0.0000040.0005
0.5-2
0.001
0.0624.25
0.005xt.
0.050.
0.03-a.
0.5
0.1&0.3
0.25
0.034.
0.0551
0.0070.
5
5
5
5
5
_
+
+
+
+
+
+
+
0
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
+
+
+
+
0
0
Modified
Vogel’s
Vogel’s
open
arm
Decreased
test
test
total
during
during
during
entries
IO min
Observations
IO min
Observations
IO min
Observations
effect
VII5
FR30
FR30
FR30
FR30
FR30
FI3
Weak
Modified
Modified
test
test
rats
Vogel’s
Stressed
Modified
FR8
VI20
VI30
GellerrSeifter
Stefanski
Kshama
Moser.
Moser
Critchley
Pellow
Critchley
Critchley
Sanger.
Galizio
Colpaert
Ahlers
1988
1992
1991
1987
1987
1988
1992
1991
l992b
l992a
1991
1988
1990
and
cc nl..
l989b
P, nl..
1992 1990
1992
1990
1988
1987
1986
1990
corrr;mrefi
l9RR
1987
Handley,
Handley,
er nl..
c, nl.,
and
and
I990
cr al.,
PI al..
Barrett,
1992
1988
1987 er al.. e, ol..
l993a Barrett.
et al.,
1993
1986
and Seredenin.
er al.,
er al.,
er al.,
er al..
PI al..
et al.,
Samanin.
Ed al.,
1984
1990
Moser,
CI al.. Mansbach
Witkin
Gleeson
Stefanski
Korneyev
Higgins
and
<‘I al..
and
De Vry
er al..
er al.. e, al.,
1991
Bennett,
e( al.,
and
1992
PI al..
et ol..
Stefanski
Plaznik
Higgins
Carli
Higgins
Engel
Moser
Hibert
Moser
Hascoet
De Vry
Hodges
Amrick
Sanger.
Thiebot
:
%
2
a
r.z
8,
F
6.
334
I
I
00
c
t!-t
+
+
+
+
t+l
+
+
tt
t
+
t
Ultrasonic ‘distress’ Vocalization
Shock-probe burying test
Marble burying test
Staircase test Novelty-suppressed feeding
Anxietvidefense ., test battery
Open-field
Holeboard Social interaction
0.5
Rats Wistar rats
0.25%0.5 0.0075~.03 0.14.2 0.1-l 0.54.8
Wistar rats (IO days) Wistar rats (9-l I days) wistar rats Sprague-Dawley rats (320&35Og)
0.054.2
Sprague-Dawley rats (25&35Og) AP mice (4-6 days)
i.p. I5 i.p. IO
S.C. IO 30
IS
S.C. IO
1.p. I5
i.p. I5
1.p. 15
i.p. IO
S.C. 30
+
+
0
+ +
+ +
+ + +
Hippocampus,
5
+
Hippocampus
+
+
+
Hippocampus i.p. 15
0.03 0.3%10
0.1254.75
o
+ +
5
0
+ + + + _
0
0
_ _
i.p. 0
IP S.C. IO
Wistar rats (28%35Og)
60
5
5 5 5
Nucleus accumbens. S.C. 60
SC
S.C.
S.C. 30 Dorsal raphi, Dorsal raphi, Dorsal raphe, i.p. IO Dorsal raphe, DPAG, 0
30
0.05-0.5 0.0324. I25
0.5
0.0001~.001 0.0005 0.01-l
0.025~. I 0.025Il.05 0.005
2.5-S
0.000-0.005 0.1254.5
0.1254.5
0.05-6.25 0.00002JJ.001 0.001 0.000040.005 O.l254l).25 0.00002~.001 3-25 nmol 0.0254.4
0.25
Male and female Long-Evans rats (98-I I I days) Rats Sprague-Dawley rats (270-32Og) Rats Female MFI mice (23-35g) Wistar rats
Wistar rats (I SC-200g) Rats DAP mice (22&3Og) Lister rats (201X2808) L1ster rats (200-2508) Lister rats (210~27og) Wistar rats (225-250~) Lister rats (2OlX28Og) Lister rats (2Ol-25Og) Sprague-Dawley rats (28&320g) CDJZOBS rats f20&3OOej Wista; rats (18c22Og) CDXOBS rats (20&3oog) Sprague-Dawley rats (20&25Og) Rats Wistar rats (18&22Og) Rats CD-COBS rats (2W25Og) Wistar rats (I 8&220g) rats
Warm condition Cold condition
+ 537.DHT
decreased
+ 5.7.DHT
Locomotion
Stefanski er al., 1993a Carli PI al.. 1989a
Carli PI al.. 1989a
Kshama er ol., 1990 Crltchley e! al.. 1987 Olivier et al.. 1989 Higgins ef a/., 1992 Higgins et al.. 1987 Higgins et al.. 1988 Dunn er al., 1989 Higgins er al.. 1992 Beckett er al.. 1992 Ahlenius er al., 1991
cr al.. 1992
er al.. 1993a
(‘I al., 1991
De Vry er al.. 1991 Svensson. 1985
Hdrd and Engel. 1988 Mos and Olivier, 1989
Nastiti
FernPndez-Guasti PI al., 1992b Fernindez-Guasti and Hong, 1989 Meert, 1989 Fernlndez-Guasti er al.. 1992b Treit PI a/., 1993
Rex e/ al., 1991 Njung’e and Handley.
199lb
Boaventura rr al., 1986 Fletcher and Davies, 1990
Blanchard
Stefanski
Plaznik ec al.. 1991 Stefanski et al., l992a Stefanski QI al., l992b Carli er al.. 1993
increased Lucki er ol., 1989
65 dB noise
Locomotion
Stressed rats
Non-stressed
HLU
LLF Isolated mice LLF HLU
E:
#
6 g 2.
3 5.
r
5-HT,”
160
5.HT,s
810
LY 228729 (5-HT14 agonist)
agonist)
1.7
5-HT,A
LY 165163 (5.HT,,
%xinoxan Full agonist)
Compounds
Atlinitles
no)
4500
5.HTla
(Ki.
5-HTI
> 10000 > 10000”
5-HTx Rats CD rats (9-13 weeks) Wistar rats (20@25Og) Rats Sprague-Dawley rats (3MOOg) Rats Sprague-Dawley rats NMRI mice Swiss mice (25-308)
Animals
0.1254.5 l-3 2.5-10
+
i.p. 30 i.p. 35
0.1-I 0.032-I
Conflict
0.54
Elevated-plus test
S.C. 30
i.p. 30 r.p. during I4 days (xl) 0.3-3
Sprague-Dawley rats (2Oa-3OOg) Rats
i.p. i.p. p.0.
0.3-3 LED = 0.3 >I
maze
30
0.3-3
i.m.0 i.m. 5 Acute and chronic
0.00-3 0.04 0.14.5
i.p. 30 S.C.
iv.
0.034.3
i.m
+
i.p. 30
0.05-O. I
References er al., 1986 and Tilson. 1989 e, ol., 1991 er al.. 1986 rr al., l988a
+
_
+
+
+
+
+
+
Foreman
(01nl.. I993
Moser.1989b
Van Dijken CI nl.. 1992
Schipper et al.. 1991 Molewijk et a/.. 1993 Schipper er ol., 1991
Schipper er al., 1991 Mos and Olivier. 1989 +
_
+
1993
1990
+
Barrett, 1992 Colpaert YI al, 1992 Rodgers CI ol.. 1993
Barrett P( ol.. 1989
Gleeson and Barrett.
Korneyev and Seredenin. Jenck er ol.. l989a
Cue er ol., 1993
Schipper ef al.. 1991 Sanger and Joly. 1989-1990 Klint. 1991
Davis, 1993 Mansbach and Geyer. 1988 De Vry er 01.. 1991 Lecci er al., 1990
Davis Nanry Hijzen D&s Davis
Schipper PI al.. 1991 Griebel. 1993 Ahlenius cl al., 1991
Warm condition Cold condition
FR30 FR30 AdditIonal measures of anxiety
FL3
Comments
+
+
+
+
+
0
+ _
+
i.p. 30 S.C. 30
+
+
+
+
0
0
0
_ _
Effects
0.3 0.1254.5 0.01-l
0.02+. I 0.2-3.2
test
Squirrel monkeys (800-105Og) White Carneau pigeons (45MOOg) Whtte Carneau pigeons pigeons maze Mice
test
!+-I.
i.p. IO i.p. 30 S.C. 30
0.124.25
S.C.
i.p. 0, IT, 30 S.C. 5 i.p. 5 i.c.v., 30 in. 0
0.63-10 0. I 14 0.5-8 0.05-0.1 2.5-10
Routes administration. latency (min)
Mice Swiss mice (IO weeks) Open-field Sprague-Dawley rats (280-32Og) Four hot-plates Mice Ultrasonic ‘distress’ Wistar rats (9-l I days) vocahzation Rats Adult rats Mice Stress-induced hyperthermia Freezing Wistar rats (25&3OOg)
Light/dark
Elevated-plus
Conflict
Passive-avoidance
Mice test Wistar rats (22&24Og) Sprague-Dawley rats (200-2500) Stress-inducedcolonic Wistar rats (25&3OOg) motor alterations Hot-plate Wistar rats (20&25Og) DPAG-Stimulation Wistar rats
Aggression-provoked Stress-induced hyperthermia
Models
Eficient doses or doses tested (mg/kg)
Table 1. Continued
cl
8 ‘p
$.
0.95”
s20500 (full agonist)
5-MeODMT (agonist)
2.5’
0.19‘
S20499 (full agonist)
U-93385 (full agonist)
0.35w
39Q
6.3
Sl4671 (full agonist) 9.3 pKi”’
s20244
6.55
0.1 Ir?y
MKC-242 (full agonist)
630h
Sl4506 (full agonist) p&l’ 9.01
0.79”
MDL 72832 (full agonist)
7.8
39Xh
l5d
16
6.64
I 5Xh
57‘
7.8
7.50
501’
6
test
Sprague-Dawley rats (20&25Og) Swiss mice (IO weeks)
Pigeons Wistar rats
Pigeons Wistar rats
Rats
i.p. 30 i.p. 20 i.p. 0 i.p. 5 DPAG, IO DPAG. IO
0.12-X 4 0.552 nmol l-2 nmol
i.p. I5
0.5-2.5
IO 0.2555
i.p. 12
l-3
IO 3-10
+
+
_
+
_
_
_
0
+
+ _
+
during I6 days (xl) p.0. i.p. Subchronic
Mice Rats
0 SC
I-IO 22
Rats
S.C.
+
i.p.
10
Mice
+
+
+
i.p. 30 i.p. 20
+
+
+
+
i.p. 20 t.p. 30 during 14 days i.p. 20
+
0
+
S.C. 30
i.m. 60 S.C. 30
p.o. and i.p.
16 2-4
I-3
4
l-3
0.05-I
0.0025-0.16 0.0006-2.5
i.m. 60 S.C. 30
3-10
Rats DAP mice (2&3Og) Marble burying test Female MFI mice (23335g) Fear-potentiated Sprague-Dawley rats startle reflex (300-3508) CD rats (9-13 weeks) DPAC-Sttmulation Wistar rats (25&35Og) Rats
Social interactton
Colpaert er ol., 1992 Millan and Brocco. 1993
+
0.0025-0.63 0.00062.5 0
Egawd et a/.. 1993
4cute and chronic
+
LED = 0.0625
Sanger and Joly, 198991990
+
Shephard CI al.. 1982
Schreur et al.. 1993 Lahti ef al.. 1993
Schreur er al., 1993
Schreur ef al., 1993
Schreur PI al., 1993
Griebel rr al.. 1992
Porsolt CI al.. 1992 Lesourd PI al.. 1993 Griebel er al., 1992 Porsolt EI al., 1992
Griebel et a/.. 1992
Curie PI al., 1991
Millan and Brocco, 1993 Millan and Brocco, 1993
Nanry and Tilson. 1989 Schiitz PI nl., 1985 Graeff er al., 1986 C0Il~iIIl4e~
Davis ef n/.. 198Oa
Observations Critchley and Handley. 1987 during IO min LLF Critchley er al.. 1987 Isolated mice Olivier et al.. 1989 Locomotion decreased Njung’e and Handley. 199lb
FR30
FR30
Moser, l989b
i.p. 30
isomer
0.25-I
(-)
_
Moser. I989a
S.C. 30
isomer
0.054.X
(+)
S.C. 30
0.4-3.2
Mice
Geller-Seifter Female Alderley Park conflict test rats (241-315g) Elevated-plus maze PVC rats (200-28Og)
Social interaction Stress-induced increases in corticosterone
Isolation-induced aggression Shock-induced aggression Center test (thigmotaxis)
Vogel’s conflict test Wistar rats (195-2458) Swiss mice (IO weeks) Light/dark test
Vogel’s confltct test Wistar rats (l95-245g) Elevated plus-maze Rats Light/dark test Swiss mice (IO weeks)
Light/dark
Elevated-plus maze
Conflict test Elevated plus-maze
Conflict test Elevated plus-maze
Conflict test (?)
Sprague-Dawley rats (200-3008) Sprague-Dawley rats (200-3OOg) Passive-avoidance test Wistar rats (22&24Og)
Elevated-plus maze
Compounds
~-HT,A
8.7
Buspirone (partial agonist)
25h
BP 554 (5-HT14 agomst)
BMY 7378 (partial agomst) PK;“‘.
BAY R 1521 (5.HT,, agonist)
&API 59 28‘ (selective agomst)
125890h 31622”
4.4
~-HTIR 5-HT,u
794h
5.7
5-HT,,,
Affinities (Ki. no)
7940h
6.6
5.HTx
> 10000”
< 6.0
5.HTJ Models
Animals
test
test
maze
maze
Geller~Seifter conflict test
Elevated-plus
Ultrasonic ‘distress’ vocalization
Ltghtidark
Conflict
Elevated-plus
SpragwDawley rats (33Om3708) Ovariectomised Long-Evans female rats
Wistar rats (229-2718) Sprague-Dawley rats Sprague-Dawley rats Rats Rats Sprague-Dawley rats (20&225g) Sprague-Dawley rats (420-48Og) Rats
Wistar rats (25tK27Og) Wistar rats Wistar rats (40&5OOg)
Wistar rats (18&2OOg) Rats Rats Rats
Rats
CD rats (16&2OOg)
Adult rats
Squirrel Monkeys (800&105Og) White Carneau pigeons White Carneau pigeons pigeons Female T/O mice (22m3Og)
PVG rats (I 8&26Og)
Wistar rats (ItO-200g)
Vogel’s conflict test Wistar rats (I 70-2OOg)
i.p. 30 r.p. 30 S.C.
2
5-10 5 5
O.lf5.6
p.o. 60
p.o. 60
p.0. 30
5-40
I
S.C. 1-p. 60
i.p. 30 1.p. I5 0” 30 i.p. 30 i.p. 30 i.p. 30 S.C. 60 1.p. I5 1.p. 30 p.0. 30 i.p. 30 i.p. p.0. 30
SC
p.o. 60
i.p.
,.m. 5 i.m. I5 im 5 S.C. 30
i.m
i.p. 30
p-0. 60
p.0.
Routes administratlon. latency (min)
2 0.04-10 I-IO I .25-5 IO-40 0.3 0.25-15 2.5-5 IO 0.5 0.3-3
‘
_(
5 I-10 0.5-10
0.1-3
LED=3
0.03-3 l-5.6 0.16
0.003~. I
O.l&l.2
I t&60
3-10
Efficient doses or doses tested (w/kg)
Table 1. Continued
I
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
0
0
0
0
0
+
+
+
+
+
+
0
+
testNagatani
e, RI.. 1991
References
Gleeson
and Barrett,
PI al., 1992
1986
1990
and Pollard.
1990
Witkm and Perez. 1989~1990
SoubriC. 1989
Young tv nl.. 1987
Zhang and Loo, 1993 Hartmann and Geller. 1981 Geller and Hartmann. 1982 Sullivan et al.. 1983 Baduel el ol.. 1986 Mason E, al.. 1987
Brocco ef nl., 1990 De Vry P, rd. 1991 Sanger. 1990
Sanger. 1992 Amrick and Bennett. Gardner, 1986 Soubrie. 1989
FRI FRIO Rats never Howard treated before (effects were always weak)
Trial I Trial 2 FR30/FRIO
VI30/FR30
Weak effect
VI/FR4
Trtal 2 Trial 3 VI30
VI30
1986
et rrl.. 1992
C, ol.. 1993
Baduel er al,
Luscombe
Molewijk
Gleeson er ul.. 1989 FR30 and weak effect Ahlers z, ul., 1992 FR30 Colpaert of ol., 1992 Asymmetric Bill (‘I al.. 1989 compartments
F13
Crltchley
Vogel’s test Takao cf nl., 1992
Vogel‘s
Observations during IO min
Modified
+
comments Modified
Effects
2
50
Rats Rats Wistar rats (30MOOg) Rats Rats C&COBS rats (20&3OOg) Wistar rats (22s240g) Female Long-Evans rats (22ft249g)
Wistar rats Sprague-Dawley rats Sprague-Dawley rats (2&3OOg) Female Long-Evans (225-249g) Wistar rats (I 5&l 66g) Lister rats (20&28Og)
Sprague-Dawley rats (200-3OOg) Lister rats (21&27Og) Sprague-Dawley rats (24@3OOg) Sprague-Da&y rats (17&2lOg) CDCOBS rats (20@3OOg) Sprague-Dawley rats (225-2758)
Rats CD rats (8s1OOg) Sprague-Dawley rats (2OOg) Rats Rats Sprague-Dawley rats (25&35Og) SpragueDawley rats (20&25Og) Rats Lister rats (200-25Og) Female rats (225-25Og)
0.5-I 1.25 0.005
Rats Wistar rats (18&2OOg) Vogel’s conflict test Wistar rats (18&22Og)
+
Median raphe, IO i.p. 10 i.p. during 8 weeks (x2) i.p. 30 S.C.
0.001Al.005 0.125-2 24
S.C. 15 p,o. 60 Dorsal raphe, S
0.125 I c-20 0.0002
30
i.p. Dorsal raphe, 5 i.p. IO S.C. IO i.p. 30 p.0. 30 Dorsal raphe, 5 S.C. 30 p.0. 30 s.c. 30
5.6-10 o.000&Oo.oo2 0.25-I 0.125-I 5-10 20 0.000~.01 0.254 l-50 0.25-2
S.C.
+
S.C. I5
0.61.2
5-10 0.054. I5 0.25-I
p.0. 30 p.0. i.p. I5
90 I-IO IO
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
Hippocampus p.o. 60 p.0. 30
S.C. 60 S.C. I5
0.04-10 0.125-0.625
0
0
0
0
0
0
+ + -
+
+
1&SO 0.5-5
i.p. 30 p.0. p.0. Dorsal raphe, IO
p.0.
I-IO 2-10 2-10 0.0001-0.01
I .25-20
i.p. 30
0.25-2
Wistar rats (25&35Og)
i.p. 30 Hippocampus, 5 Nucleus accumbens, 5
i.p.
0.25-2
Rats
test
test er al.. 1991
er al.. 1990
Goldberg PI al., 1983 Sullivan PI al., 1983 Sanger et al., I985 Budhram er al.. 1986 Gardner, 1986 Carli ef al.. 1989b
Hascoet ef al.. 1992 Sanger, I992 Stefanski er al., 1993a
Thiebot
Thiebot
1986
Carli PI al.. l989b
Moser er al.. 1988
Higgins PI al.. 1988 Vogel’s test Gower and Tricklebank,
Vogel’s test Shimizu er al.. 1987
Heym YI ol., 1987 Higgins er al.. 1987 McCloskey PI al., 1987
Pith and Samanin.
Unpredictable
PI al.. l99la
1988
Wada and Fukada, 1991 Higgins PI nl., 1992 COlIlriJU&i
shocks Costello
Modified Vogel’s test Schefke PI al., 1989 and weak effect in acute treatment De Vry CI al.. 1991 Hibcrt and Moser. 1990 Moser ct al.. 1990
Modified
Modified
Weak effect
Modified
File, 1985 Taylor er al.. 1985 Vogel’s test Eison PI al., 1986
Modified Vogel’s test Brocco er a/., 1990 Costello et al., l99la Predictable and moderate predictable shocks Plaznik cf al., 1991 Oakley and Jones, 1983 Modified Vogel’s test Weissman er al.. 1984
Modified Geller-Seifter Modified Geller-Seifter FR8 VI30
Compounds
5.HTw
5.HT,s
5-HT,o
5-HT:n
Affinities (Ki. no)
5-HTx
5.HT?
test
SPRD rats (2OOg) Wistar rats (195-245~) Wistar rats (180-2208) Rats Wistar rats (18&200g) Sprague-Dawley rats (21 I-347g) Wistar rats (200-2508) Wistar rats (12 weeks)
A”l”lals
Conflict
Rats Squirrel monkeys Squirrel monkeys Squirrel monkeys Monkeys Squirrel Monkeys (80&1050g) Squirrel monkeys Cynomolgus monkeys (4-7 kg) Squirrel monkeys (0.7-0.8 kg) pigeons White Carneau pigeons pigeons White Carneau pigeons (480-5288) White Carneau pigeons White Carneau pigeons White Carneau pigeons (500-6OOg) White Carneau pigeons White Carneau pigeons pigeons White Carneau pigeons White Carneau pigeons (1 year) Timeout from Holtzman avoidance procedure specific-pathogen free rats (SO-120 days) Holtzrnan specific-pathogen free rats (SO-120 days) Conditioned Wistar rats (40&5OOg) emotional response
Models
i.m. i.m. 60 p.0. 30 im. im. 5 i.m. 0 i.m. 5 i.m. 0 i.m. 0 i.m. 5
im. i.m. ,.“I. i.m.
i.p. 15
i.p. 15
1-p. 30
0.25-l 5 0.5-5 3-30 0.03-10 0.03-10 0.03-3 0.1-5.6 0.1-10 0.1-10 0.63 0.3-5.6 0.1-3 0.63 0.03-3 0.1-3 0.5-2
0.3-l
I .25-5
15 5 0 0
i.v. 10 i.m.
p.0.
5 IO I .25-2.5 0.01-0.3 0.0034. I
3-5 IO
0.62-2.5 0.62 340 IO p.o. 60 D.O. 30 p.o. diring 7 days i.p. 30 i.p. 30
i.p. 30 i.p. 30 i.p. 30
0.04 8
Routes administration. latency (min)
El&lent doses or doses tested @g/kg)
Table 1. Continued
+
0
0
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
+ _
+ +
+ + + + + +
Effects
VI15
VII/V13/FRIO VI3/VII/FRIO VI
FR30 FR30 FR30
FR30 FR30 FR30
FR30
1981 1982
er al., 1984 er al., 1986 and Barrett, 1986 et al., 1987
el al., 1984
Sanger.
Galizio
Galizio
1990
t’f ol.. 1993
(‘I al., 1990
Nader, 1991 Nanry er al., 1991 Colpaert et al.. 1992 Barrett and Vanover, 1993 Wojnicki and Barrett, 1993
Mansbach PI al.. 1988 Mansbach er al., 1988 Brocco PI al., 1990
Barrett Barrett Witkin Witkin
Weissman
Hartmann and Geller, Geller and Hartmann,
Modified Vogel’s test Korneyev and Seredenin, 1993 0.16 and Meneses and Hong, 1993 0.32 mA shocks Miyauchi PI al., 1993 Sullivan PI a/., 1983 Goldberg er al., 1983 Sullivan er al., 1983 Wettstein. 1988 F13 Gleeson and Barrett, 1990
Modified Modified
Modtfied
References
Horvith CI al., 1992 Porsolt et al., 1992 Vogel’s test Stefanski el al., 1992a Stefanski er al., 1992b Vogel’s test Takao PI al.. 1992 Vogel’s test Amano cf al., 1993
Comments
g
ti.
s
Q
Light/dark
test
Shuttle box Elevated-plus maze
S.C.30 S.C.during 16 days (x2) S.C. 30 S.C. 30
0.25-I 1 0.1252 l-2
r.p. 30 p.o. 60 Acute and chronic i.p. during 5 weeks (x2) i.p. 20 30 S.C. 15 i.p. 30 i.p. p.0. S.C. 30
0.125 0.01-3 0.63-5 IO
2 0.1 0.064 3.1610 10-56.2
Sprague-Dawley rats (25&35Og) Wistar rats (213-263g) Wistar rats (15&2OOg) Rats Mice (25-350)
Female T/O mice (22-308)
I
I
30 i.p. 15
2 I-10
Wistar rats (345405%) Rats Lister rats (25&35Og) Rats Lister rats (30@4OOg) Wistar rats (151&202g) PVC rats (20&26Og) SPRD rats (2OOg) Wistar rats (225-25Og) Wistar rats (18&22Og) Sprague-Dawley rats (25&35Og) Wistar rats (I 5s200g) DBA/Z mice (12-14 weeks) Wtstar rats (3454058) CD rats (I 6&2OOg) Mice i.p. 40 p.o. 60 ;.p. 30 i.p. 30 i.p. 30 Hippocampus, 20 S.C. 10
i.p. 30
0.025-5
i.p. 30
i.p. I5
1.25
0.5-20 0.5-20 2 2.5-20 0.05 0.08-l .25 0.5-I 0.0025 882048 nmol
S.C. I5 S.C.30
0.8 0.1-I
i.p. 30
S.C.30
0.0152
I4
I
30 i.p. 30 s.c. 30
I 4-8 0.125-2
0.06, 0.254
Sprague-Dawley rats (200-3OOg) Sprague-Dawley rats (34&23Og) Rats Sprague-Dawley rats (2~300g) Lister rats (i8Og) Sprague-Dawley rats (20&250e) Long-Evans-rats (32&34Og) PVC rats (18&26Og)
Rats Lister rats (25C-35Og) Sprague-Dawley rats (25&3OOe) Sprague-DawEy rats (20@3OOg) -
Kostowski et al., 1990 Moser cr al., 1990
Redfern and Williams,
Moser, 1989b
Moser. 1989a
Martin, 1993 Pellow er al., 1987 Moser PI al., 1988
+ +
+
+
0
c
Asymmetric
Asymmetric compartments Weak effect Asymmetric compartments
Bill et al.. 1989 COlIliflU~~
Young and Johnson, 1988
Pith and Samanin. 1986 Costall cr nl., 1988a
Zhang and Luo, 1993 Kshama tv al., 1990
Kostowski er 01.. 1992 Luscombe PI ol.. 1992 Additional measures Rodgers PI al., 1993 of anxiety Siiderpalm cf al.. 1993
+
Saderpalm et al.. 1989
Locomotion decreased Critchley PI al.. 1992 and observations during 10 min Kostowski er al., 1992 Onaivi. 1993 Pellow and File. 1986 File cr al., 1987 Moulton and Morinan, 1990 Wada and Fukada. 1991 Observations during Critchley er al., 1988 Horvlth er al., 1992 IO min Dunn er al.. 1989 Kostowski CI al., 1989
Lal e( al., 1991
Kshama PI al., 1990 Lee and Rodgers, 1991
+
1989
File and Andrew% 1991 Locomotion decreased Klint, 1991
PCPA pretreatment Decreased total open arm entries
Caffeine-pretreated rats
+ +
0 +
0
0
Cl
-
_ _
_
_
_
_ _
+
:
%
6
E:
rz
2 c.
Compounds
S-HTIA 5-HT,e
5.HTm
~-HT:A
Affimties (Ki, no)
5-HTxc
5.HT,
Open-field
Holeboard Social interaction
Models
+
+ + +
i.p. 30
i.p. 45 i.p. during 7 days (xl) i.p. 30 i.p. 40 30 i.p. 15 30 pa. 30 i.p. 30 i.p. 45 S.C. I5 Dorsal raphi, 5 S.C. I5 pa. 30 Dorsal rapht. 5 Dorsal raphe, 5 S.C. 30 i.p. 30 pa. during 5-10 days (xl) i.p. I5 i.p. 40 pa during 12-14 days Dorsal raphe, 5 i.p. 30 Drinking fluid during 6-8 days i.p. I5 i.p. 20 S.C. 15
l-5
0.125-4 0.25-2 3.1617.8 0.25-2
0.25-2.5 5-10 0.3-10 0.12>2 0.24.8 0.00004-0.0002 0.2 5-20 0.0004-0.002 0.0040.01 IO 5-10 2.3-2.6 1.25 l-2 3.4 0.00004-0.0002 l-5 12.8 mg/L
0.1-l
ICR mice (2&35%)
BKW mice (3C-35g) Mice Female ICR-DUB mice (I 7-350) BKW mice (25-3Og) Wistar rats (1 SO-200g) Wistar rats Rats Rats Wistar rats (18&2OOg) DAP mice (22-30g) Sprague-Da&y rats (225-2758) Lister rats (18Og) Lister rats (20&28Og) Rats Wistar rats (18&2OOg) Lister rats (20&25Og) Lister rats (21&27Og) Mice Wistar rats (225-2508) Male and female DBA/Z mice (24-368) Wistar rats Lister rats (25&3OOg) CD1 mice (40-440) Lister rats (200-280%) CD1 mice (3545g) Female CD1 mice (30-35g) Wistar rats (213-2638) Sprague-Dawley rats (33&42Og) CIXCOBS rats (20+3OOg)
0.0410
2f5
*
+
i.p. 45
0
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
0
0
0
0
0
0
0
+
+
+ + +
0.25-l
Effects
S.C. 15 Median raphe, 10 S.C. 20
0.1 0.005 0.1-10
CD-COBS rats (2W3OOg) Mice C57Bl/6J (18-2Og) BKW mice (2&3Og)
Animals
Routes administration, latency (min)
Efficient doses or doses tested (mgikg)
Table 1. Continued
Comments only
Non-stressed
l5W rats
HLU Home cage Neutral cage Oestrous mice Dioestrous mice
HLU HLU and LLF
HLU
Familiar congener HLU LLF
Familiar congener Isolated mice HLU
HLU
Asymmetric compartments and rears Transitions and asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments
Transitions
References
and Johnson,
l993b Zhang and Luo, 1993 Panickar and McNaughton, 1991 Carli t’f a/.. 198%
Gao and Cutler,
Higgins CI al., 1992 Gao and Cutler. l993a
De Vry er al., 1991 Costall P, al., 1992a Gao and Cutler. 1992a
File and Andrew, 1991 Higgins er al., 1992 Andrew and File, 1993 Guy and Gardner, 1985 Higgins er al., 1987 Higgins er al., 1988 Schreur, 1988 Dunn et al., 1989 Cutler, 199la
199lb
1991
1989
Costall PI al., 1992a Kshama er al., 1990 De Vry er al., 1991 File, 1984a File, 1984b Guy and Gardner, 1985 Olivier et al., 1989 Barnes er al., 1991
Young
Costall and Naylor,
Barnes e, al., 1991
Onaivi and Martin,
Costall PI al., 1989b
Kilfoil et al., 1989
Carli et al.. l989b
Q 3.
P
K.
burymg
Unavoidable stress (gastric lesion) Avoidance test Conditioned avoidance test
Aggression-provoked Stress-induced hyperthennia
Fear-potentiated startle reflex
Conditioned
Sprague-Dawley rats Wistar rats
Mice ICR mice (7-8 weeks)
Rats Sprague-Dawley rats (300-4OOg) Sprague-Dawley rats (3MOOg) Sprague-Dawley rats Sprague-Dawley rats (33MOOg) Wistar rats (2OOg) NMRI mice Swiss mice (25-308)
Long-Evans rats (325-500g) Wistar rats (20&25Og)
Wistar rats (18&22Og) CD-COBS rats (20&3OOg) Rats SPRD rats (ZOO& Wistar rats (18&22Og) Rats Male and female Wistar rats (180 days) Wistar rats (18&220x) Rats Staircase test Adult male and Defense test battery female R. rattus Ultrasonic ‘distress’ Wistar rats (9-I I days) vocalization Wistar rats Rats AP mice (4-6 days) Sprague-Dawley rats (9-l I days) Rats Adult rats Wistar rats (12Og) Social competition Female mice MFI Marble burying test (23-35g) Shock-probe Wistar rats (25&28Og) burying test SpragueeDawley mts (25&35Og) Wistar rats 30 S.C. 30 S.C. i.p. i.p. 30 i.p. 30 xc. 60 S.C. i.p. 30
3-6 0.3-3 0.03-4.3 LED=1 O.&l.25 I-20 0.6340 0.05-l 5
IO
!.P. 30 1.p. 45
S.C.
IO p.0. 2.5-5 p.o. 60 2-10 p.o. during 3 days 0.5-7.5 i.p. 30 EDw = 3.64, 18.2 i.p. p.0.
5 3-30 IO
1.25-5 5
0
O&5
S.C.
S.C. 0
p.0. IO
0.6 5-10
5-20
i.p. 30
i.p. I5
I-IO
8-64
30
Hippocampus, p.0. 1.p. 30
i.p. 30
Hippocampus i.p. 30 i.p. 30
5
Nucleus accumbens, S.C. I5
l-3
0.0025-0.005 I l&20 1O-20
0.62 0.3-2.5 0.62-2.5 I .25-2.5
0.0001~).005 0.1-I 5
o
+ +
0
+
+ + +
+ ++
+ +
Auditive
stimulus
Lesion of the septum
Fernindez-Guasti er al., l992b Craft et al.. 1988
++
1988
l986a
Geller and Hartmann, Allen cr nl.. 1974
Schipper et RI.. 1991 Ogawa er ol.. 1993
Munonyedi er al., 1991 De Vry PI ol.. 1991 Lecci CI al.. 1990
1982
Mansbach and Geyer. 1988 Melia and Davis, 1991
Kehne CI al.. 1988
Davis. 1988 Davis er al., l988a
Hijzen PI al.. 1991
Treit and Fundytus,
+
0
Meert and Colpaert,
+ 5,7mDHT
Locomotion
1989 De Vry et al.. 1991 Schipper PI al.. 1991 Nastiti er al., 1991 Winslow and Insel, 199la
Mos and Olivier.
Stefanski PI al.. l993a Boaventura er al., 1986 Blanchard CI al., 1989
Plaznik rr al., 1991 Horveth ct al., 1992 Stefanski et ol.. l992a Stefanski PI al.. l992b Hughes, I993
Stefanski PI al.. l993a Carli et al.. 1989a
Winslow and Insel, 199lb Molewijk er al., 1993 Joly and Sanger. 1991 decreased Njung’e and Handley. l99lb
Warm condition Cold condition
Sedation?
65 dB noise
Stressed rats
0
+ + + +
+ + + + + +
+ + +
+ + + + +
+
rz a 2 B
8 3 0 r’.
A.
7
5-HT,*
FG5893 (agonist)
0.7
E-4424 101”” (selective agonist)
Comoounds
5-HT,.
5-HT,n
~-HT.A
Affinities (Ki. tt~)
5-HTr
5-HT,
Animals
threat
Ultrasomc ‘distress’ vocalization Passive-avoidance test
Human
Social interaction
+ +
p.0. 30 p.0. 30 i.p. 30 i.p. 30 i.p. 30
8832 3 0.555 I-10 1
i.p. between 25 and 24 hr i.p. during 3, 7 or 14 days (x2) i.p. i.p. 40 S.C. between 40 and 96 hr
0.0001xt.5
+ +
0.1 Rats
+
+
+
+
+
+
+
+
0.05
0.000-0.5 0.001~.5 0.0001~.001
i.p. 30 i.p. i.p.
2.5-10 0.0001~.5 o.000-n.5
+
+
+
HLU
+
S.C. 45
0.1-I
Rats
Rats Lister rats (25&3OOg) Marmoset Callithrix jacchus (295-3358)
BKW mice (25-300)
+
S.C. 45
0.051
+
+
er al., 1992 er 01.. 1992
Andersson Andersson
Costall el al., 199la Costall CI al.. 1992a Costall CI 01.. 1992a
Costall er 01.. 1992a
Korneyev and Seredenin, Costall et al., 199la Costall et al., 199la
et al., 1993
t-tal.. 1993 Tokuyama CUP
er al., 1993
1993
1991
1990
Nishimura
Pollard et al., 1992
Pollard and Howard,
Costall er al., 1992a
Barnes er al.. 1991
Fletcher and Davies,
Bodnoff er al., 1989
0.5-2.5
0
Ogawa et al., 1993 Ervin ef al., 1987
+ + +
p.0. 60 i.p. 60 p.o. 60 i.p. 60 during 21 days (xl) S.C. 30
25 0.555 I-10 4
e, al., 1989 er al., 1989 and Jolv. 1989-1990 1991 .
Sanger Sanger Sanger Klint,
i.p.
+ + + +
Asymmetric compartments Asvmmetric compartments
References Shimizu ef ol., 1987
Comments
+
Effects
30 i.p. 30 i.p. 30 S.C. 30
p.0. 30
Routes administration, latencv (mitt)
510 5-10 5 0.01-I
EDro = 69
Effictent doses or doses tested fmelke)
1. Continued
Sprague-Dawley rats (Zoo-3OOg) Active-avotdance test Wistar rats (22&240g) Passive-avoidance test Wistar rats (220-24Og) Wistar rats (22&24Og) Sprague-Dawley rats (20&25Og) Wistar rats (7-8 weeks) Long-Evans rats Conditioned place aversion (8 weeks) Novelty-suppressed Long-Evans rats (30&325g) SpragueDawley rats (270-320~) Human threat Marmoset Callithrix jacchus (35&44Og) Marmoset Callithrix jacchus (350-4408) Cork gnawing Long-Evans rats (435-g) Ovariectomised Long-Evans CD (300g) Sprague-Dawley rats Straw suspension (14&17Og) Stress-induced ddY mice (18-2Og) antinociception Stress-induced Wistar rats (25G3OOg) colonic motor alterations Hot-plate Wistar rats (20&25Og) Elevated-plus maze Rats Light/dark test Mice
Models
Table
s % z
0
Gepirone (partial agonist)
79.4”
125893h > lOOO@ 3800”
251 lgh
> 10000’
test
Ultrasonic ‘distress’ vocalization
Defense test battery
Social interaction
Open-field
Light/dark
Conflict test Conditioned emotional response Elevated-plus maze
Vogel’s conflict test
Geller-Seifter conflict test
S.C. 15 i.p. 15 i.p. 30 S.C. I5 Dorsal raphe 5 i.p. 30 i.p. 30 im. 0 i.p. 30 i.p. 30 i.p. 30
I .25-5 IO 2.5-10 I .25 0.001 0.3-1.25 0.3-0.62 3-5 0.1-I Z-20 3-10 0.1-5 IO l-10
Female Long-Evans rats (225-249%) Sprague-Dawley rats (250-35Og) Wistar rats Female Lone-Evans rats(22G49g) Lister rats (200-2808) Wistar rats (18&22Og) Rats Wistar rats (20&25Og) White Carneau pigeons Wistar rats (40&5OOg) Wistar rats (220-2508) PVG rats (18&26Og) Wistar rats (22&25Og) Wistar rats (22&250g)
I-IO
0. I MO.62 0.34.62 2.5-5 0.0002-0.001 5-10 I .25 0.0002~.001 5-20
1.p. 15
i.p. 15 Dorsal raohe 5 i.p. 30 i.p. 15 Dorsal raphe 5 i.p. 30
i.p. 30
i.p. 30
IO
Wistar rats (22&25Og)
2.346
pa. 60 i.p. during 2 weeks (xl) Added to drinking water during 14 days S.C. 30
0.00-3 IO
Female T/O mice (22-308) Sprague-Dawley rats (44lg) Wistar rats (18&22Og) Rats Wistar rats Lister rats (20&28Og) Wistar rats (225-250~) Wistar’ rats -’ Lister rats (20&28Og) Adult male and female R. Rattus Wistar rats
i.p. 30 S.C. IO
I-2.5 8-2048 nmol
Wistar rats (225-2500) Sprague-Dawley rats (25&35Og) CD rats (I 6%2OOg) Wistar rats (22&25Og)
IO
i.p. I5 S.C. 15
10 0.125-I
Wistar rats Wistar rats (25&350g)
i.p. 30 i.p. 30
SC
30
S.C
pa
0.125-l
rats 0.3-10
2&80
rats
SpragueeDawley (420-48Og) Sprague-Dawley (33&37Og) Rats
+
+
+
+
+
Cl
+ _
+
_
0
+
+
+
+
+
0
0
0
Cl
_
+ + + + + +
+ +
+
+ +
+ et al.. 1990
rats
HLU HLU
LLF LLF
65 dB noise
After a 2-weeks period of isolation Asymmetric compartments
Isolated
Observations durine IO min Is&ed rats After a 2-hr period of isolation After a 2-week period of isolation
et al., 1993
De Vry
et al.. 1991
Stefanski et al., 1992a Stefanski PI al.. l992b De Vry PI al.. 1991 Higgins et al.. 1992 Dunn et al.. 1989 De Vry et al.. 1991 Higgins PI al.. 1992 Blanchard PIal.. 1989
PIal., 1992
et al., 1989 Knapp
Bill
Maisonnette
Luscombe er al., 1992 Motta et al.. 1992
Dunn ef al., 1989 SGderpalm PIal.. 1989
Motta et al., 1992 Maisonnette et al.. 1993
Motta et al.. 1992 Critchley et al., 1992
Higgins et al., 1992 Vogel’s test Stefanski t-t al., 1992a Stefanski PIal., l992b Modified Vogel’s test Korneyev and Seredenin. FR30 Mansbach et al., 1988 Sanger, I990 Modified
De Vry CI al., 1991 Costello er al., 1991b
Vogel’s test Eison et al., 1986
Shocks moderate
Modified
De Vry er al., 1991 Modified ThiCbot PI al., 1991 Geller-Seifter test Unpredictable shocks Costello er al.. l99lb
Thiebot
1993
and Perez, 1989-1990
Witkin
+ FR30/FRIO and weak effect Modified Geller-Seifter test
Young CI al.. 1987
+
2 B
a
z
g 5.
3 A. 2 ip
r
lpsaplrone (partial agonist)
Compounds
19”
~-H&A
5-HTIU
12589”
S-HT,s
125892h
2700’
5-HTz,,
.Affinities (Ki m)
31622h
5.HI-:<-
> 10000”
5-HTI
Animals
IO 30 30 30
Squirrel monkeys (SoCrlO5Og) White Carneau pigeons White Carneau pigeons White Carneau pigeons Conditioned Sprague-Dawley rats emotional response (30&325g) Wisiar rats (4Oi&5OOg)
i.p. 30
2.5-20
5 I5 0 15
i.m. i.m. i.m. i.p.
1.m.
i.p. 30 1-p. 30
0.1-10 l-3 0.1-53 0.5-5
0.01~1
0.002 1.25-10 0.3-1.25 0.3-0.62 3-10 3.1-10
Lister rats (200-280g) Wistar rats (18&22Og) Wwar rats (18&22Og) Rats Wistar rats (200-2508) Wistar rats (12 weeks) Confhct test
Dorsal mph&, 5 Dorsal raphk, 5 i.p. 30 1.p. 30
0.002 0.004-0.01 2.5-15 I .25-20
Dorsal raphC, 5 i.p 30 i.p. 30
1.p. 30 i.p. 30
S-20 I-IO
i.p. 25
i.p. 30
during 21 days (xl) p.0. 30
S.C.
i.p. i.p. i.p. i.p.
i.p. 60 21 days (xl) S.C. 0
1-p. 30 ip p.0. 30
2.5
SC.
during
40 i.p. i.p. 30
2.5-20 3-5.4 0.5..60
Rats
5-10
3-10 I O-20 2.5-10 20-30 IO 61 8-32
1.25-10
4
2.5-5 0.1-I 5-20
Routes admmistratlon, latency (min)
W1star rats (4OG5OOg) W1star rats Sprague~Dawley rats (42048Og) Wistar rats (IgO-200g) Vogel’s conflict test Wistar rats (12 weeks) Rats Lister rats (2OC-250g) Lister rats (21&27Og) Wistar rats W1star rats (18&22Og)
Geller Seifter conflict trebt
AP mice (46 days) Adult rats Female MFI mice Marble burying test (23-35g) Novelty-suppressed Long-Evans rats feeding (30&325g) Fear-potentiated Sprague-Dawley rats startle reflex (3MOOg) Sprague-Dawley rats Active-avoidance test Wistar rats (22&24Og) Passwe-avoidance test Wistar rats (220-2408) Aggression-provoked NMRI mice Center test Rats (thigmotaxis) Long-Evans rats Cork gnawing (435wz4Og) Hot-plate Wistar rats (200-25Og)
Models
Efficient doses or doses tested (mgikg)
Table 1. Continued
0
+
0
+
+
+
0
+
+
+
+
+
+
+
+
+
+
+
0
+
+
+
Vogel‘s test Vogel’s test
Vogel’s test
FR30 FR30
F13
Modified Vogel’s test 0.16 mA shocks
Modified Modified
Modified
1986
1986
1993
Sanger,
1990
Gleeson P, ol., 1989 Nanry er nl.. 1991 Barrett, 1992 Lorens CI nl.. 1989
Gleeson and Barrett,
1990
Sanger, 1992 Menescs and Hong. 1993 Schuurman PI nl 1986 Higgins ef al., 1987 Higgms cr al., 1988 De Vry PI nl., 1991 Chojnacka-W6jcik and Przegalinski. 1991 Higgins PI al.. 1992 Przegahnski er al., 1992 Stefanskl P! ui.. 1992a Stefbnskl PI ol., l992b Korneyev and Seredenin. 1993 Meneses and Hong. 1993
Sanger. 1990 Amrick and Bennett, Young PI ol.. 1987
Deacon and Gardner.
Korneyev and Seredenin,
0
+
1991
Mansbach and Geyer. 1988 Sanger e, al., 1989 Sanger er al., 1989 De Vry et al., 1991 Schreur er al., 1993
Kehne rf al., 1988
Bodnoff rt ol.. 1989
Pollard and Howard,
VI30 0.32 mA shocks
Locomotion
References
Nastiti et al.. 1991 Vivian and Miczek. 1993 decreased Njung’e and Handlcy, 199lb
Comments
+
+
+
+ + + +
0 + +
+ + +
Effects
E
b 2’
Q
%! m
test
maze
+
+
+ +
i.p. 30 ,.p. 30 i.p. 30 p.o. 60 S.C. 30 i.p. 30 i.p. 30 i.p. 40
i.p. 30 i.p. 30
0.5-2.5 0.5 0.25-5 0.01-l 1.5 2.5-5 17.8-31.6 l-5 5 5 0.3 I-I .25 0.3-0.62 0.0002
Wistar rats (292-368) PVG rats (I 8&26Og) CD rats (16l&2OOg) Femdk T/O mice (22-3Og) Swiss mxe (20-3Og) Female ICR-DUB mice ( I7-35g) BKW mice (25-30g) Mice Swiss Webster mice (20-309) Wistar rats (18&22Og) Rats Lister rats (200-28Og) Rats Llster rats (20%25Og) Rats Lister rats (21&27Og) DAP mice 22-308) Wistar rats Rats Lister rats (25&3OOg) Lister rats (200-2808) Rats Rats
I
l-3 l-3 5
0.0004xl.01 IO I .25 0.634 0.025-10 l-5 0.0002 l-2.5 2
0.002
+
S.C. IO
8-2048 nmol
Rats Sprague Dawley (250-3508) Rats
Lister rats (240-3008) PVG rats (20&26Og)
i.p. durmg 2 weeks (x2) i.p. 5-20 i.p. 30
0.01-I
5
i.p. 30
30
i.p. i.p. 40 Dorsal raphe. 5 i.p.
Dorsal raphe. 5 i.p. 30 i.p. 15
Dorsal raphi,
Dorsal raphe. 5
+
+
+
+
+
+
+
+
++
+
+
+
+
+
0
+
+
+
+
+
+
+
+
+
0
0
0
0
Warm condition Cold conditions
HLU HLU
Isolated mice HLU et LLF
HLU LLF
LLF
65 dB noise
Asymmetric compartments Asymmetric compartments Asymmetric compartments Transitions only
Asymmetric compartments Transitions only
Observations during IO min Rats were well nournished Observations dung IO min
Observations during IO min
Rats were
Lister rats (200-270g)
1.p. 30
i.p. 30
0.1 2.5-10 0.5-5
PI al., 1992
Critchley
Kaltwasser.
1991
Mos and Olivier.
Colltinurd
1989
Carter and Smith. 1992 Costall et ol.. 1992a Higgins e, ol., 1992 Boaventura et nl.. 1986 Rex (‘I rrl.. 1991
Stefanski PI nl., l992a Stefanski PI al., 1992b Higgins et al.. 1992 Schuurman er ol.. 1986 Higgins er al.. 1987 Critchley PI al.. 1987 Higgins er al.. 1988 Olivier er ol., 1989 De Vry 6’1al.. 1991
Fernindez-Guasti and L6pez-Rubalcava. 1992 L6pe&Rubalcava er ol.. 1992
Costall E, nl., 1992a
Fernindez-Guasti and Lbpez-Rubalcava, 1990 Young and Johnson, 1991~
Luscombe el nl.. 1992 Bill P, a/., 1989
rf al.. 1991
Almeida
Graeff er al., 1990
SGderpalm cr al.. 1989
Wright e, ol.. l992b Critchley er al., 1988
Wright er a/., 1992a
Wright PI al.. l992a File er a/., 1987 Almeida el ol., 1991
Moser, 1989b
Decreased total open arm entries
_
S.C. 30
IO
_
Pellow e, al., 1987 Moser, 1989a
_
i.p. 30 S.C. 30
2.5-10 0.15-10
Lister rats (25&350a) Sprague-Dawley rats (20@3-3oog) Sprague-Dawley rats (2w3OOg) Lister rats (200-270g) Rats Wistar rats (144196g)
Staircase test Novelty-suppressed feeding Ultrasonic ‘distress’ Wistar rats (Y-l I days) vocalization Wistar rats (22s240g)
Social interaction
Open-field
Light/dark
Elevated-plus
ii. fz n 2 %
F @ 2
5.
5-HT,a
6
5-HT,s
Spiroxatrine (agonist)
7.94
125892
RS-30199 (5.HTIA ligand) pKo”’ 1.9 < 5
LY 165.163 (agonist) pKn’ 8.2
Compounds
7943
< 5
6
5-HTio
630h
5.9
5.1
5-HTx
Affinities (Ki, no)
7943
<5
6.2
5.HT:r
5.HT, Animals AP mice (&6 days) Rats Wistar rats (20&22Og)
i.v. i.p. 30
0.5-2.5 2.5-5 +
i.p. 30 i.p. 30 p.0. 30 i.p. 30 DPAG
EDro = 2.2 I@30 l-3 3-10 l&440 nmol
0.01-0.3 0.3-3
Conflict test White Carneau pigeons Elevated-plus maze CD rats (16&200g)
+
Barrett, 1992 Luscom be PI al., 1992
Luscombe rr al., 1992
i.m. 0 p.o. 60
FR30
Weak effect
1990
Korneyev and Seredenin. 1993 Jenck er al., 198Yb Graeff ec al.. 1990
Traber er al.. 1984 De Vry et al., 1991 Pollard et al., 1992
Sanger er al., 1989 Sanger er al., 1989
Mansbach and Geyer. 1988 Schipper er al., 1991
Redfern er ol.. 1989 Moulton and Morinan, +
+
+
0
+
+
+
+
0
+
+ 5,7-DHT
Fernindez-Guasti and Hong, 1989 Bow/s et al., 1991 Fernindez-Guasti PI al., l992a Fernindez-Guasti er al., 1992a Fernlndez-Guasti et al., l992b Korte and Bohus, 1990 Korte et al., 1992 Davis PI al., 1988a
i.p. ,.p. 40
p.o. 60
+
i.p. 30 i.p. 30
2wo 1.2-10
0.03-3
+
SC. IO p.0.
+
+
+
+
+
I-10
5 i.p. 30 i.v., IO i.p. 0
i.p. 30
2.5-5
+
0.625-10 0.5-2.5 lo-40
i.p. 30
0.3-30 3
CD rats (16&2OOg)
+
i.p. 30
2.5-10 +
0
Molewijk et al., 1993 Sommermeyer er al., 1993 Njung’e and Handley, 1991b
+ +
p.o. 48 hr and during 21 days (xl) in. S.C. 15 i.p. 30
0.5 g/l LED=3 0.3-10 S-20
References Nastiti et ol., 1991 Schipper et ol., 1991 Baudrie PI al.. 1993
Comments
+ + +
Efiects
30
Routes administration. latency (min)
2.5-5
Sprague-Dawley rats Lister rats (300-4OOg)
Elevated plus-maze
Elevated-plus maze
Stress-induced hyperthermla Active-avoidance test Wistar rats (22&24Og) Passrve-avoidance Wistar rats (22&24Og) test Aggression-provoked NMRI mice NMRI mice Cork gnawing Ovariectomised LongEvans CD rats (33Og) Hot-plate Wistar rats (20&25Og) DPAG-Stimulation Rats Rats
Fear-potentiated startle reflex
Wistar rats (30&36Og) Wistar rats (29&34Og) Sprague-Dawley rats (3OwOOg) SpragueeDawley rats Mice
Swiss Webster mice (20-350) Wistar rats
Adult rats Wistar rats (20&25Og) Marble burying test Female MFI mice (23-358) Shock-probe Wistar rats (280-35Og) burying test Rats Wistar rats (30&35Og)
Models
Efficient doses or doses tested (mgikg)
Table 1. Continued
00
%
15.7”’
27
MDL 73005EF (partial agonist) pKo’
8.4
5.7
66”‘”
I
WY-50.324 (agonist)
272””
0.3
458”‘O
20
I 300”y
WY-48,723 (agonist)
6.0
> lOOtlOt
16.7
5.4
> 100000
WY-41.846 (agonist)
HT-9OB 0.4 (agonist/antagonist) (ICu$‘”
Umespirone (agonist)
Tandospirone (partial agonist)
6.2
2600
test
Geller-Seifter conflict test Vogel’s conflict test
Celler-Seifter conflict test Conflict test
Conditioned avoidance reaction
Geller-Seifter conflict test Conflict test
Geller-Seifter Vogel’s conflict test Conflict test
Vogel’s conflict test
threat
i.p. 60 i.p. 5-10 days p.o. 60 S.C. 60
5-10 IO
.
0
i.p. 30 Sprague- Dawley rats (170-2 I Og) SpragueeDawley rats
+
t.m. 20 0.03-10
White Carneau ptgeons (4506OOg) Wistar rats (l80-200g)
.
A
S.C. 0.1-3
_...
+
S.C. 30 0 3~3
0.3310
+
+
+
i.p.
20
0
+
0
0
0
+
IO
im
i.m. 20
0.1-10
0.03310
i.p. 30 i.p. 30 i.m.
l-20 I-20 O.Olxt.3
p.0.
+
S.C. 45
0.00-0.1
3-30
+
p.0. 45
+
0.00-10
p.0. 30
l&60
+
+
i.p. 30
5-20
0
+
+
p.0. 45
i.m. 15 im. 0 p.o. 60
I 0.3310 EDw > 300
0
+
+
O.ooOl-100
i.m.
0.01~.1
I
+
i.p. and p.o. 0
I .25520 +
0
p.o. 60
l-100
Rats
White Carneau pigeons (45&6OOg) Rats
Rats
CD rats (2OOg) CD rats (200-25Og) Squirrel monkeys (800~105Og) White Carneau pigeons (450-600&T)
Rats
Sprague-Dawley rats (22552758) Marmoset Cdirhrix jacchus (3504408)
Social interaction Human
BKW mice (30-35g)
test
Light/dark
Cork gnawing
Conditioned avoidance reaction Straw suspension
Conflict
Sprague-Dawley rats ( I SO-2OOg) Squirrel monkeys (80&1050g) White Carneau pigeons White Carneau pigeons Sprague-Dawley rats (200-3@)g) Sprague-Dawley rats (14&17Og) Ovariectomised LongEvans CD rats (3OOg)
Ovariectomised LongEvans CD rats (3OOg) Sprague-Dawley rats (320-37Og) Vogel’s conflict test Sprague-Dawley rats (200-30%)
Geller-Seifter conflict test
VI30
FR30
FR30
FR30
FI3
VI2
Asymmetric compartments HLU
FR30
I992
Hibert and Moser.
Moser CI ol.. 1988
Sanger.
Barrett and Zhang.
Morris er ol.. I989
Andree er nl.. 1988
Barrett and Zhang,
Andree ef al.. 1988
Barrett and Zhang.
1990
1991
1991
1991
er al.. 1993
Haskins e( al., 1989 Haskins er al.. 1989 Gleeson and Barrett.
Miyauchi
Barnes er al.. 1991
Barnes CI al., 1991
Barnes er al.. 1991
1993
1990
er al.. 1993 Pollard ef nl.. 1992
Nishimura
Pollard e( al.. 1992 Barrett and Vanover, Shimizu CI al., 1987
Modified Vogel’s test Shimizu er al., l992b + 5.7~DHT Gleeson and Barrett. 1990 FL3
Modified Shimizu ef al.. 1992a Geller-Seifter test Modified Vogel’s test Shimizu er al., 1987
Pollard PI ol., 1992
agomst)
21009
(S-HT,4
lndorenate
IC<,I*”
antagomst)
(antagomst)
(+ )WAY
IC.?
(antagonist)
(S)-UH-301
25
98
> 10000
042”’
616’
1.3’
IOh
5.HT,s
5-HTw
100135
agomst)
(antagomst)
SDZ
(!-HT,,
ND0 00X
(partial
NAN-190
Compounds
398”
790”
5-HT,”
Affinities
no)
> 10000
7200
10000”
218’
~-HT?A
(Ki.
110000
7150
501 Ih
602’
5-HTx
Models
reflex
test
maze
test
test
test
maze
test
CD
White
wistar
Wistar
rats
rats
(min)
30
30
125, 2-4
14
30
30
30
60
rats
(20-3Og)
SWISS Webster
MlCC mu
(20-30g)
(I?
L
90
+
+
+
+
+
5
i.p.
shocks
Moreau
and
mA
compartments Transitions
only
only
shocks
Asymmetric
Transitions
0.32
Hong.
Lbpez-Rubalcava
L6pez-Rubalcava.
Fernlndez-Guasti
1992
1992 CI al..
and
1990
1993 and
1992
1992
1991
Lbpez-Rubalcdva.
Fernindez-Guasti
and
CI nl..
Fletcher
Meneses
PI ol..
PI nl.. Fletcher
Fletcher
1992
1992
1992
1991
1992
1990
1989-1990
1992
1991
e, R/.. 1993
el cl/..
e, a/..
er (I/..
Przegalinski.
Bickerdike +
er a/,
er al..
ChoJnacka-W6jcik
Kostowski
Joly.
er al..
1992
1992 e, al.. and Kostowskl
Sanger
Luscombe
Colpaert
PI a/..
Przegalinski,
0
mA
and Ahlers
1990
1991
1990 Y, al..
Chojnacka-W6Jcik
Moreau
test
test
1990 1989 CI al,
Moredu
0.16
Vogel’s
FR30
FR30
Vogel’s
Hitchcock
1988
Moser.
CI al.,
and
c’r al.,
1990
References cf al.,
et al.. Misshn
Bill
Moser
Hibert
Moser
Moser
+
+
1.p. 90
1.p. 30
S.C.
Modified
Modified
compartments
A$ymmetrx
Comments
+
0
0
+
_
+ _
0
0
0
+ +
+
+ f + +
+
Effects
5
2.5-10
5.610
3.1&10
2
S.C.
I-30
Rats
s.c
3-10
S.C. 45
i.p.
i.p.
s.c
I p.
!.P. 30
30
Mice
I
0.3-30
2-8
0.125
O.Of&.
i.p.
2
60
1.m. 5 p-0.
15
60
0.003-3
i.m
i.p.
1.p. 30
S.C. 30
S.C.
S.C.
p.0.
S.C. 30
S.C. 30
latency
0.162.5
I-3
0.25-l
1.25%10
I .25%5
2
0.034
0.03-2
0.25-I
0.034.25
Routes administration,
Mice
weekr)
rats (250-280g)
(IO weeks)
rats
rats
(18&22Og)
(345445g)
Rats
rats (22&24Og)
SWISS mice
Wistar
Llster
pigeons
rats (16&2OOg)
pigeons
Carneau
rats (IS&220%)
Swiss mice
Wistar
Wistar
(IO weeks)
Rats
Swiss mice
Wlstar
T/O
(22&30%)
Female
mice
rats
(20&3OOg)
rats
SpragwDawley Sprague~Dawley
(2x-3clOg)
Sprague-Dawley
rats
0.1-3
(20&3OOg)
(mg/kg) rats
Animals
tested
Sprague-Dawley
test Wistar maze
reflex
conflict
Light/dark
Vogel’s
startle
test
mare
test
Fear-po!ent!ated
Llghtldark
Elevated-plus
Light/dark
Elevated-plus
conflict
Geller-Scifter
conflict
Elevated-plus
Passive-avoidance
Elevated-plus
test
conflict
Conflict
Vogel’s
startle
maze
test
Fear-potentiated
Light/dark
Elevated-plus
Vogel’s
I2021
5.HT,
doses
Efficient or doses
Table I. Continued
s
c,
64.y’ agonist)
1.9h agonrst)
RU 24969 (non-selective
1040 metabolite)
CGS 120668 (non-selective
I-PP (zapirone‘s
3.8’”
II&’
42”
>I0000
316”
12882”
A”’
3800’
test
maze
Swiss mice NIH (20-30g) DBA/2 mice (6-E weeks1 Liste; rats (20628Og) Sprague-Dawley rats (9-l I days) Rats
Social intcractlon Uhrasomc ‘dlslres,’ vocahzation
rats (20&28Og)
Wwar
Rats rats (Y-1
I
days)
Rats Lister rats (250-35Og) PVC rats (18&26Og)
PVG
Geller-Seifter Rats conflict test Vogel’s conflict test Wistar rats (20&25Og) Conflict test Squirrel monkeys (800-105Og) White Carneau pigeons Rats (25&28Og) Elevated-plus maze
Social interaction Ultrasonic ‘distress’ vocalization
Elevated-plus
i.p. I5 i.p. I5 i.p. 30 S.C. 0
1.25 3-10 1.25-10 0.5-40
Dorsal raphP 5 S.C. 30 S.C.
0.0025 l-3 I-3
0.3--J
0.1875-1.5 0.1875-1.5 0 5-2
0.5-3
0.03-3 0.08-3.6
0.5-2 0.003-0.
i.p. 20
2.5-10
30
i.p. 30 i.p. 30
i.p. 30
i.m. 5
i.p. 30 i.m.
p.0. 25
i.p. 30
3.125
I
i.m. 5 S.C. IO
i.p. 30 p.0. 30 p.o. during 7 days
5-10 25 5-25 0.01-3 8-2048 nmol
S.C. 30
p.0. 30
1-4
5-80
+ +
i.p. 90
Sprague-Dawley rats (420-48Og) Sprague-Dawley rats (240-3008) Wistar rats Sprague-Dawley rats (21 I-347g)
+
i.p. 90
Swiss Webster mice w35g) Wistar rats
0
_ _
+ _
0
+
0
+ _
_
0
0
0
+
0
0
_
0
+ +
+
0
+
i.p. 90
+
rats (300-35Og)
i.p. 90
Wistar
IO
rats (280-3508)
Wistar
Conflict test White Carneau pigeons Elevated-plus maze Sprague-Dawley rats (250-350%) Wistar rats Social interaction Wistar rats Ultrasonic ‘distress’ vocalization Passive-avoidance test Wistar rats (22&24Og) Sprague-Dawley rats Fear-potentiated (300-4OOg) startle reflex
Vogel’s conflict
Geller-Seifter
Shock-probe burying test
Young
f, al.. 1987
er al.. 1990
and lnsel, Deacon and Gardner.
Winslow
1986
1991 b
Higgins PI al.. 1992 Winslow and Insel. l99la
Rodgers PI al., 1992
Benjamin
Observations during IO min LLF Warm condition
and Handley.
1987
1986
Corrrb,ued
Critchley er nl.. 1987 Mos and Olivier. 1989
File YI al., 1987 Pellow r/ nl.. 1987 Crltchley cr nl., 1992
Critchley
Gleeson <‘f al.. 1989 Critchley and Handley.
Vogel’s test Korneyev and Seredenin, 1993 F13 Gleeson and Barrett, 1990
HLU
1988
Sanger and Joly. 1989-1990 Kehne et al.. 1988
De Vry er al., 1991 De Vry er nl., 1991
Barrett CI al., 1986 Saderpalm cf al.. 1989
De Vry et al., 1991 Vogel’s test Amano c, al., 1993
Vogel‘s test Cower and Tricklebank,
Observations during IO min Observations during IO min
Modified
Modified
Modified
f 5.7-DHT
Fernindez-Guasti and Hong. 1989 Fernindez-Guasti CI al., l992a Fernindez-Guasti PI al., l992a Fernindez-Guasti er al.. l992b
b.
E:
8
2 Lt.
z
210 agomst)
1.2 3938’
I-NP (agonist) pK,,“ DOI (agonist)
mCPP (non-selective
5-HT,4
Compounds
79
6.6 2041’
5-HT,tl
II00
7.8 720@
5.HT,,,
140
7.2 1.3”
5.HT?\
Affinities (Ki. no)
29
8.3 6.49
5-HTx
test
5 6’
2 -5
Wistar rats (2OG25Og)
test
SpragwDawley (2Wg)
rats
Rats Swiss mice NIH (20-3Og) Sprague-Dawley rats DBA/Z mice (6-E weeks) SpragueeDawley rats (25&3oog) Wistar rats (15&22Og) Long-Evans rats (320-34Og) Wistar rats (20&24013) Zero-maze SpragueeDawley rals Sprague-Dawley rals Llght:dark test (2Oc-25Og) Swiss mice (IO weeks) Swiss mice (IO weeks) Wistar rats (200-2508) Open-field Sprague~Dawley rats (2w25Og) Free-exploratory test SWISS mace (IO weeks) Social mtcrwtion Sprague-Dawley rats (2%28Og) Liater rats (200-X0@
Shuttle box Elevated-plus maze
Vogel’s conflict test
Marble burying
SpragueeDawley rats (9-l I days) Female MFI mice (23-35g)
i p. 30 i.p. during ?I days (xl) i.p. 30 i.p. 20
I -3 2 l-5 2.5-5
0.0005 0.0125
Dorsal mph& 5
0
1-p. during 21 days (xl) S.C. 30 1.p 20 I I 0 wI.75
i.p. 30 Amygdala.
o _ _
,,p. 30 i.p. I5
0.3-3 5
34 0.00 I
_
S.C. 20
0.5
o
_ o
o
_
1991 b
Higgins (‘I (I/.. I992
Griebel rf rrl., 1991 Whitton and Curzon.
1990
Griebel CI nl.. 1991 Griebel. 1993 Klodzinska (‘I [rl.. 1989 Sedation’? Locomotion decreased Luck! CI ol.. 1989
Griebel, 1993 Grewal r, nl.. 1993 Kenne~t c,
Griebel. 1993 Rezazadeh (‘I al.. 1993
e, a/.. 1993
_
i.p. 1.p. 30
0.5 l-4
Blackburn
Gibson er nl.. 1991 Rodgers e, nl.. 1992
_
_
Martm. 1993 Benjamm rr al.. 1990
_
Kilts PI rtl.. 1982
,.p. 30
VIZI, also decreased nonpublished responding
Njung’e and Handley.
4 1.56-3.125
+
i.p. IO
+
i.p. 30
Warm condition Cold condition Locomotion decreased Wmslow and Insel. 199la
Tomkins er ol.. 1990 Heaton er al.. 1988 Njung’e. I990 Nastiti PI nl.. 1991 Mos and Olivier, 1989
l-2
0.01-5
+
+
+ _
+
S.C. 30
30 30
0.25-0.5 0.3-3 0.034
1.p.
3
+
S.C. 30 0
Kennett.
+
i.p. 30
1992
Fern;indez-Guasti and Hong. 1989 Korneyev and Seredenin, 1993
+
ip ,,p. I5
References
Gardner. 1985~ Cold condition Mos and Olivier, 1989 Locomotion mcreased Njung’e and Handley. 1991 b
Comments
30 30
Effects
+ + +
ROUIeS administration, latency (min)
0.1
0.2-I
0.254.75
l-3 0.1-10
Wistar rats (9-I I days) Female MFI mice (23-35g) Wistar rats (28&35Og)
Rats
Animals
Sprague-Dawley rats (250-3208) Llster rats Rats Rats Ultrasonic ‘distress’ AP mice (4-6 days) vocalization Wistar rats (9-l I days)
Shock-probe burymg test Hot-plate
Marble burying
Models
Social mteraction 6.9 > lOOOo* Elevated-plus maze
5-HTI
Efficient doses or doses tested (mgikg)
Table 1. Continued
c:
m
Id
1ysn7
uoyomo3o7
svmwedwos s!,lauK”&V
+ + + 0 _
OE E
I-S 0
I-Z.0
E E’O
E-t.0
OE OE OE ‘J’S
‘d,!
OZ &I S-I
0~ _
0~ ,d,r 01-l
S-S’Z
_
0~ &I 5-S-Z SZ’YX’I
SlIq
Sit?,
,“,S!+,
, [m(j)
11~ 6)
(SLnP !FP) JJ!“J dV (Shp , 1-6) SlB, ,“lS!+, (Sh?,,
@@P
(~055-0023 La~m?a~an%?,ds
SIEJ iqmna ~an%n,ds (~OSZ~OOZ) SII?, Aa[.+tt!aman%,ds
sw
,V!,S!M
(~osz-ooz) SIB,
zlvsa
8~)
(~ozz-os I) SIB, ,&?lSl,+, (Swm
,l?lS,,+,
SWLalMt?a-an%,ds (8OOZ+lSl) SlI?JlW!M
Sl)?,
(%OEQZ) H,,,J SS!MS
av” aJ!“J
21-6)
(%OOZl)Sl) SlBJ JW!M
(Shp
S'O
Z9'ckIE'O
(~OOZIXI)
I-Z.0
SO
0~ .d.l
0~ .d.l
0~ .dy
_ _ _
+
OZ .d,l Of
5'0
(%oszmz)
OE
_
OE
_
0
0 '"I',
mo-osz) S”L?K~8”Ol
,elS!M
s”oa%!d nea”,es
s1e,
10'0
(%ZSFOSP)
aj!qM
Slp.1JW!M
0
0
I-I'0
SlBJ
,d,!
SY‘Z
SlEN (SAeP 11-6) SlQj
KalMea-an%,ds SWX
dalhwa-anhds
sle, Kalma-an%n,ds
(~055-002)
SlQJ sw Aa[Mea-an%?,ds (%OSZFOSZ) ^ slw napea-amwas
SW
SW
I-I'0 0
Sp .d.l
oz-I
OEtl;l
SC
0
0~ .d.l
.d.l +
+
1-1'0
pooo’*z~o’o
100'0
SO
I-SZ‘O
1'0
I'0 OIH'Z
I-I'0
p”l?
J,%““~N
“O!,OWOJO~
sn”olz?olW
pawanap
6861 'IJJaw ,661 "," ,,I!I!ISPN 6861 "a!A!lO P”r: sow 6536, ‘,a!.&!(0 put! SOW
yasu, put? mo,s”!M
“,”
6861 “/U Id uauuay 686,
.dalp”“H
686, “I” l.4 !yJ”T pasEa,3ap
F&$36, ‘,a”p,FtD
066, “/I7 Id uye~uag
a,661
9,661
+
+
"166, '[aS"lp"t! MO,S”!M
0
+
OZ .d.!
‘d,! 0 ‘snd”moddy 0 G’A.5’1
0, ‘J’S
6861 'l'=JW
S!Ma
Id
986,
“,U
9861 '.p 12 spea
_
0 _ _ _ _
1s31 ;i”!hnq zqo,dmyaoqs
“0!1pz!,&?50”
snld-pamalg
,ssa,is!p. 31”ore,~~n
azw
“Oy?Zy?SOA ,ssa,is!p. s!“osullfl w!k”ado
p,l?oqa,oH isai ~,ep/iq%g amw snld-palmal isai isg”o3
“oyam
“o!lep”!lS-f)Vda
amld pa”oyp”o3 “y,aq),adAq pampur-ssa,ig lsal 8”!hq alq,eW isal l”!,nq aqo,d-qaoqg “o!lszy?3oA ,ssa,is!p. 3!“ose,i~~
xaya, apis paiegualod-mad %“!paaj passa,ddns-,Q[aAoN
“0012
91’9
El
9L.P
ORL
069
6P
EO’S
(isluol~ 00s
ddW\l;ll
a.ynalas-“0”)
Zli-NW
,;.Uyd SE’S (ISI”O%Ba+salas-“0”)
79h
2600
Clorapme (Non-selective pKi’“: S-HT?< antagonist)
Methiotepm (antagomst)
ICI 169369 (antagomst) ICr,,““‘:
14@
5.6
Altanserin (antagonist): PKD”
Cinanserin (antagomst)
5-HT,ti
Compounds
50h
2000
6200’
6.0
5-HT,e
50.1”
6100
5.HT,n
76
I.5Sh
17.9
19h
8.6
5.HT:*
Affinities (Ki, no)
8.1
25h
19.2
I99h
6.9
5-HTx
3000’
1100
5.HTl Models test
test
Geller-Seifter
Fear-potentiated startle reflex
Shock-probe burying test
Light/dark
Marble burying test
Social interaction
Fear-potentlated startle reflex
Confhct test
Vogel’s conflict test
Geller-Seifter conflict test
Social mtcraction
Stress-induced hyperthermia DPAG-Stimulation
Marble burying
Animals
rats
SpragueeDawley rats contllct test
Sprague-Dawley (320-3508)
2 5-5 (260-320g)
i.p 60
J.
0
+
1.p. 70
0.31 0.1
0
0
i.p. 30
1p. 30
0
0
+
0
0.31
0.31
i.p. 30
1.p. 30
S.C. 30
i.p. I5
+
0
+
t
i.p. 30
0.25
Swiss Webster mice (2@3Og) Swiss Webster mace (20-358) Wistar rats (300-3500)
I-IO
6
IO
Swiss mice (20-3Og)
Sprague-Dawley rats (250-3208) Female MFI mice (23-35g)
i.p. 60
56 i.m.
+
i.p. 60 i.p. 30 i.p. 60
15-60 l&60 56
l-3
t
i.p. 60
60
0
0
i.p. 60
0
0
60 l&56
i.p. 0 or 80
S.C. 30
+
0
+
Effects
Rats Sprague-Dawley rats (200-320%) SpragueeDawley rats (4 months) Rats Wistar rats (22Og) Sprague-Dawley rats (20&32Og) SpragueeDawley rats (2OOg) Squirrel monkeys (55&9oog) SpragueeDawley rats (3OMOOg)
0 5-5
1.p. 45
i.p. 30
3-25
rats
5-20
I-20
(mg/kg)
Routes admmstration, latency (min)
Female CFN rats
Sprague-Dawley (25&3208)
Rats
Female MFI mice (23-3583 Swiss mice (25-3Og)
Efficient doses or doses tested
Table 1. Continued
References
1 1990
1972
1992
Geller er ol.. 1974
Sepinwall and Cook, Kilts ef al., 1981
Winter,
Kennett,
Jenck ef al., 1989b
Lecci e/ a/
Fl60IFRI
FR30
VI21
1992 199lb
Wiley CI al.. 1993
Fernlndez-Guasti ef al., 1992a Fernindez-Guasti er al., 1992a Svensson. 1985
Fernindez-Guasti and L6pez-Rubalcava, 1990 L6pez-Rubalcava e, al.. 1992
Njung’e and Handley,
Kennett.
Davis er 01.. 1988b
Brady and Barrett,
Kilts er nl., 1982
1975b 1981
1978
199lb
1985
Njung’e and Handley,
FRIO/VI30 Cook and Sepinwall, Modified Vogel’s test Petersen and Lawn, VI21 Kilts ef al., 1981
FR40
VI3O!FRIO
Locomotion decreased
Comments
E P
84Q
316h
Cyproheptadine (antagonist)
4.9
5.4
( - )Mianserin (antagontst) pK,,:,”
5.5
6390h
6.2
I OoOh
(+ )Mianserm (antagonist) pK/
Mianserin (antagonist)
39v
3.16”
1.2
8.6
7.9”
12.6D
7.0
7.9
IOh
263”
8.0
6.6
64.5**
rats
Rats
Sprague-Dawley rats (250-32Og)
Sprague-Dawley (25&32Og)
Long-Evans rats (25&3008) Long-Evans rats (280-3008) Wistar rats (37&45Og)
Rats
Swiss mice (10 weeks) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (25&32Og) Long-Evans rats (30&325g) Wistar rats (25&28Og)
Wistar rats (198-260g) Rats Sprague-Dawley rats (33&37Og) Vogel’s conflict test Sprague-Dawtey rats (2Wg) Wistar rats (22Og) Rats Conflict test White Carneau pigeons (48&528g)
Geller-Seifter conflict test
Social interaction
Social interaction
DPAG-Stimulation
Novelty-suppressed feeeding Shock-probe burying test Conditioned place aversion
Social interaction
Light/dark test Open-field
Sprague-Dawley rats (33&37Og) Rats Rats Sprague-Dawley rats (20&225g) Conflict test Squirrel monkeys (55&9Oog) Elevated-plus maze Wistar rats (150-2208) Lister rats (25&4OOg) Swiss mice NIH (24-2&g) Geller-Seifter conflict test
+ 0
S.C. 30 i.p. 60 during 21 days (xl) S.C.60
l-2
+ 5,7-DHT
i.p. 30 p.0. i.p. i.p. 30 i.p. 30 30 i.m. 0
I-18 I-IO 3 0.01
p.o. 25
S.C. 30
5.6 540 0. I-l
10
I
S.C.30
0
+
0
0
+
+
+
0
0
+
Kilts Y( al.. 1982
Graeff. 1974 Sepinwall and Cook, 1980 Witkin and Perez. 1989-1990
Deacon and Gardner, 1986
Kennett, 1992
Kennett. 1992
Cothturd
Modified Vogel’s test Petersen and Lassen. 1981 Schoenfeld, 1976 FR30 Witkm er al.. 1987
VI21
FIl/FRS FRlO/FR30 FR30/FRlO
_
i.p. 35
2z4
Rocha PI al., l993b
_
i.p.
IO 0.1-10 l-32
Jenck PI al., 1989a
Rocha PI al., 1993a
_
Rocha c, al., 1992
i.p.
Meert and Colpaert, 1986b
0
Bodnoff er al., 1989
Kennett, 1992
Kennett e/ al.. 1989
Griebel. I993 Lucki er al., 1989
_
+
Locomotion increased
Brady and Barrett, 1985
FR30
Griebel. 1993 Pellow er al.. 1985 Benjamin er al.. 1992
Van Riezen er al.. 1981 Sullivan P( al., 1985 Mason er al., 1987
Witkin and Perez, 1989-1990
Vl30/FRlO V130/FR30
FR30/FRlO
10
0.6340
IO
0
0
0
+
+
0
0
S.C.40
I c&20
2
_
+
5 2.5520 20 l-10 2.5-5
i.m
0.1-10
+
+
+
0
i.p. 30 i.p. 30 i.p. 30 i.p. 48 hr i.p. 18 days i.p. 30 i.p. 60
i.p. i.p. 60
0.74.5 3
10
i.p
0.3317
ti WI
6
%
oz
;. 6 a a.
H
selective
6309b
630”
1731’
5.HT,s
antagonist)
5.HT,*
antagonist)
(antagonIst)
Ritanserin
(5-HTzA
R 56413
(antagonist)
Pitozifen
(S-HTx
EGIS-3886
Compounds
1584”
5.HT,n
Affinities
IIM)
I .48h
4.4‘
5-HTl+
(Ki.
I 25h
7.9h
5.HTx
7244
42~
S-HT,
interaction
reflex test
mteraction
conflict
test
test
rats (2C+25Og)
MFI
conflict
test
Geller-Seifter
Rats rats
rats
(2%27Og) Rats
Wistar
rats
(33&37Og)
Sprague-Da&y W1star
rats
rats (25&28Og)
Rats
test
test
rats (25&28Og)
conflict
Shock-probe
Wistar
Wistar
rats
mice
rats (25&28Og)
Sprague-Dawley
Wistar
(25c-3208)
Sprague-Dawley
Rats
Rats
Rats
Rats
(23%35g)
Female
Rats
burying
rats
(30@4oog) Wistar rats (25&28Og)
Sprague-Dawley
rats
(ISO-200s)
rats (I 5&2OOg)
Sprague-Dawley
Wistar
Wistar
(15&2OOg)
(25-35g)
rats
Mice
Wlstar
(55&9oog)
monkeys
Animals Squirrel
Open-field
test
test
conflict
Light/dark
Vogel’s
Geller-Seifter
burying
Shock-probe
Social
Vogel’s
test
response
DPAG-Stimulation
emotional
Conditioned
mlcturition
Defecatvx-
burying
burying
Shock-probe
startle
Marble
maze test
Fear-potentiated
Social
Holeboard
Lighlldark
Elevated-plus
Models
2
3
0 lb-40
0.1-10
IO
2.5
0.01-0.63
0.16
2540
(33&37Og)
l-30
40
0.5-I
3
IO
l-5
2.540
5
2
0.5
0.5
0.05-10
0.S
0.1-l
@g/kg)
doses tested
Efficient or doses
Table I. Continued Routes (min)
15
30
30
25
+
0 +
p.0.
0
0
S.C. 60
’ P-
i.p.
+
+
+ +
S.C. 60
0
+
+
+
0
0
+
+
0
FRS.
weak
VI30
FR30iFRIO
test
effect
compartments
Asymmetric
and
Vogel’s Transitions
Modified
FR30/FRIO
and
P, rrl.,
1990
1986
l986b
1986b
1986
1989-1990
1992
Bennett.
ci rrl.. Hascoet
Perez.
Gardner.
Colpaert.
Amrick
and
1985
1985
Colpaert.
Brocco
Witkin
and
and
Deacon
and Meert
cr ol..
Meert
t,
n/~
Perez.
1986b
1989-1990
1991
1986~
199lb
1986b
1985
1982
Colpaert.
Colpaert
and
and
1992
,
File. er nl
and
I985b
Colpaert,
Colpaert
Witkin
Meert
Kennett.
Gacdlyi
Clarke
and
Handley.
Colpaert. and
and
1989
1990
1990
l988c
1988b
rr al..
PI al..
ec nl..
e, ol..
) 1990
Barrett,
References
e, a/
and
er al..
Gardner,
Meert
Njung’e
Meert
Davis
Kennett
effect
Kshama
Kshama
weak
Kshama Costall
0
and
compartments
Asymmetric
compartments
AsymmetrIc
and
Brady
0
_
-
Sedation
FR30
+ 0
Comments
Etrects
S.C. 60
i.p.
S.C. 60
S.C. 30
i.p.
i.p.
S.C. 60
i.p.
S.C. 40
30
30
1-p. 40
30
i.m.
latency
admimstration,
E
+
i.p. 45 S.C. 60 S.C. 60
0.1 0.05-0.1 and I 0.25 IO nmol 0.25 I 0.05-10
0.1-0.6 0.324.7 0.124 0.04-10
I
Lister rats Wistar rats (16196%) Lister rats (20&27Og) Lister rats (20&25Og) Lister rats (200-27Og) Rats Mice (25-35g)
CD1 mice Swiss mice (IO weeks) Wistar rats (25&28Og)
BKW mice (3&35g)
Novelty-suppressed feeding
Social interaction
Open-field
Light/dark
Rats
S.C. 40 i.p. 30 p o. 12-15 days
0.14.6 0.324.7 0.25
S.C. 60 t.p. 30
i.p. 40
i.p. during 2 weeks (x2) DPAG, IO i.p. during 2 weeks (x2)
i.p. i.p. 30
p.0. 90 i.p. 30 S.C. 30 i.p. 30
0.6
2.5-10 0.01&40 O.O‘&lO 0.04-0.63 l-5 5
i.p. 30 p.0. 12-15 days i.p. 30 S.C. 60
0.25-4 0.05XI.25 0.63-10 0.025-5
CDCOBS mice (24g) Lister rats (X0-300g) Wistar rats PVG rats (20&28Og)
Wistar rats (220-240%) Wistar rats (250-2808) Rats Wistar rats (22&24Og) Wistar rats (lSl&22Og) Rats Rats Sprague-Dawley rats (20&25og) CDI mice
+
i.p. 30 i.p. 30 i.p. 30
0.25-10 0.25-10 0.05JJ.25 0.05-I
test
i.m. 5 i.m. 5
S.C. 60 i.p. 30
+
+
0
0
+
+
+
+
+
0
0
+ _
+
+
+
+
+
+
0
0
0
0
0
_
_
+
+
+
+
+
0
2.5 1-5 2.5-5 0.03-10 0.1&2.5
0
Wistar rats (25s280g) Wistar rats (18&22Og) Rats Conflict test White Carneau pigeons White Carneau pigeons (500-6OOg) Elevated-plus maze Rats Lister rats (25&35Og) Lister rats (20&27Og) Wistar rats (292-368)
60 i.p. 60 SC.
O.l&40 0.254.5
conflicttest Wlstar rats (22C-24Og) Wistar rats (IS&22Og)
Vogel’s
Unfamiliar and neurral box
LLF
65 dB noise
Transitions and Asymmetric compartments Asymmetric compartments Sedation ?
Sedation, ataxia and Asymmetric compartments Asymmetric compartments
Rats were malnourished
Observations during IO min
Rats were well nourished
l993a
Rex er ol.. 1991
Gao and Cutler.
ColtriI1rred
1993a
Meert. 1992 Meert, I986 Meert and Colpaert. 1986b Meert. 1992 Stefanski YI al., 1992a Stefanski er al., l992b Critchley cr al.. 1987 Kennett r, ol., 1989
Barnes er al., l992a
Griebel, 1993 Colpaert PI al., 1985
Gao and Cutler.
Onaivi. 1993 Costall e, al.. 1988~
Audi PI al.. 1991 Wright et al.. l992a
Wright PI al., l992a
Tomkins e, al., 1990 Almeida ef al., 1991
e, O/q 1991 Wright e, al., 1992~1 Millan and Brocco, 1993 Critchley and Handley. 1987
%UtZ”ldfltl
File er al., 1987 Pellow CI al., 1987 Wright CI al., l992a Almeida P, al.. 1991
Vogel’s test Brocco EI al.. 1990 Vogel’s test Chojnacka-Wbjcik and Przegalinski, 1991 Modified Vogel’s test Colpaert er al., 1985 Modified Vogel’s test Stefanski ec al.. l992a Stefanski er al., 1992b Gleeson ef al., 1989 Brocco PI al., 1990 FR30
Modified Modified
2. 8 a 2 %
5-HT,a
125Sh
Compounds
Ketanserin (antagonist)
l9lOh
5-HT,s
1000”
5-HTIU
3.1‘
5.HT!n
Affimties (Ki. no)
97.7b
5.HTx
test
30 i.p. 30 i.p. 60 i.p. 30 i.p. 30
2.5-5 l-5 0.1-0.2 2.5-20 0.1~10
AP mice (46 days) ddY mice (18-20g) Swiss mice (25-308) Wistar rats (22C-2408) Male and female Long-Evans rats (IO&l03 days) Rats Wistar rats (20s2508) Rats Wistar rats (18s2508)
Open-field
i.p. p.0. i.m. i.m. 5 1.p. 30 i.p. 30 i.p. 60
S.C. 40 S.C. 30 S.C. 180 i.p. 30 i.p. 30
0.3-30 10 0.1-3 0.3-10 1 O.lwI.5 10
0.2 0.2-l I4 l-10 0.1-I
DPAG DPAG DPAG
30
0.3-3
Wistar rats (9-l I days)
IO nmol IO nmol IO nmol
S.C. 30
0.3-3
Sprague-Dawley rats (330-3700) Wistar rats Conflict test Squirrel monkeys (55&9OOg) White Carneau pigeons Elevated-plus maze Wistar rats (220-25Og) PVG rats (20&28Og)
Geller-Seifter conflict test
DPAG-Stimulation
Stress-induced antinociception Stress-induced hypcrthermia Passive-avoidance test Defense test battery
Ultrasonic ‘distress’ vocalization
Wistar rats (25&28Og) Female MFI mice (23-358) SpragueeDawley rats (9-l I days) S.C. 60 i.p. 30
Routes administration, latency (min)
2.5 l-20
Rats
Marble burying
Animals
Models Shock-probe burying test
Sprague-Dawley rats (20&25Og) Rats Social interaction Sprague-Dawley rats (20&25Og) Sprague-Dawley rats (2%3208) CD rats (9-13 weeks) Fear-potentlated (25&32Og) Female MFI mice Marble burying test (23-358) Stress-induced colonic Wistar rats (25&3OOg) motor alterations
> lOOO@
S-HT,
Efficient doses or doses tested (mg/kg)
Table 1. Conhued
References
0
+
0
0
0
0
0
+
+
+
+
0
0
0
Locomotion decreased
LLF
Observations during IO min
FR30
and Perez, 1989-1990
1991
1992
GuC CI ol., 1993
1987
l99lb
1989 Njung’e and Handley.
Nanry and Tilson,
Kennett.
Critchley CI al.. 1987 Kennett CI al., 1989
Lucki et al., 1989
Gleeson er al.. 1989 Motta PI al., 1992 Crttchley and Handley.
Amrick and Bennett, 1986 Brady and Barrett. 1985
Witkin
Jenck er a/., l989b Audi et al.. 1988 Graeff, I988 Nogueira and Graeff,
ef al., 1992
Sanger and Joly, 1989-1990
Lecci er al., 1990
Nastiti BI al.. 1991 Tokuyama P, al., 1993
1989
and Insel. 199la
Mos and Olivier,
Winslow
_ 0
l986b
Meert and Colpaert. l986a Njung’e and Handley, 1991 b
Meert and Colpaert.
Shepherd
FR30/FRIO
Warm condition Cold condition
Locomotion decreased
Comments
0
0
0
+
+
0
0
_
+
+
0
Effects
2
LY
53857
antagonist)
>4000
151
68.5,”
1258
6215
antagonist)
DAU
(S-HTI
antagonist)
46470A
(Selective
BRL
(antagonist)
Anpirtoline
(agonist)
Phenylbiguanide
(5-HTla
Seganserm
(antagonist)
RP 62203
(antagonist)
Pirenperone
(antagonist)
>10000
28
3162
>10000
>10000
0.42’
I.58h
50”
>10000
29’
50
7.9
0.32”y
3@‘X
13Ok
b1000”’
interaction
test
place
observation
Free
Four
test
test
maze
test
hot-plates
Staircase
Light/dark
Elevated-plus
conflict
Geller-Seifter
interaction
test
maze
test
test
maze
Social
Light/dark
Elevated-plus
Light/dark
Light/dark
Elevated-plus
Elevated-plus
maze
test
Conflict DPAG-Stimulation
test
conflict
Geller-Seifter
hyperthermia
Stress-induced
Social
conflict
Geller-Seifter
DPAG-Stimulation
aversion
Conditioned
(33&37Og)
rats
ICR-DUB
mice
mice mice
CDI CDI
CD1
mice
CD-l
NMRI
NMRI
mice
Wistar
Wistar
mice
mice
(2&22g)
rats
rats
(3G35g) Cynomolgus monkeys
Female
(250-3000)
rats
(4@44g)
(4&55g)
(4C-55g)
Sprague-Dawley
mice
(2%3008)
rats
(25-30g)
(I 7-35g)
CDI
(24g)
(20&28Og)
Sprague-Dawley
BKW
mice
rats
(3704508)
CD-COBS
rats
Female
PVG
Mice
Wistar
(55&9OOg)
monkeys
(33&37Og) Squirrel
rats
(25-308)
Sprague-Dawley
mice
(25c-32Og)
rats
rats (37&45Og)
Rats
Sprague-Dawley Swiss
rats
rats (25&3008)
Sprague-Dawley
Wistar
Wistar
(25&3OOg)
Long-Evans
,.p. 45
0.014l1
0
0
i.p. 0.001-0.1
45
+
i.p. 45
0
0
+
+
+
+
-t
S.C. 2s or 45
60
IS days
days
fluid
(xl)
+
+
+
0.01-l
p.o.
during
during
68
S.C. 30
days
Drinking
12-14
p.o.
30
30
30
+
0
+
+
+
0
0
0
+
0
+
0
0
0
0.015-0.15
0.01-l
0.001~.1
40 /Jg/l
0.0001-0.1
30
30
p.o. during
i.p.
0.0025-2.5
p.0.
IO
IO
90
i.p. 45
i.p.
i.p.
p.0.
i.p.
35
60
i.m.
i.p.
i.p.
i.p.
0.01
35
S.C. 30
i.p.
i.p.
DPAG
DPAG
i.p.
0.0025
0.0001-0.1
0.000001-0.001
I-31.6
0.5
0.25-4
0.1-I
0.001~.3
0.03-3
1.5-3
2-s
0.03-3
I-IO
IO nmol
10 nmol
I-IO
10 min
and
Familiar
Oestrous
compartments
mice
mice
Asymmetric
Dioestrous
box
neutral neutral
and box
Familiar
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
during
Observations
FR30
FR3O/FRIO
FR3O/FRlO
and
and
and
et al..
6’1 trl..
Cutler.
Cutler.
.
cl nl.. er al..
Borsini
ef nl.. Borsim
PI nl.. Borsini
CI ul..
er al.
Borsini
Borsin!
Piper
1992
1993b
1993
l992a
l992b
l992b
1993
1993
1993
1993
1993
1993
1992
Ciao and Cutler.
Blackburn
Gao
Gao
Gao
Blackburn
er al..
Johnson.
1987
1991~
1991
1985
1989-1990
1989-1990
Handley,
er al..
1989a
Barrett,
Perez,
1990
Cutler,
and
Metzenauer
Young
Critchley
Perez,
and
et nl.,
and
and
PI al.,
Stutzmann
Jenck
Brady
Witkin
Lecci
1986
1985
1993a
1989a
1992
and
cf al.,
Kennett.
Witkin
Jenck
er al.. er al.,
Graeff
e, al.,
Schiitz
Rocha
6
%
B
2.
F ;:
4 5.
>lOOO@
antagonist)
Granisetron
(selective
5-HI-,<
Compounds
>lOOo”
5.HT,s
5.HT:,
(Ki.
IIM)
5.HTx
>10000”>10000”>1000~
5-HT,n
Afimties
1.41”’
5-HTI
test
motor
test
alterations
colomc
observation
threat
interaction
Stress-induced
Free
Human
Social
Light/dark
maze
test
conflict
Elevated-plus
Vogel’s
conflict
Geller-Seifter
feeding
Male
rats (21s28Og3 Ca//ithri.v monkeys
(295-3358) rats (25&3OOg)
Cynomolgus
jacchus Wistar
mice
female
(2436g)
female
Marmoset Marmoset
Wistar
and
DBA/Z
Male
mice
and
Gerbils
0.1-l
0.01~.1
0.001~.1
0.000001-0.
0.00001~.0001
0.01
0.01
0.0015-0.15
p.o.
I
days
i.p.
30
p.0.
S.C. 45
5
fluid)
7-10 Amygdala.
(in drinking
5
(xl)
. (xl) aur,ng days during
S-IO
(xl) during days p.0.
II
p.o.
3 weeks
during
0.1 2
Gerbils
p.0.
p.0, 45
45
p.0,
0.0001-0.1
p.0.
0.0001xl01
0.1-10
60
Rats
rats (20@2SOg)
Lister
(200-2508)
p,o.
Amygdala
I
0.00001~.001
(21&28Og)
Rats
rats
60
60
i.p. 45
p,o.
rats
DBA/Z
during days
p.o.
12-16
0.1-l
O.OOl--0.1
0.1 2 p.o,
i.p. 45
0.00001
-0.001
1.p 45
0.00001~.001
50
i.p.
i.p.
P 0. p,o. 60
0.00001~.001
0.001-1
0.01-l
0.0005~50
p.0.
rears
0
+
+
+
+
+
+
Weak
HLU
HLU
LLF
LLF
effect
and
+
HLU
HLU
+
+
HLU
+
HLU
LLF
and
HLU
HLU
HLU
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
and
compartments
Asymmetric
compartments
+
+
0
0
0
+
+
+
+
+
0
0
0
0
Gui
Piper
1992a
198Ya
lY89b
l988a
File.
File.
PI cl/
1991
1988
1989a
l988a
1993
.
PI ol..
er nl..
1988
1989
I988
I990
1989~
Piper.
er rrl.,
l99lb
l99la
and
I990
1989
CI ol..
cf ~1.. 1988
and
c! ul..
1991
Johnston,
PI al..
1990
e, nl.,
er nl..
P, ol..
Costall
Costall
Higgins
Cutler.
Cutler,
Cutler
Cutler.
Tyers,
Costall
Piper
Johnston
I989
and et nl.,
1990
and Higgrns
File.
File
Barnes
Cutler.
Costall
Costall
1988
1993
1993
1993
er 01.. 1988 Morinan, Costall
cf ul..
PI cl/.,
ef al..
1993
References PI al..
r, ol..
Johnston
Piper
PIper
Borsini
0.0005~50
Borsmi
0
30
+
Borsmi
Borsmi
i.p.
Asymmetric
Comments
0.001-0.1
0
+
Effects
S.C. 30
(xl)
5 h
(ml”)
i.p. 45
0.1-l
Lister
Wistar
latency p-o. during
0.0154.3
0.001&0.1
0.001~.01
administration.
rats (25Og)
(3&35g)
tested
@g/kg)
or doses
ROIJlCS
Rats
mice
(2&3Og)
(2@3Og)
Gerbils
mice
Mice
rats (21 days)
BKW
Lister
(200-2508)
Rats
rats
mice
BKW
rats
rats
tmce
monkeys
rats (200-25Og)
BKW
Wistar
Lister
Lister
Wistar
aversion
Stress-suppressed
place
CD-COBS
CD-I
Cynomolgus
Animals
Conditioned
hyperthermia
Stress-induced
Aggression-provoked
Models
doses
Efficient
Table 1. Continurd 0
s!
pK:“:
<4
>10000”>1000~>10000’
antagomst)
205-930
(selectwe
ICS
antagonist)
(selective
CR68755
17000’?
5.2
>lOOOo^
<4
0.81”
9.8
test
maze
test
test
Social interaction
Open-field
Light/dark
Elevated-plus
Conflict test
conflict
conflict Vogel’s
test
interactmn
GellervSeifter
Social
Light/dark
rats
Wistar
(21&28Og)
(30&35Og)
rats
mice
0.00001-0.001
I-10
0.01
0.0001~5
0.0000001-l
Amygdala,
1.p. 30
S.C.
p.0.
i.p.
5
(18-20g)
T/O
mice
(2G35g)
(2&3Og)
0.01
0.00~1
0.00001~).001
I
(22-300) Wistar rats (25&27Og) 0.187-20 Wistar rats _ O.OOOOOl~.lXlOl Rats Wistar rats (18&22Og) 0.ooo1~.01 Rats 0.001~.1 Wistar rats 0.000001~).00001 0.000005 Rats 0.01-I Sprague-Dawley rats 0.05-I (200-2508) Wistar rats (21&28Og) 0.0001~.001 0.00005-0.005 Rats 0.0001~).01
Female
mice
ICR
mice mice
BKW
C57Bl/6J
-
0.000000010.00001 0.0001~. I
BKW mice (2s30g)
ng/kg
0.00001~).01
Mice
0.001
0.0000-0.01
Mice
BKW mice (25-30g)
0.0001&0.01
Mice
2
0.1
Gerbils
0.00001
Amygdala, Dorsal rapha 5 i.p.
Nucleus accumbens septi p.o. 60 S.C.40
i.p. 60 Hippocampus Accumbens i.p. 60
S.C. 30
i.p. 30
i.p. 30 i.p. 45
Dorsal raphe or Amygdala 1.p. 45
i.p.
i.p.
p.0. during 12-16 days (xl) i.p.
Rats Accumbens 0.0001-0.01 Wistar rats (ISO-22Og) i.p. 60 0.001~.01 Rats W1star rats 0.000005-0.00001 Hrppocampus Nucleus 0.00001 &cumbens septt White Carneau pigeons 0.001x-l.3 i.m. 5 Rats p.o. 60 0.1 Wistar rats (20%2508) 10.25+).5 i.p. 30 BKW mice (25-30g) 0.00000001 Median raphe
rats
Wistar
Rats
Lister
BKW
+
0
0
0
+t
+
+
+
0
0
+
+
+
+
+
+
+
+
+
0
0
+ + + +
+ + + +
o
0
0
+
+
Asymmetric
Vogel’s
Vogel’s
test
Gel&
LLF HLU
HLU
+ 5,7-DHT
65 dB noise
, 1991
Thiebot ef al., 1990
Hagan er al.
Costall er a/., 1991b
1989
Costail cr ol.. l987a
Higgins PI ni., 1991
Corltirlued
Johnston and File, 1988 Kennett CI nl.. 1989
Papp and Przegalinski, 1989 Stefanski PI al.. l993b Plaznik er al.. 1991 Stefanski YI 01.. 1992a Stefanski PI (I/.. 1992b Stefanski PI nl.. l993b
Bill PI al., 1992
Onaivi and Martin,
Kilfoil er al., 1989 Costall et al., l989b
Costall CI al., 1989a
Costall er al., 1989~
Costall PI al.. 1988b
Tyers er al.. 1987
Costall CI ol.. l987b
Cutler, 1990
Gleeson er al.. 1989 Johnston and File, 1988 Dunn e/ al.. 1991 Costall e, al., 1989~
Dunn P, al., 1991 Higgms CI al.. 1991 Plaznik CI al., 1991 test Stefanski et al.. l992a Stefanski et al.. l992b Stefanski of a/., 1993b test
Asymmetric compartments and rears Transitions and Asymmetric compartments Asymmetric compartments
Asymmetric compartments Asymmetric compartments Asymmetric compartments and rears Asymmetric compartments Asymmetric compartments Asymmetric compartments Asymmetric compartments
Weak effect
Modified
Modified
Seifter
Modified
HLU
compartments
> 1000””
5.HTu
antagonist)
72222
(selective
MDL
Comnounds
> 1000”
5.HT,.
> 1000”
5.HT,,,
Affinities
no)
6 3””
5-HTI
> 1000“’
5-HT,<
> 10000”~’
~-HTQ
(Ki.
test
test
maze
interaction
DPAG-Stimulation
Social
L&/dark
Elevated-plus
test
conflict
Conflict
Vogel’s
Geller~Sclfter
DPAG-Stimulation
test
test
place
Passive-avoldance
averston
ConditIoned
threat
burying
Human
Marble
feeding
Novelty-suppressed
Models
(200-25Og)
rats
45Og)
(210-28Og)
(20-3583
Wistar
rats
(37&45Og)
(25C-3008)
rats
rats (21@28Og)
Llster
Rats
Rats
rats
mice
mice
Wistar
Lister
ICR
T/O
(2&3Og)
(24m35g)
Female
mice
rats (I 5&22Og)
BKW
rats (20&25Og)
plgeons
Wistar
Rats
Carneau
rats (300-35Og)
Rats
conflict
test
(370
(25&27Og)
Rats
rats
rats
27Og)
Wistar
White
Wlstar
Wistar
Wistar
rats (250
(295-3358)
.jacchus
Cullirhr,.~
Marmoset Marmoset
mice
rats
Callrrhrr.~
(35&4OOg)
jacchus
Marmoset
Wistar
MFI
Rats (23-358)
Female
(270-3208)
SpragueeDawley
(21&28Og)
rats (25&3OOg)
Wistar
Gerbils
Mice
rats
Wistar
Lister
p.0.
1.p. 30
3 weeks
60
i.p.
S.C. 30
0.3-3
45
35
i.p
0.1-22
30 Amygdala
i.p.
p.0.
raphi
0.001-0.01
20
IO
0.001~.1
Dorsal
Amygdala
0.0010.01 0.00005~.005
i.p.
0.001~1
30
i.p. 45
IO
1-p. 30
1.p. 30
5
30
35
i p. 60
i.p.
i.m.
10
30
S.C. 45
i.p.
i.p.
S.C. 30
0.01&3 IO
45
Amygdala,
during
i.p
45
p.0.
(min) 45
p.0.
latencv
i.p.
IX75
Routes administration,
5-20
0.5-X
10
0.01~10
0.0937-O
0.125-I
0 I-I
0.0001-n.00l
0.0001~.01
0.1-10
0.001
0.01-I
0.00014.001
1
0.12
0.0000-0.1
0.0000-0.1
(meika) 0.00001~.001
Rats
tested
Animals
doses
Efficient or doses
Table 1. Continued
5
5
5
5
(xl)
0
+
+
+
+
0
+
+
rears
HLU HLU
LLF
compartments
Asymmetric
Transitions
compartments
Asymmetric
and
Asymmetric compartments +
and
effect
Vogel’s
LLF
7mm
FRX
HLU
and
Weak
Modified
HLU
during
Observations
HLU
HLU
Comments
_
+
+
+
+
0
0
0
0
+
+
+
+
+
0
+
0
+ +
+
+ + +
Effects
test
1989b
1991
1991
Jenck
er nl..
198%
1991
1991
rr al.,
Dunn
cf al..
er 01.. 1990 Higgins
ef al., Dunn
1987
CI al.,
Martm.
Tyers
Higgms
and
1989 1990
1991
P, a..
C, al.. Onaivi
Bill
Costall
1993
er al.,
Dunn Griebel,
er al..
1992 1991 et ni..
rr rrl.. Dunn
Gleeson
Dunn
1990
l9X9a
er a/..
cf ol..
Dunn Haacoi;t
1989a
l988b
1987
Handley.
Przegalinakl. c( ol..
and
1988
c, al..
e, al.,
er a/.
and
Jenck
Papp
Papp.
Costall
Costall
Tyers
Njung’e
1991 Davies, 1991
and
cf ol..
er ~1.. 1991
1989
1989
l99lb
1990
1989
1989a
Dixon,
1990
and
c, al.,
1987
References er al..
Rex CI ol.,
Fletcher
Higgins
Dunn
Cutler,
Cutler
Costall
Tyers
Ondansetron >lOOO~ (selective antagonist)
3700’
>lOOO@ >lOOO~
5000”
13.5,”
Zero-mare Light/dark test
0.01 0.01 0.00~1 0.001~10 0.1 0.00005-0.01
0.00005-0.01 0.00005--0.01 0.00005~0.01 0.0001~1 0.0000001 iI 00001 0.0001 0.5-5
0.00005~1
Wistar rats (I 5&2OOg) Mice
Mice Mice BKW rmce Mice BKW mice (25-30g)
BKW mice
BKW m,ce (25-309)
0.04
0.01
0.1-1.5 I.5 0.001-n.0025 0.001~1 0.01&0.1 0.01&l 0.1 0.01~1 0.0075~.015 0.01xJ.1 0.054. I 0.00014). I
O.Ol-a.1 0.0005-I .6 0.01&O.I 0.0005~5 0.05ll.3 0.0001~.01 0.00001xl.015
0.0005~5
Long~Evans Rats (240-2608) Female rats (160-18Og) SpragueeDawley rats Wistar rats (21 days) DAP mice
Rats Wistar rats (IgO-220g) Rats Wistar rats Conflict test White Carneau pigeons Cynomolgus monkeys Elevated-plus maze Rats Wistar rats (15l&2OOg) Lister rats (2OOG27Og) Wistar rats Rats Wistar rats (20&25Og) Wlstar CFY rats (250-3OOg) Lister rats (200&27Og)
Lister rats (200-2508) conflict test Rats Vogel’s conflict test Rats Lister rats Lister rats (200&25og) Wistar rats (30&35Og) L1ster rats (210~28og) Wistar rats
Geller-Seifter
i.p. 45
1.p.
i.p.
i.p.
30
1.p. 30 S.C. 30 i.p. 50 p.0. 30
1.p. 2 weeks (x2) i.p. 60
i.p. 45
i.p. Dorsal raphe or Amygdala Median raphC 1.p. 45
dung
1.p. 30 p.0. 30
Hippocampus i.m. 5 p.0. p.o. 60 30 i.p. 30 S.C. 25 or 45
i.p. 1.p. 30 p.0. i.p. 30 Amygdala 5 Nucleus accumbens septi Accumbens i.p. 30
p.0.
+
+
+
+
+
+
+
+
+
0
0
0
+
+
+
+
+
+
+
0
0
0
0
+
+
+
+
+
0
0
0
0
0
0
0
0
Asymmetric compartments Weak effect Asymmetric compartments and rears Asymmetric compartments
(‘I
E, nl., l988b
Costall
Costall
CI ol.. l989a
CI ol.. 1989b
Young and Johnson. Costall er
Jones 6’1al., 1988
Costall
1988
s, 6
1
Cofrtirrrted
(‘r al.. 1990
Tyers CI al., 1987
Costall
Kshama
Vasar rr nl., 1993 Grewal PI al.. 1993 Morinan. 1989 Mos PI al.. 1989
Prather e, ol., 1993
Wright CI al., 1992a
Cutler. 199la Vogel’s test Stefanski a al.. 1992a Stefanski PI al., l992b Stefanski et al., l993b Gleeson CI nl., 1989 Jones er al., 1987 Johnston and File, 1988 Kshama c, al.. 1990 Wright E! nl., ‘1992a Borsini <‘I [rl.. 1993 Dunn CI ol.. 1990 Dunn CI al.. 1991 Upton and Blackburn. 1991
Asymmetric compartments Asymmetric compartments Asymmetric compartments and rears Asymmetric compartments Asymmetric compartments Asymmetric comoartments
Modified
Modified Modified
Dunn er al., 1990 Jones er nl.. 1987 Jones ef al.. 1988 Piper CI al.. 1988 Vogel’s test Dunn et al., 1991 Vogel’s test Higgins cf al.. 1991 Stefanski er al.. 1993b
Piper a al., 1988
Compounds
5-HT,a
5.HT,s
5-HT,,,
Affinities
IIM)
5-HTz*
(Ki,
5-HTx
S-HT,
test battery
mteraction
reflex
‘dlarreae‘
vocahzation
Ultrasonic
feeding
Novelty-suppressed
startle
Fear-potentiated
Defense
Social
Rats
+
p. 30
o.o1a).1
60
p.o.
Rats
rats (200-25Og)
Lister
rats
Long-Evans
(375415g)
Rat\
Rats
L1ater rats
(I 54-253~)
female
rats (210-28Og)
Lister and
rats(25&300%)
W1star
Rats
Rats
(2OOGZSOg)
rats
Lister
Rats
rats (IX&23Og)
O.l&lO
0.1
0.001~1
0.001
0.01
0.001~).1
O.OOOOOOl~.OOOl
0.05
0.01~1
0.01~1
0.0005a.
I
I
0.0005-0. 0.001-1
I
0.0005~).
0.00005~.01
0.00005~.005
30
45
1.p.
30
1.p. 45
i.p. 45
Amygdala.
i.p.
i.p.
5
0
+
+
0
+
+
+
+
+
+
+
+
+
+
45
p.0.
5
HLU
LLF
HLU
and Higgins
and
MO,
1987
(‘( ril..
rrl
1989
1991
1989
1991
1989
1988
1993
1991
1991
Naylor.
1990
I989a
1988
1988
Green.
CI
l987a
1991
1987
6’1 ol..
Rex 8, rrl..
Glenn
Shepherd
P, al..
Costall Dunn
PI nl.,
er al..
Costall
PIper
PI al..
Jones HLU
PI nl.,
Tyers
er al..
er al..
1990
HLU
HLU
File,
l993b
1992b
1992a
1989
1991~
1991
1993b 1991
Johnston.
and
CI ol..
CI a/..
er al..
Costall
Higgins
a/.. E, al..
Jones
HLU
and
and
rl
Ed al..
HLU
LLF
File. 0
0
p.0.
45
p.0.
5
File
Johnston 0
HLU
Stefanski
+
0
Stefanski
+
p-0. 45
45
i.p.
raphi. p.0.
Dorsal
Amygdala,
0.1&I 0.0001~.001
RalS 28Og)
60
septi
accumbens 60
Nucleus
Plaznik Stefanski
i.p.
noise
+ +
Accumbens 30
Stefanski
0
1990
1993
1992
Przegalinski.
PI nl..
er al..
and
Hippocampus
Borsini
er al..
1992
1992a
Johnson,
Naylor,
er al.,
and
and
e/ al., Fontana
Bill
Barnes
Papp
65 dB
compartments
Asymmetric
compartments
Asymmetric
compartments
Asymmetric
0
p.o.
rats (210
Asymmetric compartments
Young
60
i.p.
0.1-l
0.00-0.0025
0.001~.1
0.1-1.5
0.25-20
Asymmetric compartments
Costall
1989
References PI al..
Kshama
+
30
0. I
Asymmetric compartments
Mos
0
+
30
i.p. 45
0.001
p.0.
+
O.OO~l 0.00-3
+
p. 45 S.C. 30
0.0000-0.1
rats (25Og)
Rats
rats (2ooG25og)
Male
+
p. 30
0.00005~.01
compartments
Comments Asymmetric
+
(min)
EffeCtS
latency
p.o.
rats
Routes administration,
S.C. 30
0.1
(mg/kg)
tested
0.01~1
Wistar
Rats
rats (18&22Og)
rats
Lister
Lister
Llster
g)
(15&2OOg)
(2&22
mice
rats (25G27Og)
rats
mice
Wistar
Lister
Wistar
Wistar
Open-field
CD-I Wistar
C57
(22-300)
mice
(3&35g)
T/O
mice
Female
BKW
ICR-DUB
(I 7-358)
mice
Mice
mice
Animals DAP
Female
Holeboard
Models
doses
Efficient or doses
Table 1. Continued
% -
Q 3.
P
Zacopnde > I0000’ > I 000~ (selectwe antagomst)
Y-25.130 (5-HT, antagomst)
WAY 10028’) (selective antagontst) <5 PK;
> I0000’
< 54
<5
3600’
26Op
0.3?’
8.8”
test
Marmoset Marmoset Callirhri.v /uccl~us (295m335g) Cynomolgus monkeys
Cynomolgus monkeys Marmoset Ca//ithri.v ,jacc/1us (35&4OOg)
Mice CD-I Female DAP mice Cynomolgus monkeys (3.1-5.4 kg)
0.000001~1 0.00001-0.001
Lister rats (295-335g) Marmoset
ddY mice antinoaception
Female T/O mxe (22.3Og) Lister rats (250-285g)
Rats Mice
I- IO 0.01 I 2 0.1~0.3
0.03xX I (I 8-2Og)
0.03-0.3
0.1-10
0.003&l 0.0000003~30
0.003-I 0.0000003~30
0.000001-10
Mice
Rats Mice
0.000000-0.0001 0.000003-3
i.p. 30 i.p. p.o. 60 30 i.p. 30 30
i.p. 30
p.0. 45 s.c 30 S.C. 30
i.p. i.p.
i.p. ,,p.
i.p. 40 S.C. 40
p.0. i.p. 40
I.D. 40 p.b. 30
+ +
p.0.
during I5 davs (xl) _. ’ 1.p. 60 i.p. 30 i.p. 35
O.OIut. I 0.125-I 0.0625XI.5 0.1~10
+
S.C. 45
0
+
0
0
0
+
+
+
+
0
0
0
+
+
+
+
+
0
+
+
i.p.
0.001 0.0001-0.001 0.1-l
+ + + +
0 0 + +
0
0 0 + 0
p.0. p.0. p.o. during 5 hr S.C. 45
i.p. 30 p.0. 3os.c. 30 p.0.
i.p. 45
30 i.p. 30
30
0.01~.1 0.01-0.1 0.1 0.0001~.01
0.01-0.1 0.001~10 0.001 o.o1a).1
0.0001~.1
2.5-5 0.01-l
0.3-3
Lister rats (295-335g) C57 mice
Vogel‘s conflict test Wistar rats (300-350g) Elevated-plus mare Lister rats (250g) Wistar rats (I 50 2OOg) Wistar rats (200&25Og) Light dark tcbt Wlstar rats (I 50 2OOg)
Stress-Induced
Fear-potentiated startle reflex
Light/dark
Vogel‘s conflict test Light/dark test
(S)-RS-56812 (selectwe antagonIst)
<5
maze test
Social interaction Human threat
Elevated-plus Light/dark
Vogel’s conflict test Light/dark test
0.12’”
days)
AP mtce (4-6 days) Female MFI mice (23-358) Swiss mice (25-30%)
I
test Wistar rats (25&27Og) Wistar rats (22&24Og) DPAG-Stimulation Wistar rats (37M50g)
Passive-avoidance
(R)-RS-56812 (selective antagonist)
RS-42359- I97 (S-HT? antagonist)
test
Aggression-provoked Human threat
Four hot-elates Free ob&ation
Stress-induced hyperthermia
Marble burying
Wistar rats (9-I 1989
l99lb
e, al., 1993 <‘I al.. 1993
er al.. 1993 PI al., 1993
Tokuyama
er al.. 1993
Bill CI rrl., 1992
Bill E! rrl., 1992
Fontana Fontana
Fontana Fontana
Costall Pf al.. 1993 Costall P, al.. 1993
Costall Pf al.. 1993
Costall (‘I al.. 1993 Fontana YI al.. 1992
Papp and Przegalinski. 1989 Sanger and Joly, 1989-1990 Jenck CI al.. 1989a
Piper cf al.. 1992
Tyers el nl., 1987 Costall er al.. 1988b Costall er al.. 198%
Jones <‘I al.. 1988 Piper er al.. 1988 Borsini (‘I al.. 1993 Jones rr ul.. 1988
Borsini er al., 1993 Mos CI al., 1989 Tyers et al.. 1987
Lecci el ol.. 1990
Nastiti CI a/.. 1991 Njung’e and Handley.
Mos and Olivier.
Vogel’s test Dunn E, nl.. 1991 File and Johnston. 1989 Kshama CI rrl.. 1990 Dunn <‘I
Modllied
Asymmetric
Asymmetric compartments Asymmetric compartments
Weak effect
Weak effect
Warm condition Cold condition
&f WI
6
”
rz
6 ;: a.
g 4 &.
rr (I/
l9YO: ,‘:‘Wona
(‘I r/i..
IYXY: ‘Lqwn
1993. ‘Takao
<‘r ol
19’) I, “‘Colpacrt
1992. ,‘“K!lpalrlck
(‘I (I/.
(‘I u/
test
maze
= Low
,“‘Millan
I YY2. ~““M~rrenaucr
rats (250
3OOg)
[CR-DUB
doses
(mnikn)
= High
(‘I ul..
(31 ol..
““Mlyauchl
(2, ul..
l9Y3.
(‘I
,.p. 45
1.p.
1.p. 4s
i.p. 45
ElTechvc
and Hartlg. (‘I nl.. ‘“‘Da
VI
Prada
<‘I ol..
Asymmetric
vehicle
<‘I al..
Interval; 1992: “Hoycr
= Variable
compartments
Asymmetru
compartments
Asymmetric
compartments
Asymmetric
compartments
1982.
E, ol.. lY9l; ‘“Maitre. ‘“Brown PI a/
‘“Andcrsson
1989a
l989b
lY92b
Z, ol..
ef al..
1990; and
CI “1.. 1991: “‘Barnes
P, al..
1992: ‘Con”
and Thomas.
1992. “‘Hyttel. 1977; ,“‘Berendsen 1989; .“:Audmot er
1992. “‘Brumvels
1988; “Doble
1989; “Ybema
= Flxed
199la
1991: ‘Peroutka. cc nl.. 1990”: ‘Nelson
and Schoeffter.
199la
1993
FR
l992b
1992
1992a
Interval:
Barnes (‘I al..
Cheng
Barnes L’I al..
1992b
and Johnson. Barnes CI al.,
Young
File and Andrews.
l992b
and Johnson,
PI al..
Barnes er nl..
Young
Barnes
1992b
and Andrew,
CI al.
1989
l9Ylb
I988
1993
1990
et iii , 1991
CI ul..
Barnes er al..
File
Costall
and NelJt.
~‘r II/.. 1992: ,“Hoyer
1985. ‘Ktlpatrlck
Costall Dun”
?I ul.,
1993 and Johnston.
Fl = Fixed
rats (14 days) AsymmetrIc
treated
Chronic
compartments
Asymmetric
compartments
Asymmetric
compartments
days)
vehxle rats (I4
Chronic treated
(21(I/.. 1990: LKllpatrtck
(31 (I/
19910: IYY I. ,‘“Fletcher
‘“Cosl;~ll (,I
+
*Olivicr
gray;
+
+
f
+
0
_
+
0
0
0
+
+
+
File
Kshama
0
Griebel,
1992b
Johnson.
1989b
1992
CI al..
and
e/ al..
and Johnson.
1988a
References PI al..
Bill PI a/..
Barnes
Young
Costall
Young
Costall
0
compartments
Asymmetric
compartments
Asymmetric
compartme”ts
Asymmetric
and rears
compartments
Asymmetric
Comments
+
+
+
+
+ + +
+
Etfccts
6’1 cr/. 198X: “Kenncrl.
IYY3; ‘Yagaloff
. 19Yl:
Dox.
pruaqueductal
198’): “Peroulka
(21 (I/
30 1.p. 60
I p.
1988: ‘VanWlJngaarden
= Lower
1992: ,‘“‘M”Jo~ (11 (I/
1991: ‘llKllpiltrIck
and Hoyer. and van de Kar.
Dorul 1983: ‘Sanders-Bush. 1993: ‘Malgouri, 1992. ,“Schoefftcr
,IRhodcs
=
I
IO
IO
LED
DPAG Unfamiliar. r, II/,
Light 1990. “Gozlan
HLU
Injection,
0.00001-1
0.0001~.
0.000001
0.00001
0.001 ~1
1.p. 45
1.p. 60
0.01&l 0.00001~1
1.p. 4.5
1.p. 45
0.0000 I~-0 01
0.000001~
1-p. 30
S.C. 45
0.001~1
i.p. 30
i p. 45
0 3-l
IO
30
1.p. 60
30
p.0.
S.C. 30
p. 45
p. 30
p. 45
0.0001-n.00l
0.001~10
0.01~1
2
0.001 a.01
1
17x
0.001~1
0.01~0
0.0001
0.001~.05
1.p.
45
p.0.
i.p
(min)
0.0001-17.8
L1ater Td,> (250~3oog) 1.t = mtrathecal
Routes latency
administration.
0.001-100
0.0001~10
001
mice (30.35g)
BKW
Efficient or doses tested
Mice
mice (3&35g)
BKW
mice (I 7-35g)
Female
L1stcr rats (25Og)
Lister
DUB
mice (I 7-358)
ICR
nuce (3&35g)
BKW Femitle
nuce (3Om35g)
rats (25Og)
(35woog)
BKW
Lister
/rw/!lr
Cullithr~ \
rats (2%3OOg)
(225-275g) Marmoset
W1star
rats
rats (25Og)
Sprague-Dawley
Lister
rats (I 5CrZOOg)
Swiss mice (IO weeks)
I YY2: ,“‘Lcvy IYYI:
(‘I ul..
TiO
(3&35g)
mice (22. 308)
1993: ,,“‘Dc Vry vi lr/
‘Moreau
(a( ol..
(2, u/
IYYI.
lY87.
mxe
Female
BKW
mice (I 7v35g)
ICR-DUB
m,ce (2&m30g)
Mwz
mice (30-358)
Ammals
Female
BKW
BKW
Wistar
and Pcroutka.
Familiar:
v, II/..
Light
inJectmn:
SOCl,ll Inler‘icllo”
Light’dark
IYXY: PThom.ir
IYYOb,
test
maze
mteraction
dark
Elevated-plus
Social
Light
Elevated-plus
threat
interaction
Human
Social
Holeboard
Models
IYX2. ‘Schmidt
LLF
IYY?. ‘Hoyer.
PI (I/
ri I//..
19X6: ‘,Schhcker
2.29”
0.33””
5.HT?
= lntracercbroucntricular
Schedule.
I c.1
5-HTx
1992: ~‘“Bolano, v( 111 1990. “‘Blackburn
vi u/,
IIM)
Rcmforcement
19X8. ~Nclson ri II/..
IY86; “Kldd
(KI.
S-HTx
= ‘\“xloge”esls:
19X5. “Engel r’i (I/..
19’) I. d’c’Barrcc~ and Zhdng.
Broekkamo.
P, (I/..
,“Heuring
-
5.HT,u
Affimties
= Continuous
I”acllvc.
5.HT,H
IYX7. .*-Bill (‘I (I/..
(2, (I/
and SandcwBubh.
IYXY: “‘Hoyer
CRF
and I~lclcr.
\chedulc.
IYX6: ‘Lyon
Ratm
0 =
dntagonrsr)
- = d”\lOl),I~.
(selecrlvc
5-HT,a
anraponw)
( + )Zacopridc
(selecwe
( ~ )Zacopride
Compounds
Table I. Continued g
5-HT-interacting of the central 5-HT system in the regulation particular experimental procedures.
2. ANIMAL
MODELS
OF ANXIETY
361
drugs
of anxiety-
or fear-related
DISORDERS:
ATTEMPTS
responses
is only evident
in
AT CLASSIFICATION
A survey of current animal models of anxiety reveals a bewildering diversity of procedures (for reviews, see Treit, 1985; Lister, 1990; Sanger, 1991). There are more than 30 animal behavior paradigms that claim to model anxiety (Fig. 1). Most of them involved exposure of animals to external (e.g. cues previously paired with footshock) or internal (e.g. drug states) stimuli that are assumed to be capable of inducing anxiety in humans. The first category can be grouped into two subclasses: the first includes ethologically based paradigms and involves animals’ spontaneous or natural reactions to stress stimuli that do not explicitly involve pain or discomfort (e.g. exposure to a novel test chamber); the second involves animals’ conditioned responses to stressful and often painful events (e.g. exposure to electric footshock). Some authors have attempted to classify anxiety models more precisely into three, four or more categories. For instance, Treit (1985) further divided the models based on conditioned reactions into two subgroups; models based on traditional learning paradigms (e.g. Geller-Seifter conflict test) and those involving phylogenetically prepared forms of aversive learning (e.g. conditioned taste aversion, conditioned defensive burying). More recently, Handley (1991) proposed a classification based on the nature of the aversive stimulus and on the response elicited, suggesting that the neuronal control of anxiety may differ according to whether the interpretation of a signal as aversive is innate or learned (Gray, 1982) and whether it causes the emission of a response or conversely inhibits an ongoing, rewarded behavior. Hence, Handley distinguished three main types of animal models of aversive behavior, namely, passive avoidance tests, active avoidance tests and conflict tests. For the sake of convenience, anxiety models in the present review are placed into one of the following two categories: (a) tests based on unconditioned responses and (b) models based on conditioned reactions (Fig. 1). The first category can be further divided into four subgroups: (al) models based on exploratory behavior in rodents (e.g. elevated plus-maze; light/dark test); (a2) models based on rodent and monkey social behavior (e.g. social interaction test; human threat in monkeys); (a3) situations based on somatic stress reactions (e.g. stress-induced hyperthermia). and in the last group, we can find some miscellaneous models that do not fit easily into the other subgroups, such as the marble burying test or the anxiety/fear test battery. In the second category, the traditional conflict paradigms (e.g. Geller-Seifter and Vogel conflict tests) are distinguished from a number of other models involving conditioned responses, including the fear-potentiated startle reflex or the conditioned emotional response (CER) test.
3. BEHAVIORAL EFFECTS OF DRUGS MODULATING 5-HYDROXYTRYPTAMINE NEUROTRANSMISSION IN ANIMAL MODELS OF ANXIETY 3.1. Behavioral Actions of Central Application of 5-Hydroxytryptamine and Peripheral Administration of 5-Hydroxytryptamine Indirect Ligands 3.1.1. 5-Hydro.yytryptumine As shown by Fig. 2a, a direct application of 5-HT in brain structures has been found to produce an anxiogenic-like profile in several studies. These results seem consistent with the observation that intraventricularly administered 5-HT is accumulated (with a half-life of about 445 hr) in several brain regions, including the periaqueductal gray area of the midbrain, the septum and the amygdala (Aghajanian and Bloom, 1967) regions frequently associated with punished and aversive behavior (Adams, 1979; Olds and Olds, 1962). Furthermore, they fit well with the 5-HT hypothesis of anxiety, as the increased availability of 5-HT in the brain may have potentiated emotional reactivity in the animals. However, as also illustrated by Fig. 2a, a similar treatment often reduces anxious responses. This inconsistency from one study to another probably is due to a number of factors. For example,
BASED ON ExPLmAlmN
-Elevated plus-maze -Free-exploration lest -H&board - Light/dark lest -Open-field -Staircase test - Zer*ma.ze
MoMLs
Mooas
I
RESPOHSES
-
of the existing
Corticosteron~ response Defecalion/micturation Nociceptio” Thermic response
Fig. 1. Classification
-Social competition - Social interaction test - Ultrasonic Distress vocalization
_Human threat
I
BASED ON UNCONDITIONED RESPONSES
MODELS BASEDON Soc!AL
1
animal
models
-
of anxiety
AnxielyiFear test baltery - cork gnawing - Marble burying
disorders
- Vogel
tests
_ Geller-Seiftet - Pigeons and monkeys wnflid
CONFLICT TEST8
-Active/passive avoidance test - Caditioned emotional response - Condtiioned tale aversion - DPAG-stimulation - Fear-pot&i&d starlle reflex - Hot plate -Shock-probe buying teat
MwxLLAPlsoUS
5-HT-interacting
369
drugs
it is obvious that the target site into which the injection was performed explains, at least in part, this variability. Several authors who found an anxiolytic-like action of 5-HT (Thiebot et ul., 1982. 1984; Higgins ef al., 1991) injected the neurotransmitter directly into the dorsal raphe. Yet, it is clearly established that this area contains a great density of 5-HT,,, receptors, which are localized on the cell bodies. The activation of these binding sites provides an inhibitory control on ascending serotonergic activity. Therefore, the anti-anxiety effect of such injections probably involves reduced 5-HT function. This variability could also be attributed to the use of different experimental paradigms. As is made clear by Fig. 3a, the anxiolytic-like actions of 5-HT have been found more often in conditioned procedures (64%) than in models based on spontaneous responses (20%). Thus, ethologically based tests may provide results more consistent with the classic S-HT hypothesis of anxiety.
5-HT
5-HT
REUPTAKE
0
8or
-
+
PCPA
INHIBITORS
146 y
60 7
8 6
40 kit
a
d)
-
o
+
f)
o
.‘I.‘._. :. I:::. ;. :. kl -
Cl RU
BUSPIRONE
8-OH-DPAl
3
20
+
24969
80
80
r
21 y 5 2 a
60
40
60
I 23
40
5 k.? B
6
6 .. .. . 20 /I 0
.“. .’ ..:
mCPP
Fig. 2. Illustration neurotransmission
23
5
a h)
‘. :.
‘I
-.
20 & o
0
RITANSERIN
+
ONDANSETRON
of the outcomes of the most studied compounds modulating 5-HT after a single acute dose in animal models of anxiety disorders. -. anxiogenic; +. anxiolytic; 0. inactive.
G. Griebel
370 3.1.2. 5Hydro.uytryptamine
Reuptake
Inizibitors
1SRls)
Several lines of evidence indicate that extracellular 5-HT concentration is increased by SRIs (e.g. Auerbach et al., 1989; Rutter and Auerbach, 1993). Various functional measures also indicate that serotonergic function is increased acutely after SRIs are given (Fuller et al., 1991). Consequently, we can expect that the administration of these compounds may modulate fear-related behaviors in animal models of anxiety. Single acute doses of these agents have been investigated largely in animal models of anxiety. More than 70 experiments have been carried out with SRls. Incontestably, the most studied agent in this group is imipramine. The initial work of Cook and Davidson (1973) suggested that imipramine was inactive in the Geller-Seifter conflict procedure. However, more recently, authors using either unconditioned models or learning paradigms demonstrated a modification of the animals’ emotional reactivity after a single acute dose of imipramine. Anxiogenic-like effects have been recorded in the Geller-Seifter (Sanger. 1992) and Vogel’s (McCown rt al.. 1983; Fontana and Commissaris, 1988) conflict tests. but also in the CER (Sanger, 1990). However, contradictory evidence has also been reported. Indeed, imipramine was found to be anxiolytic by a number of groups (Meert and Colpaert, 1986a; Craft et al., 1988 in the shock-probe burying test in rats; Young and Johnson, 1991~ in the light/dark test in mice). Variable effects have also been reported for other SRIs (e.g. amitriptyline, citalopram, fluoxetine). Nearly 38% of the studies failed to detect effects of these compounds. while the same percentage revealed an increase in the anxious responses of the animals (Fig. 2b). Finally, 26% of the investigations found some evidence for an anxiolytic-like action of SRIs. The suggestion that the behavioral effects of these compounds, which are all potential antidepressant drugs, cannot be detected in anxiety models, should be tempered by a number of clinical studies showing a potentiation in anxious symptoms early in the treatment, especially in patients suffering from panic attacks (Gorman et al., 1987; van Praag. 1988; Westenberg and den Boer, 1988; Humble et al., 1989; Giesecke, 1990; Westenberg, 1992). Analysis of the different experimental procedures used provides evidence that some models are more sensitive than others to the behavioral action of SRIs. As summarized in Fig. 3b. tests based on spontaneous responses more often revealed a modification in the behavioral responses of baselines (70%) than did conditioned paradigms (48%). In addition, results from ethologically based models seem more consistent with the ‘classic’ hypothesis of 5-HT function in anxiety, as 45% of the experiments revealed an anxiogenic-like profile of SRIs. whereas only 20% of the investigations using conditioned paradigms showed such an activity. It must be emphasized, however, that several models from the first group revealed anxiolytic-like effects of SRIs. Such an action is notably observed with the marble burying test (Njung’e and Handley, 1991 b) and the ultrasonic distress vocalization model (Mos and Olivier. 1989; Winslow and Insel. 1991 b). Nevertheless, the results from these models must be considered with caution. For example, it is striking that the marble burying test was unable to reveal any anxiogenic-like action of compounds known to possess such an effect, such as yohimbine or P-CCE (Njung’e and Handley. 199 I a). Furthermore, the ultrasonic distress vocalization test could not detect the anxiolytic effect of mcprobamate (Benton and Nastiti. 1988) and revealed an ‘anxiolytic’ profile of morphine (Carden and Hoffer. 1990).
3.1.3. p-Chloropl~en~~lc~lar~irlr (PCPA) Koe and Weissman (1966) and Jequier et al. (1967) were the first to show that the administration of PCPA depletes in a specific manner the synthesis of 5-HT by inhibiting the release of tryptophan-hydroxylase, which is involved in the formation of 5-HTP. More recently, Chaput et al. (1990) reported that 350 mg!‘kg of PCPA (during 2 days, with a daily injection) reduced the dorsal hippocampal 5-HT concentration by about 95%. The evidence that pretreatment (during 3 days, with a daily injection in most cases) with PCPA may modulate animals’ emotional reactivity first arose from the study of Tenen (1967). who demonstrated the efficacy of this 5-HT depletor in counteracting the disruption of drinking induced by stress. Since this initial experiment. more than 30 studies have investigated the behavioral effect of PCPA in anxiety models (Fig. 2~). Seventy per cent of these studies revealed an anxiolytic-like action of PCPA, whereas only 9% showed the opposite effect. Although some learning paradigms
5-HT-interacting
371
drugs
100
80
E 2
4
11
60
d 4
2
80
Y 8
Iu
3
:::,I .:::c ::::. ‘.‘I’.’
-
0
+
4:
C a c
60
z nu f?
40 18 20
d)
6 :.:.:.:.:. 0
-
0
+
Fig. 3. Illustration of the outcomes of the most studied compounds modulating 5-HT neurotransmission after a single acute dose in animal models of anxiety disorders subdivided into unconditioned procedures and conditioned tests.
periaqueductal gray (DPAG) stimulation) showed PCPA potentiation of anxiety, more than 60% of the experiments using such procedures provided evidence for an anti-anxiety action of this compound (Fig. 3~). It appears, therefore, that most anxiety models can reveal an anxiolytic-like profile of PCPA. Such an effect is consistent with the classic hypothesis of 5-HT in anxiety.
(e.g. dorsal
3.2. Behavioral Effects of Direct-acting
5-Hydroxytryptamine
Ligands
The focus on the involvement of 5-HT in modulating anxiety disorders coincided with the identification of various 5-HT binding sites in the brain (Hamon et al.. 1990). Molecular biological data concerning 5-HT receptor subtypes are increasing exponentially. At the present time, the 5-HT receptor family can be split into seven groups: 5-HT,-like, 5-HT,-like, 5-HTj, 5-HT4, 5-HTs, 5-HT6 and 5-HT,. Within the 5-HT, family, five subtypes have been described, i.e. 5-HTIA, 5-HTle, 5-HTlo, 5-HTIE and 5-HTIF. The 5-HT2 group can be further divided into 5-HT2A, 5-HTle and 5-HTrr (Hoyer et al., 1994). Of these, at least the 5-HTIA, 5-HTle, 5-HT?A zc and 5-HT3 receptors have been implicated in anxiety.
G. Griebel
312
5-HTIA receptors are located both presynaptically (somatodendritic autoreceptors) on the 5-HT cell bodies in the raphe nuclei of the brainstem, which innervate the forebrain. and postsynaptically, in particular in limbic structures, such as the hippocampus and the amygdala. Activation of presynaptic S-HT,, receptors results in an inhibition of cell firing and. hence, a decrease in 5-HT neurotransmission. while the activation of postsynaptic S-HT ,,, receptors leads to a neuronal inhibition in some limbic structures (e.g. hippocampus. septum). Both of these actions provide a rationale for studying 5-HT14 receptor ligands in animal models of anxiety. The amount of data that has been accumulated on the effects of 5-HT14 receptor ligands in the various anxiety procedures is vast. The most widely studied agents in this group are the pyrimidiny;p:?erazine partial agonist buspirone and the aminotetralin full agonist &OH-DPAT. Within the past I2 years, the behavioral effects of buspirone have been investigated in about 200 experiments, while more than 100 studies have involved 8-OH-DPAT. Anxiolytic-like properties of buspirone and 8-OH-DPAT have been shown in 71 and 61% of the experiments, respectively (Fig. Zd,e). Reports of an opposite effect have also been found. while several studies could not reveal any modification of baseline levels after the administration of buspirone or 8-OH-DPAT. Numerous previous and recent reviews have discussed extensively the variability in the effects of 5-HT,, ligands, in particular, those observed with the two drugs mentioned above (e.g. de Vry ct al., 1991: Handley. 1991; Treit, 1991: Oakley and Tyers, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a.b.c). Some authors (Treit. 1991; Oakley and Tyers, 1992) have suggested that pharmacological variables. such as the route of administration or the doses used. may account for some of this variation. For example. Treit (1991) suggested that the outcome of an administration of 5-HT14 receptor agonists into the central nervou’: system is more reliable than peripheral application. However. detailed examination of the literature indicates that neither route of administration or drug dose can satisfactorily explain these inconsistencies. For instance, both anxiolytic- and anxiogenic-like properties of X-OH-DPAT have been revealed in a large dose-range (0.001&S mg/kg). To explain this variability. most authors have focused on the procedures used and/or the experimental conditions. A common opinion is that traditional conflict paradigms are less sensitive to the action of 5-HT,, agonists than unconditioned models. However, as is made clear by Fig. 3d,e, both types are equal in revealing anxiolytic-like effects of these compounds. A more reliable explanation involves the experimental and/or the environmental conditions used by each laboratory. For instance. the evidence for both anxiolytic and anxiogenic effects of 5-HT, 4 ligands in the elevated plus-maze is extensive. Handley and McBlane (1993b) recently investigated the possibility of obtaining either effect at will in one laboratory by altering the conditions of the experiments. They showed that increasing illumination from 170 to 785 lux reversed the effect of 8-OH-DPAT from anxiogenic to anxiolytic. Moreover. they demonstrated that these differences cannot be accounted for by any simple differences in strain. maze construction protocol or control baseline. Furthermore, a series of experiments in conflict-type procedures (Costello ct trl.. 19913: Sanger. 1990, 1992; Wojnicki and Barrett. 1993) has shown that there are conditions under which it is possible to obtain increases in suppressed responding of rats or pigeons with buspirone. For example, Sanger (1990) demonstrated that when responding was suppressed in the presence of a stimulus correlated with r.p.spotz.rC-ir7~/~~p~~~~~/~~t~t .r/7ock. buspirone produced a similar behavioral pattern to that seen with benzodiazepines. In contrast, when responding was suppressed by ~c.s~)orl.~c~-c~cp~~~~(~~~ni ,sl7ock. buspirone did not produce an increase in punished responding of rats. It is obvious from these studies that the behavioral effects of 5-HT,,, ligands easily can switch from ‘anxiolytic’ to ‘inactive’ or even ‘anxiogenic’ when small alterations are made in the procedure used. However. further studies with other 5-HT14 ligands are needed in order to establish the generality of the effects of such procedural variations on the behavior change associated with this class of compounds.
3.2.2. 5-H,.~lro.\-?~tr~~~I,tNlllit~~~,~ Rmeptor 5-HTIH sites arc both presynaptic exist as heteroceptors on cholinergic
Agmists
terminal autoreceptors and postsynaptic receptors. They also neurons (Hoyer and Middlemiss, 1989: Middlemiss and Hutson,
SHT-interacting
drugs
373
1990; Palacios et al., 1992). Contrary to recent theories based on species variations in pharmacological measurements (Heuring et al., 1987; Hoyer and Middlemiss, 1989), molecular biological data have demonstrated that 5-HT,, receptors exist in numerous species, including humans (Jin et al., 1992). Owing to the lack of selective ligands, the evidence for the involvement of 5-HT,, sites in anxiety states is limited. A recent preliminary study using mutant mice showed, however, that this receptor plays a determinant role in the modulation of emotional responses (Hen et al., 1993). These authors generated, by homologous recombination, mutant mice lacking the gene encoding 5-HT,, receptor and showed that this binding site is totally absent in the homozygous mutant mice. They further demonstrated a lack of anxiogenic-like responses to RU 24969 (a mixed S-HTIA/5-HTIB agonist) in mice that do not possess the 5-HTIe receptor subtype. Experiments with RU 24969 using normal mice or rats have shown anxiogenic- as well as anxiolytic-like effects; and, in some studies, the drug was found to be inactive (Fig. 2f). A more detailed analysis of the data indicates that in ethologically based procedures, RU 24969 produced an anxiogenic effect in 60% of the experiments, whereas it was inactive or even showed an anxiolytic-like profile in 10 and 30% of the studies, respectively. In contrast, authors using conditioned paradigms reported an anxiolytic-like action of the compound in 60% of the investigations, or could not reveal any effect in 40% of the experiments. In the first category, studies using the ultrasonic distress vocalization paradigm (Gardner, 1985~; Mos and Olivier. 1989) and the marble burying test (Njung’e and Handley, 199la) revealed an opposite effect (anxiolytic) of RU 24969 compared with the other tests of this group (elevated plus-maze and social interaction test). Thus, results of both tests should be approached with caution. Data obtained with RU 24969 in traditional conflict procedures are also inconsistent: it was found anxiolytic in the Vogel’s conflict test in rat (Korneyev and Seredenin, 1993) and in pigeons (Gleeson et al., 1989) and inactive in the Geller-Seifter paradigm in rats (Deacon and Gardner, 1986) and in monkeys (Gleeson and Barrett, 1990). This variability might be due, at least in part, to the use of various types of schedules in conflict procedures or to species differences (particularly in the ‘5-HTle-like’ receptors). 3.2.3. 5-HydroxytryptaminezA
and 5-H>!dro.yytryptamine2(
Receptors
5-HTzA (previous name: 5-HT,) receptors are located postsynaptically in many areas of the cortex, the claustrum, some components of the limbic system and parts of the basal ganglia (Hoyer et al., 1986). 5-HTz, (previous name: 5-HTIc) sites are found predominantly in the choroid plexus, as well as the limbic and basal ganglia areas (Pazos et al.. 1984). In general, compounds claimed to be 5-HTzA receptor selective show similar affinity for 5-HT2(. receptors (Hoyer, 1988, Hoyer et al., 1989), which is not surprising, given the very close structural similarity of these two receptors (Hartig. 1989; Julius et al., 1988). For that reason, the study into their specific roles in anxiety states is limited. 3.2.3.1. 5-Hydro,~?~tr~pta~~~ine2.1,rc. receptor agonists. The most studied drugs of this group are TFMPP and mCPP, two mixed 5-HTzA.,, receptor agonists. The latter has been assessed in more than 30 studies using anxiety models. Most of them described anxiogenic-like effects of mCPP (Fig. 2g). These results are in accordance with clinical data that demonstrated that mCPP had anxiogenic effects in healthy subjects and potentiated anxious reactions in agoraphobic, obsessive-compulsive disorder and panic disorder patients (e.g. Klein et al., 1991; Germine et al., 1992; Pigott et al., 1993). As shown in Fig. 3g, unconditioned paradigms seem particularly sensitive to the anxiogenic effects of mCPP, as 75% of the studies observed a potentiation in the anxious responses in animals. Again, the marble burying test (Njung’e and Handley, 1991 b) and the ultrasonic distress vocalization test (Winslow and Insel, 1991a) revealed an opposite effect. The result of the latter study is surprising, as the same authors found an anxiogenic-like action of TFMPP, a compound pharmacologically closed to mCPP. Only eight studies have investigated the effect of mCPP in conditioned procedures (compared with 24 in unconditioned models). Some of these found an anxiogenic-like effect (Kilts et al., 1982 in the Vogel’s conflict test; Mansbach and Geyer, 1988 in the fear-potentiated startle reflex test; Martin, 1993 in the shuttle box), while others reported an anxiolytic-like profile (Davis et al., 1986 in the fear-potentiated startle reflex test; Jenck ef al., 1989a in the DPAG-stimulation paradigm; Meert, 1989 in the shock-probe burying test) or no effect at all (Davis et al., 1986 in the fear-potentiated startle reflex test; Rocha et al., 1993a in the conditioned taste aversion). Differences in procedures
314
G. Griebel
or methodology might explain some of these discrepancies in the results obtained with these latter tests. Thus, studies using the rat fear-potentiated startle reflex paradigm, in which mCPP was variously found to be anxiolytic, inactive or anxiogenic, used four different administration routes: subcutaneous (anxiogenesis), intrathecal (inactive), intraperitoneal (anxiolysis) and intracerebroventricular (anxiolysis). Results obtained with unconditioned procedures are closer to the clinical results, and this must be taken into account in future investigations of such agents. 3.2.3.2. 5-H~dro.ul’tr?.ptanline~,~.~~ receptor antagonists. As with ligands for other 5-HT receptors, studies with 5-HTZA.2c receptor antagonists have produced equivocal results. Figure 2h shows results obtained with ritanserin, the most studied compound in this category. To date, 50 experiments have investigated the behavioral effects of ritanserin in animal models of anxiety. The drug has been found to produce anxiolytic-like effects in more than 40% of the studies, while 12% of them reported evidence for increasing anxiety. Finally, 44% of the reports indicated a lack of activity of the drug in these tests. There is no evidence for a greater sensitivity for one or the other category of models (Fig. 3h). Thus, ritanserin has been reported to have disinhibitory effects, anxiogenic-like effects and/or even no effect in the traditional conflict procedures (Geller-Seifter and Vogel), as well as in exploration tests, such as the elevated plus-maze, the light/dark test or the open-field. It must be emphasized. however, that in one of the models (pigeon conflict paradigm), ritanserin produced reliable and reproducible anti-conflict activity, although the magnitude of the effects is less than those observed in this particular model with benzodiazepines (Gleeson et al., 1989; Brocco et al., 1990). A similar behavioral profile is seen with other mixed 5-HT2,&..?(receptor antagonists, such as ketanserin, cinanserin, ICI 169369, mianserin or the more recently synthesized compound LY 53857. Clinical studies with ritanserin also reported a variety of effects. Thus, it was found to be effective in generalized anxiety disorders (Ceulemans et al., 1985; Arriaga et ul., 1986; da Roza Davis et al., 1992) agoraphobia (Humble et al., 1986) and aversive classical conditioning in healthy volunteers (Hensman et al.. 1991) but these effects have not been confirmed systematically (Ceulemans, 1985) and do not appear to extend to panic disorder. Indeed, panic may even be exacerbated by ritanserin (Den Boer and Westenberg, 1990). The reasons for this apparent difference in anxiety-modulating action of ritanserin and related compounds remain to be determined. Perhaps the evaluation of the behavioral effects of more selective ligands for either the 5-HT,* or the 5-HT:(. site now available (e.g. SR 46349B for the 5-HTZA subtype) could shed light on the differential involvement of these receptors in the modulation of emotional responses. 3.2.4. 5-H?,dro.~~tr~pturniI~~~ Receptor
Antagonists
The identification and characterization of 5-HTI binding sites in brain tissue, in particular in limbic areas such as the amygdala (Kilpatrick et ul., 1987; Barnes et al., 1988; Peroutka and Hamik, 1988) and the synthesis of highly selective ligands for these receptors, have been the starting point of numerous studies that investigated the behavioral action of 5-HT, receptor antagonists in animal models of anxiety. A number of 5-HTj receptor antagonists has been examined for potential anxiolytic-like activity in animals: anpirtoline, DAU 6215, GR 68755, granisetron (BRL 43694) MDL 72222, ondansetron (CR 38032F), RS-42359-197, tropisetron (ICS 205-930) WAY 100289, Y-25,130 and zacopride. Among these compounds, ondansetron has been the most studied. More than 75 experiments have investigated the modulatory action of ondansetron on anxiety-related responses in animals. As shown in Fig. 2i, 66% of the results provided evidence for an anxiolytic-like action of this compound, while 33% of them did not observe any modification in the animals’ responses. Only one study reported an anxiogenic action of ondansetron (Gleeson et al., 1989). This is surprising in view of the outcomes of the other drugs mentioned in Sections 3.1.1-3.2.3, which all reported clear evidence for both anxiolytic- and anxiogenic-like effects. More precisely, authors using ethologically based tests reported an anxiolytic-like effect in 72% of the cases (Fig. 3i). Interestingly, most of these studies revealed a positive effect over a wide dose range, with minimum dose levels in the nanojpicogram range. Furthermore, ondansetron mimics the anxiolytic activity seen with benzodiazepines. However, they differ from the latter as they lack the sedative and muscle relaxant effects of benzodiazepines and fail to antagonise electric shock and leptazol-induced convulsions (Costa11 et al.,
5-HT-interacting
drugs
375
1988e). In addition, unlike benzodiazepines, ondansetron and 5-HT, receptor antagonists, in general, have been found to enhance performance in tests of cognition (Costa11 et al., 1992b). As shown in Fig. 3i, however, in some studies using these same models (28%), ondansetron has failed to show anxiolytic-like effects. Obviously, some methodological problems with procedures involving spontaneous behavior influence the data obtained. For example, negative results have been observed in the light/dark choice paradigm when rats were the experimental subjects (Morinan, 1989; Kshama et al., 1990). Furthermore, ondansetron was found to be inactive in a few studies using the elevated-plus maze. As mentioned in the Introduction, these differences evidently are produced by a multitude of, perhaps small, methodological differences that do not necessarily become clear, even with the most detailed scrutiny of published reports. In addressing the problem raised by the plus-maze data, Handley and McBlane (1993b) recently questioned whether such differences could involve genetic variability in rats or even investigation, as minor stressors often affect positively motivated behavior. When the reliance has been placed on conditioned procedures, the potential anti-anxiety actions of 5-HT1 receptor antagonists have been observed in only a few studies. For instance, ondansetron was found to be anxiolytic in 44% of the investigations using conditioned procedures, whereas it was ineffective in 50% of such studies (Fig. 3i). Costa11 and Naylor (1991) recently have suggested that the models failing to show anxiolytic-like effects of 5-HT, receptor antagonists may be insensitive to novel pharmacological mechanisms involved in anxiety. Alternatively, Barrett and Vanover (1993) speculated that the specific conditions of the models revealing an anxiolytic-like action of these agents may be sensitive to a behavioral effect other than an anxiolytic effect. No matter what approach is used, only positive effects in clinical trials can help to decide which of the animal models are the best predictors of these effects. Even less is known, from a clinical point of view, about possible anxiolytic effects of 5-HT3 receptor antagonists. Whilst a number of open and placebo-controlled studies have either been carried out or are under way since 1986 (Schweizer and Rickels, 1991), only one has been published so far. Lecrubier et al. (1993) recently reported that tropisetron is efficacious in the treatment of generalized anxiety disorder. However, no data from any other of these studies have been made available yet, apparently because 5-HT3 receptor antagonists do not show significant treatment differences between drugs and placebo. In conclusion, in the case of 5-HT, receptor antagonists, both types of animal models appear to have little problem finding an anxiolytic-like effect. Yet, this does not show up in the clinical tests. Insofar as this is true, it indicates that we can get good agreement (in the published literature at least) regarding a particular effect in animal models, yet not predict good clinical efficacy. This suggests (a very practical outcome) that more favorable attention be given to the publication of nonsignificant effects, and, second (of more scientific interest) that we continue and, in fact, enhance our efforts to understand why animal models sometimes predict and why they sometimes do not.
4. PERSPECTIVES
AND
SUMMARY
It is obvious from the data discussed above and summarized in the table that 5-HT-related drugs have equivocal anxiety-modulating properties in animal models. The reasons for this variability in drug effect remain in great part unknown, but certainly include some factors (such as species differences or sex of the animals), which have been widely assessed in many recent reviews (e.g. Barrett and Gleeson, 1991; Briley et al., 1991; Costa11 and Naylor, 1991; de Vry et al., 1991; Handley, 1991; Treit, 1991; Oakley and Tyers, 1992; Wettstein, 1992; Barrett and Vanover, 1993; Handley and McBlane, 1993a,b,c; Hughes, 1993; Schreiber and de Vry, 1993). Much of the current interest in this field is focussed on differential responsivity of various animal paradigms after 5-HT drug challenge. As reviewed in the present paper, agents triggering the release or increasing the availability of 5-HT, such as the neurotransmitter itself, 5-HT reuptake inhibitors, RU 24969 or mCPP usually promoted anxiety responses in ethologically based procedures, whereas they were inactive or even decreased emotional reactivity in traditional learning paradigms. Clearly, the results obtained in unconditioned models seem more consistent with the classic 5-HT hypothesis of anxiety, which assumes that 5-HT activity enhances anxiety. Hence, these results question the validity ofconditioned paradigms, in particular conflict tests, in the investigation of the behavioral effects of drugs known
376
G. Griebel
to possess anxiogenic properties, including compounds stimulating 5-HT neurotransmission. As mentioned by Treit (1985), one of the problems with conflict tests is that significant anticonflict effects have been produced by drugs that either produce or potentiate anxious responses in humans. such as amphetamine (Lehman and Ban, 1971; McMillan, 1973; Miczek, 1973; McKearney and Barrett, 1975). LSD (Commissaris and Rech. 1982), caffeine (Beer rt ul., 1972). isoproterenol (Pate1 and Malick. 1980) or the &adrenoceptor antagonists idazoxan and yohimbine (Sanger. 1991). Obviously, the data from these latter studies. as well as some that reported anxiolytic-like action of drugs stimulating the 5-HT system. confirm Treit’s assumption (Treit. 1985) that conflict tests are not totally selective, and strongly suggest that these paradigms are ‘only’ animal models of ‘anxiolytic’ drugs. This is problematic when considering the behavioral studies of newly synthesized drugs, as we do not necessarily expect one or the other effect of these compounds. Thus, to detect false-positive effects in conflict procedures, authors should complete their studies by adding results obtained in models able to reveal both anxiolytic- and anxiogenic-like properties of drugs. This is less likely to happen, however, when it is required that conditioning task researchers should adopt ethological tasks, or vice versa. In contrast, data showing anxiolytic-like effects with compounds interacting seiectively with .5-HTIA receptors. or even with drugs blocking 5-HT2,< 2(.binding sites, did not provide evidence that one particular category of models is involved in one particular effect. As with benzodiazepine receptor agonists, both conditioned and unconditioned tests revealed, in the majority of cases. an anxiolytic-like action of 5-HT,, full or partial agonists. even if these effects were more variable and smaller in magnitude when compared with standard anxiolytics. As it has been assessed in previous reviews (see references above), these phenomena are not discussed in the present paper. Furthermore, Treit’s assertion that only the light/dark choice paradigm. the social interaction test and the fear-potentiated startle model show “good sensitivity to both benzodiazepine and 5-HT,, agonists” is unacceptable, as both 8-OH-DPAT and buspironc were found to have anxiolytic, anxiogenic or null effects in all three models (see Table I). At this time. only the conflict procedure in pigeons revealed invariably an anxiolytic-like action of 5-HT14 compounds, and this effect is comparable to that obtained with benzodiazepines (Barrett and Vanover, 1993). However, these results must be confirmed by laboratories other than that of Barrett’s group. which investigated in great part the effects of these drugs in the pigeon’s conflict test. Anxiolytic-like effects of 5-HT? receptor antagonists have also been established only in selected test procedures. Consideration of the distinction between ethologically based tests. and ‘conventional’ testing procedures indicates that these effects only occur in the first mentioned models. In these, only the lightidark choice paradigm in mice constantly showed an anxiolytic-like action of these agents. Variation in the effects of 5-HT drugs in animal models of anxiety could reflect differences in the degree to which the models themselves represent fear or anxiety (Treit. I991). It is obvious that all models are not equivalent. Thus. models based on reactions to non-painful strcssors or on spontaneous responses, in particular exploration procedures or the social interaction test, may reflect a type of anxiety linked with uncontrollable stress (‘depressive anxiety’), as animals are exposed by force to a novel and/or aversive environment from which they cannot escape. while those based on conditioning and/or reactions to painful stressors, especially the Geller-Seifter and Vogel’s conflict tests, may reflect a type of anxiety associated with controllable aversive events (‘anticipatory anxiety’) (Gardner. 1986; Soubrii and Thikbot. 1986). Thus, 5-HT modulation at 5-HT, target sites might be selectively involved in situations dealing with the so-called ‘depressive anxiety’, whereas 5-HT,,, and perhaps S-HT:% Jc receptors. may be involved in both types of anxiety-related responses. This view is akin to Gardner’s, Handley’s and McBlane’s assumption of the existence of multiple 5-HT mechanisms in anxiety (Gardner, 1986; Handley. 1991; Handley and McBlane, 199 1). To shed light on the complex story concerning the involvement of 5-HT neurotransmission in the regulation of emotional reactivity, clinical investigations more and more hold the key. Several 5-HT-interacting compounds are now in various phases of clinical development, in particular, drugs acting selectively at 5-HT,,% sites (e.g. S20499, MDL 73005EF, WY-50.324). Information from clinical trials should permit future experimental research in this area to focus more precisely on the behavioral paradigms that are particularly sensitive to the effects of 5-HT drugs and on the 5-HT receptor subtypes that are specifically involved in the modulation of fear-related behaviors.
5-HT-interacting
drugs
311
AIknoM,/ed~enlents-The author thanks Prof. R. J. Blanchard (Bekesy Laboratory of Neurobiology and Department of Psychology, University of Hawaii, U.S.A.), Prof. D. C. Blanchard (Btkesy Laboratory of Neurobiology. University of Hawaii, U.S.A.), Prof. R. Misslin (Laboratoire de Psychophysiologie, Universite Louis Pasteur, Strasbourg, France) and Dr H. K. Taukulis (Department of Psychology, University of New Brunswick, Canada) for their kind reviewing of this manuscript.
REFERENCES Adams. D. B. (1979) Brain mechanisms for offense, defense and submission. Behav. Brain Sci. 2: 2Oll241. Aghajanian, G. K. and Bloom, F. E. (1967) Localization of tritiated serotonin in rat brain by electron-microscopic autoradiography. J. Pharn?ac. e.up. Ther. 156: 23-30. Ahlenius, S., Larsson, K. and Wijkstriim, A. (1991) Behavioral and biochemical effects of the 5-HTlh receptor agonists flesinoxan and S-OH-DPAT in the rat. Eur. J. Pharmac. 200: 259-266. Ahlers, S. T.. Weissman. B. A. and Barrett, J. E. (1992) Antagonism studies with BMY-7378 and NAN-190: effects on &hydroxy-2-(di-n-propylamino)tetralin-induced increases in punished responding of pigeons. J. Pharmnc~. e_yp. Ther 260: 474-48 I. Akai. T., Takahashi, M., Nakada, Y., Ohnishi, R., Ikoma, Y. and Yamaguchi, M. (1991) Anxiolytic effects of lisuride and its action to central 5-HT,, receptors. Foliu pharmac. ,jap. 90: 209-220. Allen, L. E., Fergusson, H. C. and Cox, R. H. (1974) Pharmacologic effects of MJ 9022-1, a potential tranquilizing agent. Arxeimittel-Forsch. 24: 917-922. Almeida, S. S.. de Oliveira, L. M. and Graeff, F. G. (1991) Early life protein malnutrition changes exploration of the elevated plus-maze and reactivity to anxiolytics. Ps>~chopharmacology 103: 513-518. Amano, M., Goto. A., Sakai, A., Achiba, M., Takahashi. N., Hara. C. and Ogawa, N. (1993) Comparison of the anticonflict effect of buspirone and its major metabolite I-(2-pyrimidyl)-piperazine (1-PP) in rats. Jop. J. Phnrmnc. 61: 311-317. Amrick, C. L. and Bennett. D. A. (1986) A comparison of the anticonflict activity of serotonin agonists and antagonists in rats. Sot. Neurosci. Abstr. 12: 907. Andersson, G.. Christensson. E., Eriksson, E., Fex, T.. Klint, T., Lundstedt, T., Pettersson, G. and Svartengren, J. (1992) Neuropharmacology of FG5893. a new psychotropic drug with high affinity for both the S-HTIA and the S-HT, serotonin receptor. In: 211d ktetvationul Symposium on Serotonin, from Cell Biology ro Pllcrrr?lcrc,olog~, ~rd Thercrpeutics, p. 16, Houston. 15-l 8th September. Andree, T. H., Moyer. J. A., Stack, G.. Muth, E. A. and Haskins, J. T. (1988) Preclinical nemopharmacological profile of WY-48.723. a potent serotonin (S-HT,,,) agonist. Sot. Neurosci. Abstr. 14: 555. Andrews. N. and File, S. E. (1993) Increased 5-HT release mediates the anxiogenic response during benzodiazepine withdrawal: a review of supporting neurochemical and behavioural evidence. P.s~~c~hopl2rrrniL~~~)log~. 112: 2 1-25. Aprison. M. H. and Ferster. C. B. (1961) Neurochemical correlates of behavior - II. Correlation of brain monoamine oxidase activity with behavioural changes after iproniazid and 5hydroxytryptophan administration. J. Ncurochem. 6: 350-357. Arriaga. F., Leitao. J.. Padua. J., Ruiz, I., Tropa, J., Sousa, M. P., Mills, F. J. and Gelders, Y. (1986) Ritanserin, an original sleep quality improving agent in generalized anxiety disorders. In: C.I.N.P. Congress, Puerto Rico, p. 174. December 14-l 7. Audi. E. A., de Aguiar, J. C. and Graeff. F. G. (1988) Mediation by serotonin of the antiaversive effect of zimelidine and propranolol injected into the dorsal midbrain central grey. J. Psychopharmac. 2: 26-32. Audi. E. A.. de Oliveira. R. M. W. and Graeff, F. G. (1991) Microinjection of propranolol into the dorsal periaqueductal gray causes an anxiolytic effect in the elevated plus-maze antagonized by ritanserin. P.,~~(~llophrrrr,2frc.ol~)g~~ 105: 5533557. Audinot. V.. Canton, H., Jacques. L., Verriele, L. and Millan, M. J. (1993) Receptorial profiles of atypical antipsychotics at cloned human dopamine Dz and D, receptors and at rat D? and 5-HTlc ?receptors in ritro:e.y riro. SW. Neuro.cci. Ahstr. 19: 1 169. Auerbach. S. B., Minsenberg, M. J. and Wilkinson, L. 0. (1989) Extracellular serotonin and 5-hydroxyindoleacetic acid in hypothalamus of the unanesthetized rat measured by in piz%odialysis coupled to high-performance liquid chromatography with electrochemical detection: dialysate serotonin reflects neuronal release. Brain Res. 499: 28 lL290. Baduel, A.. Lemoal, M. and Stinus, L. (1986) Comparison of the effects of buspirone, diazepam, haloperidol and sulpiride on a conflict schedule in rats. Neurosci. Lett. 26 (Suppl.): S278. Barnes, N. M.. Costall, B., Ironside. J. W. and Naylor. R. J. (1988) Identification of 5-HT, recognition sites in human brain tissue using [‘Hlzacopride. J. Pharm. Phurmuc. 40: 668. Barnes, N. M.. Costall. B.. Domeney, A. M., Gerrard, P. A.. Kelly, M. E., Krlhling. H., Naylor, R. J., Tomkins, D. M. and Williams. T. J. (1991) The effects of umespirone as a potential anxiolytic and antipsychotic agent. Phcrrmnc~. Biodlem. Behur 40: 89-96. Barnes, N. M.. Cheng. C. H. K., Costall. B., Ge. J.. Kelly, M. E. and Naylor, R. J. (1992a) Profiles of interaction of R( +):S( -)-zacopride and anxiolytic agents in a mouse model, Eur. J. Pharmnc. 218: 91-100.
378
G. Griebel
Barnes, N. M., Costall, B., Ge, J., Kelly, M. E. and Naylor, R. J. (1992b) The interaction of R( +)- and S( -)-zacopride with PCPA to modify rodent aversive behaviour. Eur. J. Pharmac. 218: 15-25. Barrett, J. E. (1992) Studies on the effects of 5-HT,,A drugs in the pigeon. Drug Dw. Res. 26: 299-317. Barrett, J. E. and Gleeson, S. (1991) Anxiolytic effects of 5-HT,, agonists, 5-HT, antagonists and benzodiazepines: conflict and drug discrimination studies. In: 5-HTI1 Agonists, 5-HTI Antagonists and Benzodiazepines, Their Comparative Beharioural Phrrr~?l~:c,olog~~.pp. 59 105, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley and Sons, Chichester. Barrett, J. E. and Vanover, K. E. (1993) 5-HT receptors as target for the development of novel anxiolytic drugs: models, mechanisms and future directions. Ps.vchr/ppllarnluco/og~, 112: I ~ 12. Barrett, J. E. and Zhang, L. (1991) Anticonflict and discriminative stimulus effects of the S-HTIA compounds WY-47,846 and WY-48,723 and the mixed 5-HT,,, agonist/S-HT1 antagonist WY-50,324 in pigeons. Drug Dec. Res. 24: 179-188. Barrett, J. E., Witkin, J. M. and Mansbach, R. S. (1984) Behavioral and pharmacological analysis of the effects of buspirone. FASEB J. 43: 931. Barrett, J. E., Witkin, J. M., Mansbach, J. M., Skolnick, P. and Weissman, B. A. (1986) Behavioral studies with anxiolytic drugs. III. Antipunishment actions of buspirone in the pigeon do not involve benzodiazepine receptor mechanisms. J. Pharmac. exp. Ther. 238: 1009-1013. Barrett, J. E., Gleeson, S., Nader. M. A. and Hoffmann, S. M. (1989) Anticonflict effects of the 5-HTIA compound flesinoxan. J. Psychopharmac. 3: 64-69. Baudrie, V., de Vry, J., Broqua, P., Schmidt, B., Chaouloff. F. and Glaser. T. (1993) Subchronic treatment with anxiolytic doses of the 5-HT,, receptor agonist ipsapirone does not affect 5-HTz receptor sensitivity in the rat. Eur. J. Pharmac. 231: 395-406. Beckett, S. R. G., Lawrence, A. J., Marsden, C. A. and Marshall. P. W. (1992) Attenuation ofchemically induced defense response of 5-HT, receptor agonists administered into the periaqueductal gray. P.svchophurmacolog~ 108: 110-l 14. Beer, B., Chasin, M., Clody, D. E., Vogel, J. R. and Horovitz. Z. P. (1972) Cyclic adenosine monophosphate phosphodiesterase in brain: effect on anxiety. Science 176: 42X-430. Benjamin, D., Lal, H. and Meyerson. L. R. (1990) The effects of 5-HT,, characterizing agents in the elevated plus-maze. Li/k Sci. 47: 195-203. Benjamin, D., Saiff, E. I., Nevins, T. and Lal, H. (1992) Mianserin-induced 5-HT1 receptor downregulation results in anxiolytic effects in the elevated plus-maze test. Drug Der. Rex. 26: 287-297. Benton, D. and Nastiti, K. (1988) The influence of psychotropic drugs on the ultrasonic calling of mouse pups. Psychopharmacology
95: 99-l 02.
Berendsen, H. H. G. and Broekkamp, C. L. E. (1990) Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. Br. J. Pharmac. 101: 667-673. Bickerdike, M. J., Fletcher, A. and Marsden, C. A. (1993) CCK-induced anxiety in rats on the elevated X-maze can be antagonised by (+)WAY100135, a 5HT,, receptor antagonist. Sot. Neurosci. Ahstr. 19: 173. Bill, D. J., Fletcher, A. and Knight, M. (1989) Actions of 5-HT,, ligands and standard anxiolytics on mouse exploratory behaviour in a two-compartment light: dark arena. Br. J. Pharmac. 98 (Suppl.): 679P. Bill, D. J., Fletcher, A., Glenn, B. D. and Knight. M. (1991) Behavioural effects of WAY 100289, a novel 5-HT3 receptor antagonist, in two animal models of anxiety. In: SEROTONIN 1991, 5-Hydrayytryptamine-CNS Receptors and Brain Function, p. 143. Birmingham, 14-17th July. Bill, D. J., Fletcher, A.. Glenn, B. D. and Knight, M. (1992) Behavioural studies on WAY 100289, a novel 5-HT? receptor antagonist, in two animal models of anxiety. E‘ur. J. Pharmac. 218: 327-334. Blackburn, T. P., Baxter. G. S., Kennett, G. A., King. F. D.. Piper. D. C., Sanger, G. J.. Thomas. D. R., Upton, N. and Wood, M. D. (1993) BRL 46470A: a highly potent, selective and long acting 5-HT? receptor antagonist with anxiolytic-like properties. Pslchopharf?luccllog~ 110: 257-264. Blakely. T. A. and Parker, L. F. (1973) The effects of parachlorophenylalanine on experimentally induced conflict behavior. Pharmuc. Biochem. Behar. 1: 609-613. Blanchard, D. C., Hori, K., Rodgers, R. J.. Hendrie. C. A. and Blanchard, R. J. (1989) Differential effects of benzodiazepines and 5-HT,A agonists on defensive patterns in wild rattus. In: Behaz,ioura/ Pharmacology of 5-HT, pp. 145-147, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Blanchard, D. C., Shepherd, J. K., Rodgers, R. J. and Blanchard. R. J. (1992) Evidence for differential effects of 8-OH-DPAT on male and female rats in the Anxiety;Defense Test Battery. P.s~~ckopharmacolog~ 106: 53 l-539.
Blanchard, R. J., Shepherd, J. K., Rodgers, R. J., Magee. L. and Blanchard. D. C. (1993) Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine. P,~~~cl~opharmac,o/og~~ 110: 245-253. Boaventura, A. M., Blaquiere, B., Palou, A. M. and Oberlander, C. (1986) Possible involvement of 5-HT,& sites in the anxiolytic response to diazepam. Neurosci. Let?. 26 (Suppl.): S278. Bodnoff, S. R., Suranyi-Cadotte, B., Aitken. D. H., Quirion, R. and Meaney. M. J. (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Ps,c,/zopllronltrco/(~g~. 95: 298-302. Bodnoff, S. R., Suranyi-Cadotte, B.. Quirion, R. and Meaney, M. J. (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacolog_v
Bolanos,
97: 277-279.
F. J., Schechter.
L. E., Miquel.
M. C., Emerit.
M. B.. Rutnigny,
J. F.. Hamon.
M. and Gozlan,
H.
5-HT-interacting
drugs
379
(1990) Common pharmacological and physicochemical properties of 5-HT, binding sites in the rat cerebral cortex and NG 108-15 clonal cells. Biochem. Pharmac. 40: 1541-1550. Borsini, F., Brambilla, A., Cesana, R. and Donetti, A. (1993) The effects of DAU 6215, a novel 5HT-3 antagonist, in animal models of anxiety. Pharmacol. Res. 27: 151-164. Bouws, G. A. H., Korte, S. M. and Bohus, B. (1991) Plasma catecholamine and corticosterone levels during active and passive coping in the conditioned defensive burying paradigm in rats; effects of ipsapirone. In: SEROTONIN 1991, 5-Hydro.yJtryptamine-CNS Receptors andBrain Function, p. 168, Birmingham, 14-17th July. Brady, L. S. and Barrett, J. E. (1985) Effects of serotonin receptor antagonists on punished responding maintained by stimulussshock termination or food presentation in squirrel monkeys. J. Pharmac. esp. Ther. 234: 106-l 12. Briley, M., Chopin, P. and Moret, C. (1990) Effects of serotonergic lesion on ‘anxious’ behaviour measured in the elevated plus-maze test in the rat. Psychopharmacology 101: 187-189. Briley, M., Chopin, P. and Moret, C. (1991) The role of serotonin in anxiety: behavioural approaches. In: Ne)b Concepts in Anxiety,. pp. 56-73, Briley, M. and File, S. E. (eds) MacMillan Press, London. Brocco, M. J., Koek, W.. Degryse, A.-D. and Colpaert, F. C. (1990) Comparative studies on the anti-punishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller-Seifter and Vogel conflict procedures. Behac. Pharmac. 1: 40334 18. Broekkamp, C. L. and Jenck, F. (1989) The relationship between various animal models of anxiety, fear-related psychiatric symptoms and response to serotonergic drugs. In: Behacioural Pharmacology of‘ 5-HT, pp. 321-335, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Brown, C. M., Kilpatrick, A. T., MacKinnon, A. C., Kenny, B. A., Broudiscou, A., Clague, R. U., Clark, R. D., Weinhardt, K. K. and Spedding, M. (1989) RS-30199. an azepine with affinity for the 5-HT,, site. Br. J. Pharmac. 98 (Suppl.): 681P. Bruinvels, A. T., Landwehrmeyer, B., Waeber, C., Palacios, J. M. and Hoyer, D. (1991) Homogeneous 5-HT,,, recognition sites in the human subtantia nigra identified with a new iodinated radioligand. Eur. J. Pharmac. 202: 89-9 1. Budhram, P., Deacon, R. and Gardner, C. R. (1986) Some putative non-sedating anxiolytics in a conditioned licking conflict. Br. J. Pharmac. 88 (Suppl.): 331P. Cadogan, A. K., Wright, 1. K.. Coombs, I., Marsden, C. A., Kendall, D. A. and Tulloch, I. (1992) Repeated paroxetine administration in the rat produces an anxiolytic profile in the elevated X-maze and decreased “H-ketanserin binding. Neurosci. Lert. 42 (Suppl.): S8. Carden, S. E. and Hoffer, M. A. (1990) Independence of benzodiazepine and opiate action in the suppression of isolation distress in rat pups. Behaz). Neurosci. 104: 160-166. Carli. M. and Samanin, R. (1988) Potential anxiolytic properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin IA receptor agonist. Ps~c,kopharn?acolog?? 94: 84-91. Carli, M., Prontera, C. and Samanin. R. (1989a) Effect of S-HTIA agonists on stress-induced deficit in open field locomotor activity of rats: evidence that this model identifies anxiolytic-like activity. Neuropharmacolog~~ 28: 47 l-476. Carli, M., Prontera, C. and Samanin, R. (1989b) Evidence that central 5-hydroxytryptaminergic neurons are involved in the anxiolytic activity of buspirone. Br. J. Pharmuc. 96: 829-836. Carli, M., Tatarczunska. E., Cervo, L. and Samanin, R. (1993) Stimulation of hippocampal 5-HT,+,-receptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat. Eur. J. Pharmac. 234: 215-221. Carlton, P. L. and Advokat, C. (1973) Attenuated habituation due to parachlorophenylalanine. Pharmacy. Biochem. Behar. 1: 6577663. Carter, R. B. and Smith, H. L. (1992) Loss of ipsapirone efficacy in the rat social interaction paradigm during diazepam withdrawal is attribuable to formation of the metabolite I-(2-pyrimidinyl)-piperazine (1-PP). In: The Role af’Serotonin in Pqchiatric Disorders. p. 44. Castres, 24-26th June. Cassella, J. V. and Davis. M. (1985) Fear-enhanced acoustic startle is not attenuated by acute or chronic imipramine treatment in rats. Ps~chopharmacolg~~ 87: 2788282. Ceulemans, D. L. S. (1985) The antagonism of serotonin receptors in the treatment of anxiety disorders. In: Proceedings of the 5th European Winter Conference on Brain Research, Vars-Les-Claux, France. Ceulemans, D. L. S., Hoppenbrouwers, M.-L. J. A., Gelders, Y. G. and Reyntjens, A. J. M. (1985) The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam. Pharnlcrcop.s~chiatr?. 18: 303-305. Chaput, Y., Lesieur, P. and de Montigny. C. (1990) Effects of short-term serotonin depletion on the efficacy of serotonin neurotransmission: electrophysiological studies in the rat central nervous system. Synapse 6: 328-337. Cheng, C. H. K., Costall, B., Kelly, M. E. and Naylor, R. J. (1992) 5-Hydroxytryptophan as an anxiogenic agent in a mouse model. In: 2nd International S_vmposium on Serotonin, ,from Cell Biologra to Pharmacologic crntl Therapeutics, p. 59, Houston, 15518th September. Chojnacka-Wojcik, E. and Przegalinski. E. (1991) Evidence for the involvement of 5-HT,* receptors in the anticonflict effect of ipsapirone in rats. N~~Ltrop/7arn7acolog~,30: 7033709. Chopin, P. and Briley, M. (1987) Animal models of anxiety: the effect of compounds that modify serotonergic function. TIPS 8: 383-388.
380
G. Griebel
Clarke, A. and File, S. E. (1982) Effects of ACTH. benzodiazepines and 5-HT antagonists on escape from periaqueductal grey stimulation in the rat. f’rog. N[,rtro-P.rr~r.hop/~rrr-nlnc,. hiol. P.s~~chirr/. 6: 27-35. Colpaert, F. C., Meert. T. F., Niemegeers. C. J. E. and Janssen. P. A. J. (1985) Behavioural and 5-HT antagonist effects of ritanserin: a pure and selective antagonist of LSD discrimination in rats. P.s~~c~/70~~~/7~7’~7~7~7~.~7/0~~~ 86: 45-54. Colpaert, F. C., Koek, W., Lehmann, J.. Rivand. J.-M., Lejeune. F., Canton. H.. Bervoets. K., Millan, M. J.. Laubie, M. and Lavielle, G. (1992) S 14506: a novel, potent. high-efficacy 5-HT I4 agonist and potential anxiolytic agent. Drug DEP. Rrs. 26: 21-48. Commissaris. R. L. and Rech, R. H. (1982) Interactions of metergoline with diazepam, quipaLine. and hallucinogenic drugs on a conflict behavior in the rat. P.s~~c~hr~~7/7n~7r7trc~o/og~~ 76: 2X2 285. Conn, P. J. and Sanders-Bush. E. (1986) Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HTz binding site. J. Nrurmci. 6: 3669%3675. Conner, R. L., Stalk, J. M.. Barchas, J. D. and Levine, S. (1970) Parachlorophenylalanine and habituation to repetitive auditory startle stimuli in rats. Phyriol. RCIINI.. 5: I7 I5 I21 9. Cook. L. and Davidson, A. B. (1973) Effects ot behaviorally active drugs in a conflict punishment procedure in rats. In: Tl7~ Benzodia~~~pirws. pp. 379-404. Garattini. S., Mussini, E. and Randall, L. 0. (eds) Raven Press. New York. Cook, L. and Sepinwall. J. (1975a) Psychopharmacological parameters of emotion. In: E771otiom Tlwir Paramrtm~ md Meusuremmt, pp. 379-404, Levi, L. (ed.) Raven Press. New York. Cook. L. and Sepinwall, J. (1975b) Behavloural analysis of the effects and mechanisms of action ol benzodiazepines. In: Mrchanisn7s of’f’A~~tio77sof Bc77loditr_cpir7c~.s.pp. I-28. Costa. E. and Greengard. P. (eds) Raven Press, New York. Costall, B. and Naylor, R. J. (1991) Anxiolytic effects of S-HT; antagonists in animals. In: 5.HT, , Agotri.sr.s, 5-HT, Antagoni.stsand Benzodiazcpines, Tlwir Cornpclrrrtirc Brlrtrr~iourc~l Pl7r7rt~7~7r~oln~~~. pp. I 33 I 5X, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Costall, B., Domeney, A. M., Hendrie. C. A., Kelly. M. E.. Naylor, R. J. and Tyers. M. B. ( IY87a) The anxiolytic activity of GR38032F in the mouse and marmoset. BK .J. P/INI.I~~u~~. 90 (Suppl.): 257P. Costall, B., Domeney. A. M., Kelly, M. E.. Naylor. R. J. and Tyers. M. B. (1987b) The behavioural consequences of treatment with selective 5-HT? receptor antagonists. Br. J. Pl7crrr77rrc.92 (SuppI.): 657P. Costall, B., Domeney, A. M., Gerrard, P. A., Kelly. M. E. and Naylor. R. J. ( 19XXa)Zacopride: anxiolytic profile in rodent and primate models of anxiety. J. Phm. P/7crm7trc~. 40: 302 305. Costall, B.. Domeney, A. M.. Gerrard, P. A.. Kelly. M. E., Naylor. R. J. md Tyers. M. B. (19XXb) Effect> ol the 5-HT receptor antagonists GR38032F. ICS205-930 and BRL43694 in tests for anxiolytic activity. Br. .J. Plxfrffxx. 93 (Suppl.): 195P. Costall. B., Domeney, A. M., Gerrard. P. A. and Naylor, R. J. (19XXc) A primate model for the assessment of anxiolytic drug action. Br. J. Phormac~. 95 (Suppl.): 475P. Costall, B.. Kelly, M. E.. Naylor. R. J. and Onaivi. E. S. (198Xd) Actions of buspirone in a putative model 01 anxiety in the mouse. J. Pharrt7. Pharmrrc. 40: 4944500. Costall. B., Naylor. R. J. and Tyers, M. B. ( 19XXe) Recent advances in the neuropharmacology of5-HT,agonists and antagonists. Rev. ;Veurosci. 2: 41 65. Costall. B., Domeney. A. M., Gerrard. P. A.. Jones. B. J.. Kelly, M. E.. Oakley. N. R. and Tyers. M. B. ( I9X9a) The anxiolytic activities of the S-HT, receptor antagonists GR38032F. ICS 305-930 and BRL 43694. In: Bchriowtrl Phrrrrwucolog~~of 5-HT. pp. 3X3--3X7. Beban. P.. Cools. A. R. and Ai-chcr. T. (eds) Erlbaum. Hillsdale. Costall. B.. Jones, B. 3.. Kelly. M. E.. Naylor. R. J. and Tomkins, D. M. (lOX9b) Exploration of mice in a black and white test box: validation as a model of anxiety. Pi7ur777nc. Biwi7tv7~. Bchw. 32: 777 7X5. Costall. B., Kelly, M. E.. Naylor. R. J.. Onaivi. E. S. and Tyers. M. B. (lYX9c) Neuroanatomical sites of action of 5-HT, receptor agonist and antagonists for alteration of aversive behaviour in the mouse. By. .J. Plrrrrn7ur 96: 325-332. Costall. B., Domeney, A. M., Kelly. M. E.. Martinez. L.. Naylor. R. J. and Farre. A. J. (l99la) Anxiolytic-like activity in the rat. mouse and monkey of E-4413. a new 5-HT IA receptor ligand. In: SEROTOh’/N /WI, 5-H!~dro.x!~tr!~ptan~ine-CNS Receptors m7d Bruit7 Fw7c~ttot7. Birmingham. p. 141. 14-17th July. Costall. B.. Kelly. M. E.. Naylor, R. J. and Tyer\, M. B. (1991 b) The profile of action of GR68755: a novel 5-HT, receptor antagonist in a mouse model of anxiety. In: SERO7‘0,YIS /WI. 5-H., (/1.o\l./lll.l)7l/)77;)7(,-~‘~~.S Rrwptor.s md Brain Function. Birmingham. p. 144. 14 17th July. Costall. B.. Domeney. A. M., Farre. A. J., Kelly. M. E.. Martine/. L. and Naklor. R. J. (199%) Profile ofaction IAreceptor ligand E-4424 to inhibit aversive behavior in the mouse. rat and of a novel 5-hydroxytryptamine marmoset. 1. Phurmnc. c.up. T/w. 262: 90 9X. Costall, B., Domeney, A. M.. Kelly, M. E. and Naylor. R. J. (l992b) Intlucnce of 5-HT on cognitive performance. In: Serotonin. CNS Rewptor.~ n77d Brnir7 F7o7ctio77. pp. 147 104. Bradley. P. B.. Handlcy, S. J., Cooper. S. J., Key, B. J.. Barnes. N. M. and Coote. J. H. (eds) Pergamon Presa. Oxford. Costall, B., Domeney, A. M., Kelly, M. E.. Tomkins, D. M.. Naylor. R. J., Wong, E. H. F., Smith. W. L., Whiting, R. L. and Eglen, R. M. (1993) The effect ofthe 5-HT: receptor antagonist. RS-4235X-197. in animal models of anxiety. Eur. .J. Pharmu. 234: 91-99. Costello, N. L., Carlson. J. N. and Glick. S. D. (199la) Acute ~ldministration of d~axpam and busplrone in
5-HT-interacting
drugs
381
rats trained on conflict schedules having different degrees of predictability. Plinmznc. Biochenz. Behm. 40: 787-794. Costello, N. L.. Carlson, J. N., Glick, S. D. and Bryda, M. ( 199 I b) The effects of acute administration of gepirone in rats trained on conflict schedules having different degrees of predictability. Pharmac. Biochem. Behm. 40: 795-800.
Craft, R. M., Howard, J. L. and Pollard, G. T. (1988) Conditioned defensive burying as a model for identifying anxiolytics. Pharrmc. Biocirem. Behat>. 30: 775-780. Critchley, M. A. E. and Handley. S. L. (1986) Anxiogenic-like effects of three 5-HT agonists. Ps~~~i~ophamlcrcolog~~ 89: S56.
Critchley. M. A. E and Handley, S. L. (1987) Effects in the X-maze model of agents acting at 5-HT, and 5-HT, receptors. P.s~‘c~hopilcrrnzn~ol~)g~93: 502-506. Critchley, M. A. E.. Njung’e, K. and Handley, S. L. (1987) 5-HT ligand effects in the social interaction test of anxiety. Br. J. Phrwnz~~c. 92 (Suppl.): 660P. Critchley, M. A. E.. Njung’e. K. and Handley, S. L. (1988) Prevention of 8-OH-DPAT anxiogenic effect by ipsapirone and by 5-HT, antagonist b-adrenoceptor antagonists. Br. .I. Phrrrtncrc. 94 (Suppl.): 389P. Critchley, M. A. E., Njung’e, K. and Handley. S. L. (1992) Actions and some interactions of 5-HT,, ligands in the elevated X-maze and effects of dorsal raphe lesions. P.s~~~ilopiznmlacolog? 106: 484-490. Crow, T. J. and Deakin. J. F. W. (1981) Affective change and the mechanism of reward and punishment: a neuro-hormonal hypothesis. In: Der~elopments in P.yhiatry, Vol. 5, pp. 536-541, Perris. G., Struwe, G. and Jansson. B. (eds) Amsterdam. Elsevier. Curle. P. F., Guardiola. B.. Renard, P. and Vitte, P.-A. (1991) Anxiolytic-like activity of (+-) S 20244 in the elevated plus maze test in rat. In: SEROTONIN 1991, 5-h~drosytr~~ptarnine-CNS Receptors ad Bruin Fuwtiotl. p. 139, Birmingham. l4-17th July. Cutler. M. G. (1990) Behavioural effects in gerbils of the 5-HT, receptor antagonists, BRL 43694 and ICS 205-930, under circumstances of high and low light intensity. Neuropiznrnlncok,g~, 29: 5 15520. Cutler, M. G. (199la) An ethological study of the effects of buspirone and the 5-HT, receptor antagonist. BRL 43694 (granisetron) on behaviour during social interactions in female and male mice. NeuropilLlnllaco/og~, 30: 2999306. Cutler, M. G. (1991 b) Effects of social environment on the behavioural responses by mice to the 5-HT, receptor antagonist, granisetron (BRL 43694). Br. J. Phnrwm~. 102 (Suppl.): 254P. Cutler, M. G. and Dixon, A. K. (1989) Effects ofthe 5-HT, antagonist. ICS 205-930, on behaviour ofmice during social encounters. Br. J. Pharnmc~. 96 (Suppl.): 12P. Cutler, M. G. and Piper, D. C. (1990) Chronic administration of the 5-HT, receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil. P.s~~izopizrrmzu~o/og~.101: 2446249. Da Prada. M.. Keller. H. H., Burkard, W. P., Schaffner, R., Bonetti. E. P., Launay, J. M. and Haefely, W. (19X2) Some neuropharmacological effects of Ro 1l-2465 - A novel tricyclic antidepressant with potent inhibitory activity on the uptake of 5-HT. In: T~~picularui At.vpicni Allti~~~prc.sJ(1nt.r:Moleculcu Mcdzmi.snzs. pp. 235.-248. Costa, E. and Racagni, G. (eds) Raven Press, New York. Da Roza Davis, J. M.. Sharpley. A. L. and Cowen, P. J. (1992) Slow wave sleep and 5-HT? receptor sensitivity in generalized anxiety disorder: a pilot study with ritanserin. P.s~‘(.i~opiz~lrt)~n~.oio,~~, 108: 387-389. Davis. M. (1988) The potentiated startle response as a measure of conditioned fear and its relevance to the neurobiology of anxiety. In: Atlirmi Models irz P.s~~c~hiatric~ Di.sor&r.s, Vol. I, pp. 61 ~89. Simon, P.. Soubrie. P. and Wiedlocher. D. (eds) Karger, Basel. Davis. M. (1993) Pharmacological analysis of fear-potentiated startle. Brrrr. .I. Med. hiol. Rcs. 26: 735mm260. Davis. M. and Sheard. M. H. (1976) p-Chloroamphetamine (PCA): acute and chronic effects on habituation and sensitization of the acoustic startle response in rats. Eur. J. Phtrvmnc. 35: 261-273. Davis, M.. Redmond. D. E. and Baraban, J. M. (1979) Noradrenergic agonists and antagonists: effects on conditioned fear as measured by the potentiated startle paradigm. P~s~.(.izopii”r”?~~~,~~/~~~~~, 65: I I Ill 18. Davis. M., Astrachan, D. I.. Gendelman, P. M. and Gendelman. D. S. (1980a) 5-Methoxy-N.IY-dimethyltryptamine: spinal cord and brainstem mediation ofexcitatory effects on acoustic startle. P.s~,c,hophcrrr,7rrl~oio,~~, 70: 123-l 30.
Davis. M.. Astrachan. D. I. and Kass, E. (1980b) Excitatory and inhibitory effects of serotonin on sensorimotor reactivity measured with acoustic startle. .%ierzc,r 209: 521-523. Davis. M.. Cassella. J. V., Wrean, W. H. and Kehne, J. H. (1986) Serotonin receptor subtype agonists: differential reactivity measured with acoustic startle. P.s~.c.ilopirclr~l2cr(.. Bull. 22: 837-843. Davis. M., Cassella. J. V. and Kehne. J. H. (1988a) Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone. P.s~~c~i~~/li~~~~~~~t~.~~i~~g~~ 94: 14-20.
Davis. M.. Hitchcock. J. M. and Rosen, J. B. (1988b) Anxiety and the amygdala: pharmacological and anatomical analysis of the fear-potentiated startle paradigm. In: The P.s~~cho/og~~ o/‘Lenrr?iug md Motirwtiou. Vol. 21. pp. 263-305. Bower. G. H. (ed.) Academic Press, New York. Deacon. R. and Gardner. C. R. (1986) Benzodiazepines and 5-HT ligands in a rat conflict test. Br. ,I. Phclrwrrc. 88 (SuppI.): 33OP. De Angelis. L. (1992) The nootropic drugs piracetam and oxiracetam do not reduce anxiety in mice during elevated-X-maze testing. C‘rrrr. Ther. Res. 52: 230-237.
382
G. Griebel
Den Boer, J. A. and Westenberg, H. G. M. (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Ps,rchopharmacolog~ 102: 85594. De Vry, J.. Glaser, T., Schuurman, T.. Schreiber, R. and Traber, J. (1991) S-HTIA receptors in anxiety. In: Near Conceprs in An.uief~~, pp. 94-129, Briley, M. and File, S. E. (eds) MacMillan Press, London. Doble, A., Allam, D., Blanchard, J. C., Boireau, A., Comte, M. T., Farges, G., Ferris, O., Gueremy, C., Laduron, P. M., Malleron, J. L., Perrier, M. L. and Zundel, J. L. (1990) RP 62203, a novel naphtosultam derivative with potent and selective 5-HTz antagonist properties: I. Binding and second messenger studies. Eur. J. Pharmac. 183: 1744. Dunn, R. W., Corbett. R. and Fielding, S. (1989) Effects of 5-HTI,b receptor agonists and NMDA receptor antagonists in the social interaction test and the elevated plus maze. Eur. J. Pharmuc. 169: I-10. Dunn, R. W., Corbett, R., Hubbard, J. W., Tobiasz, P., Nordstrom, L. C., Carlezon, W. A., Cornfield. M. L. and Fielding, S. (1990) The preclinical anxiolytic profiles of the 5-HT, antagonists ondansetron, zacopride and MDL-72222. FASEB J. 4: A812. Dunn, R. W., Carlezon, W. A. and Corbett, R. (1991) Preclinical anxiolytic versus antipsychotic profiles of the 5-HTI antagonists ondansetron, zacopride, 3a-tropanyl-lH-indole-3-carboxylic acid ester, and IcrH. 3a, 5?H-tropan-3-yl-3,5-dichlorobenzoate. Drug Dev. Res. 23: 289-300. Durel, L. A., Krantz, D. S. and Barrett, J. E. (1986) The antianxiety effect of beta-blockers on punished responding. Pharmac. Biochem. Behac. 25: 371-374. Dwyer, K. D. and Roy. E. J. (1993) Juvenile desipramine reduces adult sensitivity to imipramine in two behavioral test. Phurmac. B&hem Behar 45: 20 I-207. Egawa, M., Abe, M., Tabata, R., Saito, K.-I., Tobe, A.. Matsuda, T. and Baba, A. (1993) Pharmacological effects of MKC-242: a novel potential anxiolytic and antidepressant compound with selective 5-HT,, agonistic profile. Sot,. Neurosci. Ahstr. 19: 1243. Eison. A. S., Eison, M. S., Stanley, M. and Ribland. S. A. (1986) Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmnc. Biochem. Behav. 24: 7OlL707. Ellison, G. D. (1977) Animal models of psychopathology. The low-norepinephrine and low-serotonin rat. Am. Pswhol.
32: 1036-1045.
Engel. G.. Gothert, M.. Hoyer, D.. Schhcker. E. and Hillenbrand, K. (1986) Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT,u binding sites. Naun~n-S~,hnlierb~,rg’s Arch. Pharmac. 332: l-7. Engel. J. A., Hjorth, S.. Svensson. K., Carlsson, A. and Liljequist, S. (1984) Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetrahn (X-OH-DPAT). Eur. J. Pharmac. 105: 3655368. Erwin, G. N.. Soroko, F. S. and Cooper, B. R. (1987) Buspirone antagonizes the expression of conditioned taste aversion in rats. Drug Der. Res. 11: 87-95. Fechter, L. D. (1974) Central serotonin involvement in the elaboration of the startle reaction in rats. Phnrmnc. Biochem. Behar. 2: 161&171. Fernindez-Guasti. A. and Hong. E. (1989) Antianxiety effect of various putative 5-HT, receptor agonists on the conditioned defensive burying paradigm. In: Behdourul Phnrmacolog_v qf’5-HT. pp. 3777382, Bevan, P., Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Fernandez-Guasti, A. and Lopez-Rubalcava, C. (1990) Evidence for the involvement of the 5-HT14 receptor in the anxiolytic action of indorenate and ipsapirone. Ps~ehop/zarmac,o/og~’ 101: 354-358. Fernandez-Guasti, A. and Lopez-Rubalcava, C. (1992) Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolytics. In: The Role of Serotonin in Ps>,chiurrk Disorders. p. 49. Castres. 24-26th June. Fernandez-Guasti. A.. Hong, E. and Lopez-Rubalcava, C. (1992a) Speciesdifferences in the mechanism through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic action. P.s~~c~hophcrrnzac~)l~~g~~ 107: 6 l-67.
Fernandez-Guasti, A., Lopez-Rubalcava, C., Perez-Urizar, J. and Castaiieda-Hernindez. G. (1992b) Evidence for a postsynaptic action of the serotonergic anxiolytics: ipsapirone, indorenate and buspirone. Brain Rex. Bull. 28: 497 -501. File, S. E. (1981) Behavioural effects of serotonin depletion. In: Metabolic, Disorders qf the Nerwus SJ’.stem. pp. 429-445, Rose. F. C. (ed.) Pitman. London. File, S. E. (1984a) The validation of animal tests of anxiety-pharmacological implications. PO/. J. Phrrrmnc. Phnrm.
36: 505-5
12.
File, S. E. (1984b) The neurochemistry of anxiety. In: Drugs in Psychiatry,. Norman. T. and Davies, B. (eds) Elsevier, Amsterdam. File, S. E. (1985) Animal models for predicting clinical efficacy
Vol. 2, pp. I3 -30, Burrows, of
anxiolytic:
social
G. D..
behaviour.
Neurop.s!~chobiolog~~ 13: 55-62.
File. S. E. (1990) Preclinical studies of the mechanisms of anxiety and its treatment. In: Neurobio/og>, qf’Puni( Di.sorder, pp. 31 --48, Ballenger, J. C. (ed.) Liss, New York. File, S. E. and Andrews. N. (1991) Low but not high doses of buspirone reduce the anxiogenic effects ofdiazepam withdrawal. P~~,‘,lzc’~/?crrnl~~~~~/(~g~, 105: 578-582. File, S. E. and Andrews. N. (I 993) Enhanced anxiolytic effect of zacopride enantiomers in diazepam-withdrawn rats. Eur. J. Phurmac. 237: 127-l 30.
5-HT-interacting
drugs
383
File, S. E. and Hyde, J. R. G. (1977) The effects of p-chlorophenylalanine and ethanolamine-o-sulphate in an animal test of anxiety. J. Pharm. Pharmac. 29: 7355738. File, S. E. and Johnston, A. L. (1989) Lack of effects of 5-HT, receptor antagonists in the social interaction and elevated plus-maze tests of anxiety in the rat. Psvchopharmacology 99: 24825 1. File. S. E. and Mabbutt, P. S. (1991) Effects of tianeptine in animal models of anxiety and on learning and memory. Drug Det’. Res. 23: 47-56. File, S. E., Hyde, J. R. G. and McLeod, N. K. (1979) 5,7_Dihydroxytryptamine lesions of dorsal and median raphe nuclei and performance in the social interaction test of anxiety and in a home-cage aggression test. J. &j%ct. Dis. 1: 115-122. File, S. E., Johnston, A. L. and Pellow. S. (1987) Effects of compounds acting at CNS 5-hydroxytryptamine systems on anxiety in the rat. Br. J. Pharmac. 90 (Suppl.): 265P. Fletcher, A., Bill, D. J., Bill, S. J., Brammer, N. T., Cliffe, I. A., Forster, E. A., Reily, Y. and Lloyd. G. K. (1991) WAY 100135: a novel and highly selective 5-HT,, receptor antagonist. Sot. Neurosci. Abrtr. 17: 92. Fletcher, A., Bill, D. J., Cliffe, I. A.. Forster, E. A., Hartley, J. and Dourish, C. T. (1992) Behavioral profile of the enantiomers of the selective 5-HT,, antagonist WAY 100135. In: 2nd International Symposium on SEROTONIN, from Cell Biolog,v to Pharmacology and Therapeutics, p. 30, Houston, 1S-1 8th September. Fletcher, P. J. and Davies, M. (1990) Effects of 8-OH-DPAT, buspirone and ICS 205-930 on feeding in a novel environment: comparisons with chlordiazepoxide and FG 7142. Psvchopharmacologv 102: 301-308. Fontana, D. J. and Commissaris, R. L. (1988) Effects of acute and chronic imipramine administration on conflict behavior in the rat: a potential ‘animal model’ for study of panic disorder? Ps.v~hopllarnla~f~/og~, 95: 147-l 50. Fontana, D. J., Carbary, T. J. and Commissaris, R. L. (1989) Effects of acute and chronic anti-panic drug administration on conflict behavior in the rat. Psychopharmacofogv 98: 157- 162. Fontana. D. J., Wong, E. H. F., Kilfoil, T. and Eglen, R. M. (1992) A behavioral analysis of RS-42358-197, a novel 5-HTI receptor antagonist, suggests a selective anxiolytic action. In: 2nd Interna/iona/ Symposium on SEROTONIN,,from Cell Biology to Pharmacology and Therapeutics. p. 59, Houston, 15-18th September. Fontana, D. J., Henderson, C. A., Daniels, S., Nunes, J., Wong, E. H. F., Whiting. R. L. and Eglen. R. M. (1993) Behavioral profile of(R) and (S) RS-56812, novel 5-HT, receptor antagonists with cognition-enhancing properties. Sot. Neurosci. Abstr. 19: 1234. Foreman, M. M., Fuller, R. W., Leander, J. D., Benvenga, M. J., Wong, D. T.. Nelson. D. L.. Calligaro. D. 0.. Swanson, S. P., Lucot, J. B. and Flaugh, M. E. (1993) Preclinical studies on LY228729 - a potent and selective serotonin,, agonist. 1. Pharmac. e.up. Ther. 267: 58-71. Fuller, R. W., Wong, D. T. and Robertson, D. W. (1991) Fluoxetine, a selective inhibitor of serotonin uptake. Med. Res. Rer. 11: 17-34. Gacsalyi, I., Gyertyin, I., Kapolnai, L.. Somogyi, 8. and Gigler, G. (1991) Serotonin antagonistic activity of a novel putative anxiolytic agent EGIS-3886. In: SEROTONIN 1991, 5-H~~dro.u!~trvptamine-CNS Receptors and Brain Function, p. 142, Birmingham, 14-17th July. Galizio, M., Journey, J. W., Royal, S. A. and Welker, J. A. (1990) Variable-interval schedules of timeout from avoidance: effects of anxiolytic and antipsychotic drugs in rats. Pharmac. Biochem. Behar. 37: 2355238. Galizio, M., Hale, K. L., Liborio, M. 0. and Miller, M. (1993) Variable-ratio schedules of timeout from avoidance: effects of anxiolytic drugs. Behat>. Pharmac. 4: 487-494. Gao, B. and Cutler, M. G. (1992a) Effects of sub-chronic treatment with chlordiazepoxide, buspirone and the 5-HT, receptor antagonist, BRL 46470, on the social behaviour of mice. Neuropllrcrrnaccl/og~ 31: 2077213. Gao, B. and Cutler, M. G. (1992b) Effects of acute administration of the 5-HT, receptor antagonist, BRL 46470A, on the behaviour of mice in a two compartment light-dark box and during social interactions in their home cage and an unfamiliar neutral cage. Neuropharmacologv 31: 7433748. Gao, B. and Cutler, M. G. (1992~) Effects of acute and subchronic administration of propranolol on the social behaviour of mice; an ethopharmacological study. Neuropharmacologl~ 31: 749-756. Gao, B. and Cutler, M. G. (1993a) Effects of acute and subchronic administration of ritanserin on the social behaviour of mice. Neuropharmacoiog~~ 32: 2655272. Gao, B. and Cutler, M. G. (1993b) Effects of chlordiazepoxide, buspirone and the 5-HT, receptor antagonist. BRL 46470, on the behaviour of oestrous and dioestrous female mice when encountering male partners, Neuropharmacolog_v 32: 969-975. Gardner, C. R. (1985a) Distress vocalisations in rat pups: a simple screening method for anxiolytic drugs, J. Pharmac. Meth. 14: 181-187. Gardner, C. R. (1985b) Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxide and diazepam. Drug. Der. Res. 5: 1855193. Gardner, C. R. (1985~) Pharmacological studies of the role of serotonin in animal models of anxiety. In: Neuropharnzacolog~ of Serotonin, pp. 281-325. Green, A. R. (ed.) Oxford University Press, Oxford. Gardner, C. R. (1986) Recent developments in SHT-related pharmacology of animal models of anxiety, Pharmac. Biochem. Behar. 24: 147991485. Geller, I. and Blum. K. (1970) The effects of 5-HTP on parachlorophenylalanine (P-CPA) attenuation ofconflict behavior. Eur. J. Pharmac,. 9: 319-324. Geller, I. and Hartmann, R. J. (1982) Effects of buspirone on operant behaviour of laboratory rats and cynomolgus monkeys. J. c/in. Psvchiar. 43: 25-32. Geller, I.. Hartmann, R. J. and Croy, D. J. (1974) Attenuation ofconflict behaviour with cinanserin. a serotonin
384
G. Griebel
antagonist: reversal of the effect with 5hydroxytryptophan and -methyltryptamine. Res. Conumu~. C’/ICW. Par/ml. Pharmacy. 7: 165-l 74. Germine. M.. Goddard, A. W., Woods. S. W.. Charney. D. S. and Heninger. G. R. (1992) Anger and anxiety responses to r)t-chlorophenylpiperazine in generalized anxiety disorder. Biol. Ps)diur. 32: 457~ 461. Geyer, M. A.. Warbritton, J. D., Menkes. D. B., Zook. J. A. and Mandell, A. J. (1975) Opposite effects o! intraventricular serotonin and bufotenin on rat startle responses. Plzarmac~. Biodwm. Be/m. 3: 687.~691. Geyer. M. A., Petersen. L. R. and Rose, G. J. (1980) Effects of serotonergic lesions on investigatory responding by rats in a holeboard. Behcw. Nwral Bid. 30: 16OGl77. Gibson, L., Barnfield, A. and Curzon. G. ( 1991) Erect of chronic diaLepatn on hippocampal dialysate 5-HT and subsequent anxiogenic response to mCPP. In: SEROTONIN IY9l. 5-H1,dro.ul.t~~pfrlrnir7e-C’.Y.S R~wpto~s cd Braitz Furzc~fior~,p. 134, Birmingham. 14--l 7th July. Giesecke. M. E. (1990) Overcoming hypersensitivity to fluoxetine in a patient wtth panic disorder. ,4rtt. /. P.s,dIiar. 147: 532-533. Gleeson. S. and Barrett. J. E. (1990) S-HT,,, agonist effects on punished responding of squirrel monkeys. P/~riwm~. Biod1~w7. Be/w. 37: 335 337. Gleeson. S.. Ahlers. S. T.. Mansbach, R. S.. Faust. J. M. and Barrett, J. E. (IYXY) Behavioral studies with anxiolytic drugs. VI. Effects on punished responding of drugs interacting with serotonin receptor subtypes. J. Plwnmc~. c.~p. T/w. 250: 809 -8 I I. Glenn. B. and Green. S. (1989) Anxiolytic profile of GR 3X032F in the potentiated startle paradigm. Bclttrr,. P/tarntrrc,. I: 9 l&94. Goldberg. M. E., Manian. A. A. and Efron. D. H. (1967) .4 comparative study of certain pharmacological responses following acute and chronic administration of chlordiazepoxide. Life Gi. 6: 48 I 49 I. Goldberg. M. E.. Salama, A. I.. Patel. J. B. and Malick. J. B. (19X3) Novel non-benzodiaLepine anxiolytics. Nt~ltrop/lril~,~lfl~~~~/~J~~~~ 22: 1499 I 504. Gorman. A. L. and Dunn. A. J. (1993) Beta-adrencrgic receptors are involved in stress-related behavioral changes. P/I~I~~ILI~.Bioc~het~~.BcJ/Ju~..45: I 7. Gortnan, J. M., Liebowitz. M. R., Fyer. A. J.. Goetz. D., Campeas. R. B.. Fyer. M. R.. Davies. S. 0. and Klein, D. F. (1987) An open trial of fluoxetine in the treatment of panic attacks. .l. c,/ir~. P.,~,c,ho~~hcrr-r~~~~(,. 7: 329-333. Gower. A. J. and Tricklebank, M. D. (19X8) Alpha?-adrenoceptor antagonist activity may account for the efccccts of buspirone in an anticonflict test in rat. Gdr. J. Phrrrtnc~c~. 155: I29 137. Go7lan. H.. El Mestikawy. S.. Pichat. A., Glowinski, J. and Hatnon. M. (1983) Identification of presynaptic serotonin autoreceptors using a new ligand [‘HI-PAT. Ncrttrrc, 305: l40& 142. Graeff. F. G. (1974) Tryptatninergic antagonists and punished behavior. J. Pl7trrnuc~. CY/J. T/w. 189: 344- 350. Grael’C F. G. (1988) Anitnal models ofaversion. In: ~I/til~t(~/;\4orl~~/.sof P.\:l,c/~iu/ric,Disorr/c~r.c.Vol. I. pp. I I5 I4 I. Simon. P.. Soubrik. P. and Wiedlocher. D. (eds) Karger, Base]. GraelT. F. G. and Schoenfeld, R. I. (1970) Tryptatninergic mechanisms in punished and nonpunished behaviour. J. Phrtwc. o.Y/~. Thu. 173: 777 2X3. Grae& F. G.. Brandzo, M. L.. Audi. E. A. and Schlitz. M. T. B. (1986) Modulation ofthe brain aversive system by GABAergic and serotonergic mechanisms. Bclrur. Bruin Rev. 21: 65-72. Graeff. F. G., Audi. E. A., Almeida. S. S.. Graeff, E. 0. and HunLiker, H. L. (1990) Behavioral effects of 5-HT receptor ligatnds in the aversive brain stimulation, elevated plus-maze and learned helplessness tests. ,Vc,uro.,c,i. Biohch~. Rcr 14: SOlm~506. Graeff. F. G.. Russo. A. S., Guitnliraes. F. S. and Audi. E. A. (IY91) Effect of anxiolytics tnicroinjecled tnto the periaqueductal grey in (he elevated plus-mare. In: SEROTONIN 199 I. 5-lf~~~/ro.\-~,tr~~/~/~/~~~~~~~~-~’,~’~~ Rcwptor,\ md Barrio Fur~c~tim, p. I 17. Birmingham. I4 17th July. Gray, J. A. ( 1982) Prkcis of T/w ,V~,~rr-op.r!,c~/~r~/~~~~~, 0/‘.417\-icr.r: an enquiry into the functions ofseplo-hippocampal system. Bch. Bruh Sd. 5: 469- 534. Grewal. S. S.. Shepherd. J. K.. Fletcher. A., Bill. D. and Dourish. C. T. (1993) Effect of serotonergic agents in the Lero-maLe lesl of anxiety. In: Brifid~ ~-l.s.\oc~itrrio~tfor P.\:1~c~/to/~/trr,.~~7~/(~~~/~~~~~~. A 19. Cambridge. 15m2Xth July. Griebel. G. (1993) Systt;me s&otoninergiquc ct r&acti\iti &iotionnclle chez le rat et che7 la sour,>. Approche phartn~tcologiquc. Ph.D. thesis. UniversitP Louis Pasteur. Strasbourg. France. Griebel. G., Saffroy-Spittler. M., Missltn, R.. Vofcl. E. and Martin, J. R. (1990) Serenics fluprazine (DU 77716) and eltopra/ine (DU 28853) enhance neophobtc and ernolional behnviour in mice. P.,~~c~/lo/~/~trr,)~t/~~~~/~~~.~~ 102: 498-502. Griebel. Cr.. Missltn. R.. Pawlowjski. M. and Vogel. E. ( IYYI) /It-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice. NcuroReport 2: 617 62Y. Griebel. G., Misslin. R., Pawlowski. M.. Guardlola-Lemaitrc. B.. Guillaumc~. G. and Bizot-Espiard. J. (1992) Anxiolytic-like efTects of a selective 5-HT,, agonist, S20244. and its enantiomers in mice. ,VeuroRcport 3: 84_~Xh. Griebel. G.. Moreau. J.-L.. Jenck. F.. Martin. J. R. and Misslin. R. (1903) Some critical dctcrminants of the behaviour of rats in the elevated plu\-maze. Bdw. Proc~c,.s.\,29: 37 4X. Griebel. G., Moreau. J.-L.. Jenck, F.. Martin, R. and Misslin. J. R. (1994) Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate etnottonal responses in anxiety models in rodents. Ps,.c,hoplltrrnzr/~,~~/(~,~~, 1 13: 463 -470.
5-HT-interacting
drugs
385
G&, M., Alary, C., Del Rio-Lacheze, C.. Junien, J. and Buino, L. (1993) Comparative involvement of 5-HT,, 5-HT2 and 5-HT, receptors in stress-induced colonic motor alterations in rats. Eur. J. Piwrn~crc. 233: 193-199. Guy, A. P. and Gardner, C. R. (1985) Pharmacological characterization of a modified social interaction model of anxiety in the rat. N~uvop.s?,~hohiolog~, 13: 194-200. Hagan, R. M.. Oakley. N. R., Burrldge, J.. Kilpatrick, G. J. and Tyers. M. B. (1991) Effects of the 5-HT1 receptor antagonist. GR68755. in models of anxiety and raised mesolimbic dopaminergic activity in the rat. In: SEROTOiVIN 1991. 5-H~~~o.\-?,tr?~tnn?Dw-CNS Rrwptors md Bra& Function. p. 145. Birmingham. 14-l 7th July. Hamon, M., Lanfumey, L., El Mestikawy. S.. Boni. C.. Miquel, M.-M., Bolanos, F.. Schechter. L. and Gozlan. H. (1990) The main features of central 5-HT, receptors. Ps?,ci2opharnzaco/~/g~~ 103: 349~-360. Handley, S. L. (1991) Serotonin in animal models of anxiety: the importance of stimulus and response. In: Serotonirz, S/wp and Merttul Disor&r.s. pp. 89--l 15, Idzikowski, C. and Cowen, P. J. (eds) Wrightson Biomedical Publishing, Petersfield. Handley, S. L. and McBlane. J. W. (1991) 5-HT ~ the disengaging transmitter’?J. P.s~~c~hop/~rrt.r~~~(.. 5: 322 326. Handley, S. L. and McBlane. J. W. (1992) Opposite effects of Auoxetine in two animal models of anxiety. Br. J. Phrmm. 107 (Suppl.): 446P. Handley, S. L. and McBlane, J. W. (1993a) 5HT drugs in animal models of anxiety. Ps~~~~l~o~/7~11.1~1~1~~010,~~~ 112: 13 -20. Handley, S. L. and McBlane, J. W. (1993b) An assessment of the elevated X-maze for studying anxiety and anxiety-modulating drugs. J. Phnrnmc. Touir. Met/z. 29: 129-138. Handley. S. L. and McBlane. J. W. (1993~) Serotonin mechanisms in animal models of anxiety. Brrr:. J. Mu/. Bid. Rex. 26: l-13. Hird, E. and Engel, J. (1988) EfTects of 8-OH-DPAT on ultrasonic vocalization and audiogenic immobility reaction in pre-weaning rats. Nrlrrop/lnrr,lncolg.~ 27: 981-986. Hfird, E.. Engel. J. and Musi. B. (1982) The ontogeny of defensive reactions in the rat: influence of the monoamine transmission systems. Scatztl. J. P.syho/. 1 (Suppl.): 90-96. Hartig, P. (1989) Molecular biology of 5-HT receptors. TIPS 10: 64-69. Hartmann. R. J. and Geller, I. (198 1) Effects of buspirone on conflict behaviour of laboratory rats and monkeys. Ptw. b’e.ct Phurrnac. Sot. 24: 179- 18 1. Hascott. M.. Bourin. M. and Bradwejn, J. (1992) The anti-conflict effect of drugs acting on serotonin system. J. Ps,~c~ltopita~n~(~r,.6: 129. Haskins, J. T.. Moyer. J. A., Andree, T. H.. Muth, E. A. and Abou-Gharbia, M. (1989) Preclinical profile of the pyrimidinylpiperazinyl imide compound WY-47,846: a potential anxiolytic. Drug Dec.. Rc,.s. 18: Z-45. Heaton. J. C. P., Njung’e. K. and Handley. S L. (1988) Behavioural profile of I-(2.5-dimethoxy-4-iodophenyl)2-aminopropane (DOI) a selective 5-HT, agonist. Br. J. Phcvtnw. 91 (Suppl.): 388P. Hen. R.. Boschert, U.. Lemeur. M., Dierich. A.. Ait Amora. D., Buhot, M. C., Segu L., Misslin, R. and Saudou. F. (1993) 5-HT,,, receptor ‘knock out’: pharmacological and behavioral consequences. SOC,.Ncuro.rci. Ahtr.. 19: 632. Hensman. R.. Guimaraes, F. S., Wang, M. and Deakin. J. F. W. (I 991) Effects of ritanserin on aversive classical conditioning in humans. P.s~.L./~o~/Iu~~~IL~~~~~/~~~~~. 104: 220-224. Heuring. R. E., Schlegel. R. J. and Peroutka. S. J. (1987) Species variations in RU 24969 interactions with non-5-HT,, binding sites. Eur. J. Pi~arrmc. 122: X%282. Heym. J.. Mena. E. E. and Seymour, P. A. (1987) SM-3997: a non-benzodiazepine anxiolytic with potent and selective effects on neurotransmission. Sot. Ncrtro.sc,i. Ahstr-. 13: 455. Hibert. M. and Moser. P. (1990) MDL 77837 and MDL 73005EF: novel, potent and selective 5-HT,, receptor ligands with different pharmacological properties. Drugs Fur. 15: 159- 170. Higgins. G. A., Jones. N. R. and Oakley, N. R. (1987) Compounds selective for the j-HT,* receptors have anxiolytic effects when injected into the dorsal raphe nucleus of the rat. Br. J. Pi7nrn~u~. 90 (Suppl.): 65XP. Higgins. G. A.. Bradbury. A. J., Jones. B. J. and Oakley, N. R. (1988) Behavioural and biochemical consequences following activation of 5-HT,-like and GABA receptors in the dorsal raphi nucleus of the rat. Nrrr~o~/~i?r/r-r,lr[,~~~~~,~,~. 27: 993-l 00 1. Higgins. G. A., Jones. B. J., Oakley. N. R. and Tyers. M. B. (1991) Evidence that the amygdala is incoILed in the disinhibitory effects of 5-HT; receptor antagonists. P.s~~c~izopilc~r-r~lcrc~olog~~ 104: 545-55 1. Higgins. G. A.. Jones. B. J. and Oakley. N. R. (1992) Effects of 5-HT,, receptor agonists in two models ofanxiety after dorsal raphe injection. P.s~.c.ito~pi7~t,./?,ac~(~/~~g~~ 106: X-267. Hijzen, T. H., Rijnders. H. J. and Slangen. J. L. (1991) Effects ofanxiety drugs on the modification ofthe acoustic startle reflex by noise gaps. Pi~crr-nrac,. fhhf~?. Beiw. 38: 769-773. Hitchcock. J. M.. McCloskey. T. C.. Padich. R. A.. McCarty. D. R.. Dudley. M. W.. Sprouse, J. S., Freedman. J. and Kehne. J. H. (1991) Potential anxiolytic activity of 5-HT,,, partial agonists MDL 102.181 and MDL 73,005EF in animal models of anxiety sensitive to buspirone. SOC,. Nc~rrosci. Ah.str. 17: 78 1. Hjorth. S.. Stiderpalm. B. and Engel. J. A. (1987) Biphasic effect of L-5-HTP in the Vogel conflict model. ~.S~‘~~i7~JiJilfJ~JJl~l~‘O/~J~~’ 92: 96-99. Hodges. H.. Green. S. and Glenn. B. (19X7) Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination. P~?.c,hopilcr,.,lt~I(.OIOX1.92: 49lL504. HorvLith. K., Andrasi. F., Botka, P. and Hhmori. T. (1992) Anxiolytic profile of girisopam and GYKI 52 322 (EGIS 6775). Comparison with chlordiazepoxide and buspirone. Acttr pi~~~.siol. ixmg. 79: I53 161.
G. Griebel
386
Howard. J. L. and Pollard, G. T. (1990) Effects of buspirone in the GellerSeifter conflict test with incremental shock. Drug Del?. Re.s. 19: 37-49. Hoyer. D. (1988) Molecular pharmacology and biology of 5-HT,, receptors. TIPS 9: 89-94. Hoyer, D. (1991) The 5-HT receptor family. In: 5-HT, , Agonists. 5-HT, Antagonistsand Benzodkeppines, Their Con7purutir~e Bei7a7~iourui Pi7nmmcolog~. pp. 31-58, Rodgers, R. J. and Cooper. S. J. (eds) John Wiley, Chichester. Hoyer. D. and Middlemiss. D. N. (I 989) Species differences in the pharmacology of terminal 5-HT autoreceptors in mammalian brain. TIPS IO: 130~132. Hoyer. D. and Neijt, H. C. (1988) Identification of 5-HT1 recognition sites in membranes of NIE-I I5 neuroblastoma cells by radioligand binding. MO/W. Phurmuc. 33: 303-309. Hoyer, D. and Schoeffter. P. (1991) 5-HT receptors: subtypes and second messengers. J. Receptor Res. 11: 197-214. Hoyer. D.. Engel. G. and Kalkman, H. 0. (1985) Molecular pharmacology of 5-HT, and 5-HT, recognition sites in rat and pig brain membranes: radioligand binding studies with [‘HIS-HT. [‘H]X-OH-DPAT, [“‘I]iodocyanopindolol, [‘Hlmesulergine and (‘Hlketanserin. Eur. J. Pizurmuc. 118: 13-23. Hoyer, D., Pazos, A.. Probst. A. and Palacios. J. M. (1986) Serotonin receptors in the human brain II. Characterization and autoradiographic localization of 5-HT,, and S-HT, recognition sites. Brtrit7 Res. 376: 97FlO7.
Hoyer, D.. Schoeffter. P.. Waeber. stimulation of inositol phosphate Naun?‘77-S[,i7777icdehergp’.r Arch
C.. Palacios, J. M. and Dravid. A. (1989) 5-HT,, receptors-mediated production in pig choroid plexus; a pharmacological characterization.
Phurrnac,.
339: 252-258.
Hoyer, D., Clarke, D. E.. Fozard. J. R.. Hartig, P. R., Martin, G. R., Mylecharane. E. J.. Saxena, P. R. and Humphrey, P. P. A. (1994) VII. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharnzuc~. Rer. 46: 157-204. Hughes, R. N. ( 1993) Effects on open-field behavior of diazepam and buspirone alone and in combination with chronic caffeine. Lifi~ SC,;. 53: 1217 1225. Humble, M., Asberg-Wistedt. A.. Wistedt. B. and Bertilsson. L. (1986) A pilot study of ritanserin (a selective serotonin-2 receptor antagonist) in panic disorder and agoraphobia. Clinical and biochemical effects. In: C.I.N.P. Cor7gr~~x.s.p. 165. Puerto Rico. December 14-17. Humble. M.. Koczkas, C. and Widstedt, B. (1989) Serotonin and anxiety: an open study ofcitalopram in panic disorder. In: Ps~~f7icr/r>, Toduy: 1’111 World C‘ongrrxs of’Pswi7iutr~., p. I5 I. Stefanis. C. N., Soldatos, C. R. and Rabavilas. A. D. (eds) Elsevier, New York. Hyttel, J. (1977) Neurochemical characterization of a new potent and selective serotonin uptake inhibitor: Lu IO- I7 I P.s~~c~i7oJ~iiur7~7~7~01og~~ 51: 2255233. Jenck, F.. Broekkamp. C. L. E. and van Delft, A. M. L. (1989a) Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5-HT,, 5-HT: and 5-HT, receptors. P.s~~~hophurn7c7c~ol~~g~~ 97: 489%495.
Jenck. F., van Delft. A. M. L. and Broekkamp, C. L. E. (1989b) Serotonergic control of dorsal periaqueductal grey (PAG) induced aversion: a functional role for the brain 5-HT,, receptors. In: Scrofor7i7z,,fi.o777 CeUBiolog~~ to Pi7urn7ucolog~~ und Ti7cwpc~uric~s, Florence, April. Jequier, E.. Lovenburg. W. and Sjoerdsma, A. (1967) Tryptophan hydroxylase inhibition: the mechanism by which p-CPA depletes rat brain serotonin. Mo/c,r,. Pizurn7uc~. 3: 2744278. Jin. H.. Oksenberg. O., Ashkenazi, A.. Peroutka, S. J., Rozmahel. R.. Yang, Y., Palacios. J. M. and O’Dowd. ,” receptor. .I. ho/. Ciw77. B. E. (1992) Identification and characterization of the human 5-hydroxytryptamine 267: 573555738. Johnston. A. L. and File. S. E. (1988) Effects of 5-HT, antagonists in two animal tests of anxiety. Nrurosci. Left. 32 (Suppl.): S44. Joly, D. and Sanger, D. J. (1991) Social competition in rats: a test sensitive to acutely administered anxiolytics. Bei7m.. Pi7urn7uc. 2: 205 ~213.
Jones. B. J.. Oakley, N. R. and Tyers, M. B. (1987) The anxiolytic activity of GR38032F. a 5-HTl receptor antagonist, in the rat and cynomolgus monkey. Br. /. Phurn7uc. 90 (Suppl.): 88P. Jones. B. J.. Costall, B., Domeney, A. M., Kelly, M. E.. Naylor. R. J.. Oakley, N. R. and Tyers. M. B. (1988) The potential anxiolytic activity of CR 38032F, a 5-HT; receptor antagonist. Br. .J. Pi7urn7uc. 93: 9X5-993. Julius, D.. McDermott, A. B.. Axel. R. and Jessel. L. (1988) Molecular characterization of a functional cDNA encoding the serotonin IC receptor. Sciorw 241: 558 564. Kaltwasser, M. T. (1991) Acoustic startle induced ultrasonic vocalization in the rat: a novel animal model of anxiety‘? Bci7trr.. Bruir7. Rc.s. 43: 133 137. Kehne. J. H.. Cassella. J. V. and Davis. M. (1988) Anxiolytic effects of buspirone and gepirone in the fear-potentiated startlc paradigm. P.s~~c.ho~pi7trrnrrrc~olog~~ 94: 8- 13. Kennett. G. A. ( 1992) 5-HT,, receptor antagonists have anxiolytic-likeactions in the rat social interaction model. P.s~~c~i7opi7trrn7cic~olog~~ 107: 379-384.
Kennett, G. A.. Whitton, I’., Shah. K. and Curzon. G. (1989) Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT,, receptor antagonists. Eur. J. Pi7trrnruc~. 164: 445 454. Kidd. E. J., Haj-Dahmane. S., Jolas. T.. Lanfumey. L., Fattaccini. C.-M.. Guardiola-Lemaitre. B., Gozlan. H. and Hamon, M. (1993) New methoxy-chroman derivatives. 4[N-(5.methoxy-chroman-3-yl)N-propylaminolbutyl-%araspiro-(4,5)-decane-7.9-dione [O-S 202441 and its enantiomers, ( + )-S 20499 and (-)-S
5-HT-interacting
drugs
387
iAreceptors. J. Pharmac. e-up. Ther. 264: 20500, with potent agonist properties at central 5-hydroxytryptamine 863-872. Kilfoil, T., Michel, A., Montgomery, D. and Whiting, R. L. (1989) Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety in mice. Neuropharmacology 28: 901-905. Kilpatrick, G. J., Jones, B. J. and Tyers, M. B. (1987) The identification and distribution of 5-HT, receptors in rat brain using radioligand binding. Nature 330: 746-748. Kilpatrick, G. J.. Jones, B. J. and Tyers, M. B. (1989) Binding of the 5-HTi ligand, [?H]GR 65630, to rat area postrema, vague nerve and the brains of several species. Eur. J. Pharmac. 159: 1577164. Kilpatrick, G. J., Butler, A., Hagan, R. M., Jones, B. J. and Tyers, M. B. (1990a) [‘H]GR 65630, a very high ligand for 5-HT? receptors. Naunyr-Schmiedeberg’s Arch. Pharmac. 342: 22-30. Kilpatrick, G. J., Butler, A. and Oxford, A. W. (1990b) M chlorophenylbiguanide is a potent high affinity 5-HT-3 receptor agonist. Br. J. Pharmac. 99 (Suppl.): 32P. Kilpatrick, G. J., Hagan, R. M., Butler, A., Burridge, J., North, P. C., Oxford, A. W. and Tyers, M. B. (1991) GR68755, a potent and selective antagonist of 5-HT3 receptors. In: SEROTONIN 1991, 5-Hydroxytryptamine-CNS Receptors and Brain Function, p. 50, Birmingham, 14-17th July. Kilts, C. D., Commissaris, R. L. and Rech, R. H. (1981) Comparison of anti-conflict drug effects in three experimental animal models of anxiety. Psychopharmacology 74: 290-296. Kilts, C. D., Commissaris, R. L., Cordon, J. J. and Rech, R. H. (1982) Lack of central 5-hydroxytryptamine influence on the anticonflict activity of diazepam. Psychopharmacology 78: 156-164. Kiser, R. S. and Lebovitz, R. M. (1975) Monoaminergic mechanisms in aversive brain stimulation. Physiol. Behue.
15: 47753.
Kiser, R. S., German, D. C. and Lebowitz, R. M. (1978) Serotonergic reduction of dorsal central gray area stimulation-produced aversion. Pharmac. Biochem. Behav. 9: 27-3 1. Klein, E., Zohar, J., Gerazi, M. F., Murphy, D. L. and Uhde, T. W. (1991) Anxiogenic effects of m-CPP in patients with panic disorder: comparison to caffeine’s anxiogenic effects. Biol. Pswhiat. 30: 973-984. Klint, T. (1991) Effects of 8-OH-DPAT and buspirone in a passive avoidance test andin the elevated plus-maze test in rats. Behat). Pharmac. 2: 481-489. Klodzinska, A., Jaros, T., Chojnacka-Wojcik, E. and Maj, J. (1989) Exploratory hypoactivity induced by m-trifluoromethylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP). J. Neural Transm. 1: 207-218.
Knapp, D. J., Benjamin, D. and Pohorecky, L. A. (1992) Effects of gepirone on ethanol consumption, exploratory behavior, and motor performance in rats. Drug Der. Res. 26: 319-341. Koe, B. K. and Weissman, A. (1966) p-Chlorophenylalanine: a specific depletor of brain serotonin. J. Pharmac. e.yp. Ther.
154: 4999516.
Korneyev, A. Y. and Seredenin, S. B. (1993) Effects of 5-HT-IA receptor agonists on paw licking reaction on hot plate and unpunished drinking in rat. L$ Sci. 52: 997-1004. Korte, S. and Bohus, B. (1990) The effects of ipsapirone on behavioural and cardiac responses in the shock-probe/defensive burying test in male rats. Eur. J. Pharmac. 181: 307-310. Korte, S. M., Bouws, G. A. H., Koolhaas, J. M. and Bohus, B. (1992) Neuroendocrine and behavioral responses during conditioned active and passive behavior in the defensive/probe avoidance paradigm: effects of ipsapirone. PhJviol. Behac. 52: 355-361. Kostowski, W., Plaznik, A. and Stefanski, R. (1989) Intra-hippocampal buspirone in animal models of anxiety. Eur. J. Pharmac.
168: 3933396.
Kostowski, W., Dyr, W. and Krzascik, P. (1990) The effects of 5-HTIA receptor agonists in animal models of anxiety and depression. Psychopharmacology 101: S3 1. Kostowski, W., Dyr, W., Krzascik, P., Jarbe, T. and Archer, T. (1992) 5-HydroxytryptaminelA receptor agonists in animal models of depression and anxiety. Pharmac. To.uic. 71: 24-30. Kshama, D., Hrishikeshavan, H. J., Shanbhoge, R. and Munonyedi, U. S. (1990) Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms. Behar. Neural Biol. 54: 234-253.
Lahti, R. A.. Evans, D. L., Nichols, N. F. and Figur, L. M. (1993) Anxiolytic activity of the 5-HTlA agonist U-93385. attenuation of stress-induced increases in rat corticosterone levels. Sot. Neurosci. Absrr. 19: 1867. Lal, H., Prather, P. L. and Mehdi Rezazadeh, S. (1991) Anxiogenic behavior in rats during acute and protracted ethanol withdrawal: reversal by buspirone. Alcohol 8: 467-471. Lecci, A., Borsini, F., Mancinelli, A., D’Aranno, V., Stasi, M. A., Volterra, G. and Meli, A. (1990) Effects of serotonergic drugs on stress-induced hyperthermia (SIH) in mice. J. Neural Transm. 82: 219-230. Lecrubier, Y., Puech, A. J., Azcona, A., Bailey, P. E. and Lataste, X. (1993) A randomized double-blind placebo-controlled study of tropisetron in the treatment of outpatients with generalized anxiety disorder. Psychopharmacology 112: 129-133. Lee, C. and Rodgers, R. J. (1991) Effects of buspirone on antinociceptive and behavioural responses to the elevated plus-maze in mice. Behac. Pharmac. 2: 491-496. Lehman, H. E. and Ban, T. A. (1971) Effects of psychoactive drugs on conflict avoidance behavior in human subjects. Acta New. Sup. 13: 82-85. Leone, C. M. L., de Aguiar, J. C. and Graeff, F. G. (1983) Role of 5-hydroxytryptamine in amphetamine effects on punished and unpunished behavior. Psychopharmacology 80: 78-82. Lesourd, M., Curie, P. F., File, S., Hamon, M. and Chouvet, G. (1993) S-20499 - a new selective 5-HT,, agonist:
388
G. Griebel
mechanistn of its anxiolytic activity. In: Atz.uier>,~ Ncurohio/ogic,tr/. Clinical ta7d T/7cvtrprutic~.s ,4.s/w~~7.~,p. 18 (Suppl.). Dinard. 20-2lsl September. Levy. A. D. and van de Kar, L. D. (1992) Endocrine and receptor pharmacology of serotonerglc anxiolytics. antipsychotics and antidepressants. Lif? Sci. 51: 83-94. Leysen. J. E.. Niemegeers. C. J. E.. van Nueten. .I. M. and Laduron. P. M. (1982) [‘HlKetanserin (R41 46X). a selective ‘H ligand for serotonin 2 receptor binding sites. Molcc,. Phrrvn7uc. 21: 3Ol--314. Lightowler, S.. Williamson, I. J. R., Hegarty. J.. Kennett. G. A.. Fears. R. B. and Tulloch. I. F. ( 1992) Anxiolytic effect of paroxetine in the rat social interaction model of anxiety. By. J. PAcrrr?~rrc~. 106 (Suppl.): 44P. Lister. R. G. (1990) Ethologically-based animal models of anxiety disorders. P/M~-~KK. T/w. 46: 321 340. Lbpcz-Rubalcava. C., Saldivar, A. and Fernlindez-Guasti. A. (1992) Interaction of GABA and serotonin in the anxiolytic action of diazepam and serotonergic anxiolyttcs. Phovn7c7c. Bioc,/7et77. Beh7~. 43: 433-440. Lorens. S. A.. Mitsushio. H. and Van de Kar. L. D. (1989) Effects of the 5-HT,,, agonist ipsapirone on the behavioural. endocrine and neurochemical responses to conditioned fear. In: Beha7+~u~tr/ Phtrr777nc,o/o~~,of 5-HT. pp. 1:~7~369. Bevan, P.. Cools. A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Lucki. I., Ward. H. R. and Frazer. A. (1989) Effect of I-(r77-chlorophenyl)piperazine and I-(777-trifluoromethylphenyl)piperazine on locomotor activity. J. Pl7rrr771trc..(‘\-/7. 7%cr. 249: 155-164. Luscotnbe. G. P.. Mazurkiewicz. S. E and Buckett. W. R. (1990) Evaluation of tricyclic antidepressants in the elevated plus-maze in rats: anxiolytic effect of dothiepin and doxepin. Br. J. Pl7crrr77crc. 100 (Suppl.): 356P. Luscombc, G. P.. Mazurkiewicz. S. E. and Heal, D. J. (1992) The 5-HT,, l&and BP 554 mimics the anxiolytic activity of buspirone. gepirone and ipsapirone in the elevated plus-maze in rats. Br. J. Pl7rrrrntrc~.106 (Suppl.): l3OP. Lyon, R. A. and Titeler. M. (1988) Pharmacology and biochetnistry of the 5-HT, receptor. in: T/w .Sr,ro707ti77 Rct.(~p/7t07..(.. pp. 59-88. Sanders-Bush. E. (ed.) Humana Press. Clifton. Maisonnette. S., Morato, S. and Brandao, M. L. (1993) Role ofresocialiration and of5-HT,a receptor activation on the anxiogenic effects induced by isolation in the elevated plus-maze test. Ph~~.sio/. Bchrw. 54: 753 758. Maitre. L. ( 1997) Antidkpresseurs et lithium. In: P/7tr,r77crc,ok~gi(, l&s C‘O~~CV~/~IS Fot7t/r/t77~t7ttru.\- c/LI.\’ App/icutio77.\ P/7c;rtrllcu/icluc.r. pp. 335-371, Schorderet, M. (ed.) Frison-Roche and Slarkine. Paris and Geneva. Major. J. S.. Le Count. D., Pearce, R. J.. Thornber. C. W., Walters, M. and Cox, B. (1991) ICI 169369 and related cotnpounds have high affinity for 5-HT,, and 5-HT: receptors. In: SERC~TO:VI,Y 1991. ~-H~~t/ro\-1~tr.1~/7rtrt71it7r-cn!s Rcc~c~ptor.s cm/ Bruit7 Fw7c~riotr. p. 40. Birtninehatn. I4 17th July. Malgouris. c... Flamand. F. and Doble. A. (1993) Autoradiographic studies of RP 62203. a potent 5-HT1 receptor antagonist. 177rim and P.\- riw selectivity profile. EIU.. J. Phtr~77nc.. 233: 29~ 35. Mansbach. R. S. and Geyer. M. A. (1988) Blockade of potentiated startle responding in rat> by 5-hy’lroxytrqp(amine IA receptor ligands. E7rr. J. Pl7co771rrc..156: 375 -383. Mansbach. R. S.. Harrod. C.. Hoffmann, S. M.. Nader, M. A.. Lei. Z.. Witkin. J. M. and Barrett. J. E. (19x8) Behavioral studies wjith anxiolytic drugs. V. Behavioral and it7riro neurochemical analyses in pigeons ofdrugs that increase punished responding. J. P/7rrrr77trc,.c-\-p. T/7(,,. 246: I 14~120. Martin, P. (1993) Efects of anxiolytic and antidepressant drugs in an animal tnodel of panic. In: AtI vic/.~‘ ~~ .Yr,7rr_ohio/oXit,[7/~ C’lirzic~dcrr7riT/7cwpcwric~.s A.spw/v. p. 203. Hamon. M.. Ollat. H. and Thit-bot. M.-H. (eds) Les iditions INSERM. Paris. Mason. P.. Skinner. J. and Luttinger. D. (1987) Two tests in rats for antianxiety effect of clinically anxiety attenuating antidepressants. P,s~~~~hophn~rr7r~~~~/~t~~~ 92: 30 34. McBlane. J. W.. Critchley. M. A. E. and Handley. S. L. (1992) Light intensity influences the response to X-OH-DPAT in the elevated X-maze tnodel of anxiety. Br. .J. P/wt~77rrt 105 (Suppl.): 22 I P. McCloskcy. T. C‘.. Paul. B. K. and Cotnmissaris. R. L. ( 1987) Buspirone effects in an animal contlict procedure: comparison with diazepam and phenobarbital. P/7rrrr77c7c~. Bid7cm. Behcrr. 27: I7 I 175. McCown, T. .I.. Vogel. R. A. and Breese. G. R. (1983) An efficient chronic conflict paradigm: lick suppression by incremental footshock. P/7rrrr77rrc,.Bioc,/7c,n7.Brhrw. 18: 277 279. McKearney. J. W. and Barrett. J. E. (1975) Punished behavior: increases in responding after t,-amphetamine. P.s~~(./7o/~ll~/l.t77(1~ ologitr 4 1: 23-m26. McMillan. 1). E. (1973) Drugs and punished responding I: rate-dependent efrects under tnultiple schedules. .J. c~,I. .3/7tr/. Bcl7rrr. 19: 133m145. Meer1. T. F. (19X6) A comparative study of the effects of ritanserin (R55667) and chlordiazepoxide on rat open lield behal-iour. /)~rg l)c,r.. Rc.s. 8: 197-204. Meert. T. F. (1’989)Ritanserin and risperidone in comparison with other 5-HT agonist:antagonists in different animal models in the rat. In: S~,rofor7;77.,f~ot77 C’P// Biolo,qv lo P/7urt77~(,0/(~~~’ crt7d T/~wL~J~~u~~~~J, Florence, April. Meert. T. F. (lY92) Ritanserin overcomes exploratory inhibition induced by cocaine withdrawal. Brl7trr. P/lc7,_r?lr7c~. 3: 149 154. Mecrt. T. F. and Colpaerr, F. C. (l986a) The shock probe conflict procedure. A new assay responsive to bcnzodiazepines. barbiturates and related compounds. P\~,c,/7o)/~/7rrrt77~7[,~~/~)~~. 88: 445~-450. Meert. T. F. and Colpaert. F. C. (1986b) Effects of S, antagonists in two conflict procedures that involve exploratory behaviour. P.s~~c~hophnr-777~~~~~~/~~~~~ 89: S23. Mecrt. T. F. and Colpaert. F. C. (1986~) A pharmacological evaluation of the selected emotional defecation and micturation test. P.s~,c,hophc7~777r~~~/~~~, 89: S23. Melia. K. R. and Davis. M. (1991) Effects of septal lesions on fear-potentiated startle. and on the anxiolytic effects of huspirone and diazepam. P/:,~~.sio/. Bel7m. 49: 603-61 I.
5-HT-interacting
drugs
389
Meneses. A. and Hong, E. (1993) Modification of the anxiolytic effects of 5-HT,, agonists by shock intensity. Pharmac. Biochem. Behar. 46: 5699573. Metzenauer. P., Barnes, N. M., Costall. B.. Gozlan, H., Hamon, M., Kelly M. E., Murphy, D. A. and Naylor, R. J. (1992) Anxiolytic-like actions of anpirtoline in a mouse light/dark aversion paradigm. NemoReport 3: 527-529. Miczek, K. A. (1973) Effects of scopolamine, amphetamine and benzodiazepines on conditioned suppression. Pharmac. Biochem. Behac. 1: 401-411. Middlemiss, D. N. and Hutson. P. H. (1990) The 5-HTle receptors. Ann. N. Y. Acad. Sci. 600: 132-148. Millan, M. J. and Brocco, M. (1993) Serotonin and anxiety: mixed 5-HTt4 agonists ~ 5-HTlc ?antagonists as potential anxiolytic agents. In: Anxiety - Neurohiological, Clinicaland Therapeutics Aspects, p. 153, Hamon, M., Ollat. H. and Thiebot, M.-H. (eds) Les editions INSERM, Paris. Millan. M. J., Canton, H., Rivet, J.-M., Lejeune, F., Laubie, M. and Lavielle, G. (1991) S 14671: a novel naphthylpiperazine S-HTIA agonist of high efficacy and exceptional in riro potency. Eur. /. Pharmuc. 203: 319-322. Misslin. R.. Griebel. G., Saffroy-Spittler, M. and Vogel, E. (1990) Anxiolytic and sedative effects of 5-HT,, ligands, 8-OH-DPAT and MDL 73005EF, in mice. NemoReport 1: 2677270. Miyauchi, T., Inagawa, K.. Uchida, H., Tameda, C. and Sakakibara, M. (1993) Pharmacological profile of HT-YOB, a putative anxiolytic with potent antidepressive activity. Sot. Neurosci. Ahstr. 19: 1867. Molewijk, H. E., van der Poel. A. M.. Vedder, A. W. and Olivier, B. (1993) Ultrasonic distress vocalisations in adult rats as a model for panic disorder. In: British Association far Ps?,chap,pharnlacol~~g~,,25528th July, Cambridge, A12. Moreau, J.-L.. Griebel, G.. Jenck, F., Martin, J. R., Widmer, U. and Haefely, W. E. (1992) Behavioral profile of the 5HT,, receptor antagonist (S)-UH-301 in rodents and monkeys. Bruin Res. Bull. 29: 901-904. Morinan. A. (1989) Effects of the 5-HTI receptor antagonists, GR 38032F and BRL 24924, on anxiety in socially isolated rats. Br. J. Pharmac. 97 (Suppl.): 457P. Morris, H., White, S. M., Shropshire. A. T., Abou-Gharbia, M., Boast, C. A. and Moyer. J. A. (1989) Behavioral characterization of the novel anxiolyticiantidepressant agent WY-50,324. Sot. Neurosci. ilhstr. 15: 852. Mos. J. and Olivier, B. (1989) Ultrasonic vocalizations by rat pups as an animal model for anxiolytic activity: effects of serotonergic drugs. In: Beharioural Pharmacology of 5-HT. pp. 361-366, Bevan, P.. Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Mos, J., van der Heyden, J. and Olivier, B. (1989) Behavioural effects of 5-HT, antagonists in animal models for aggression, anxiety and psychosis. In: Beharioural Pharmacology qf‘5-HT, pp. 389-395, Bevan. P.. Cools, A. R. and Archer, T. (eds) Erlbaum. Hillsdale. Moser, P. C. (1989a) An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone. Ps~chophurn~acolog~~ 99: 48853. Moser, P. C. (1989b) Buspirone, ipsapirone and 5-HT,.,-receptor agonists show an anxiogenic-like profile in the elevated plus-maze. In: Beharioural Pharmacologic af5-HT, pp. 371-375. Bevan, P., Cools, A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Moser, P. C.. Hibert, M., Middlemiss, D. N., Mir, A. K., Tricklebank, M. D. and Fozard. J. R. (1988) Effects of MDL 73005EF in animal models predictive of anxiolytic activity. Br. J. Pharmuc. 93 (Suppl.): 3P. Moser, P. C., Tricklebank, M. D., Middlemiss, D. N.. Mir, A. K., Hibert, M. F. and Fozard, J. R. (1990) Characterization of MDL 73005EF as a 5-HT,, selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam. Br. J. Phurmac. 99: 3433349. Motta, V., Maisonnette, S.. Morato, S., Castrechini. P. and Brandao, M. L. (1992) Effects of blockade of 5-HT, receptors and activation of 5-HT,,& receptors on the exploratory activity of rats in the elevated plus-maze. P.s~chopl~arr~~at~olog~107: 135- 139. Moulton, B. and Morinan, A. (1990) The effect of RS-30199 on anxiety and hippocampal monoamine oxidase activity in the rat. Br. J. Pharmac. 101 (Suppl.): 516P. Munonyedi, U. S.. Hrishikeshavan. H. J., Shanbhogue, R. S. and Devi, K. (1991) Potentiation of poststartle activity by conditioned fear: effects of anxiolytic and anxiogenic drugs. Biol. Psychiat. 29: 6833686. Nader, M. A. (1991) Behavioral effects of chronic buspirone administration in the pigeon: comparison to midazolam. Pharmac. Biochem. Be/tar. 38: 61 l-61 6. Nagatani. T., Yamamoto, T., Takao. K.. Hashimoto, S.. Kasahara, K.. Sugihara. T. and Ueki, S. (1991) Pharmacological profile of a potential anxiolytic: API 59, a new benzothieno-pyridine derivative, P.~~‘cllopharrn~~col~)g~~ 104: 432-438. Nanry. K. P. and Tilson. H. A. (1989) The role of SHTIA receptors in the modulation of the acoustic startle reflex in rats. P.~~chopharn~acolog~~ 97: 507-5 13. Nanry. K. P.. Howard. J. L. and Pollard, G. T. (1991) Effects of buspirone and other anxiolytics on punished key-pecking in the pigeon. Drug Der. Res. 24: 2699276. Nastiti. K., Benton. D., Brain, P. F. and Haug. M. (1991) The effects of 5-HT receptor ligands on ultrasonic calling in mouse pups. Neurosci. Biobehar. Ret.. 15: 4833487. Nelson, D. R. and Thomas, D. R. (1989) [‘H]BRL 43694 (granisetron), a specific ligand for 5-HT? binding sites in rat brain cortical membranes. Biochem. Pharmac. 38: 1693-1695. Nelson, D. R.. Thomas, D. R. and Johnson, A. M. (1989) Pharmacological effects of paroxetine after repeated administration to animals. Acta psjchiat. stand. 80 (Suppl.): 21-23. Nishimura. H., Tanaka, M.. Tsuda. A. and Gondoh, Y. (1993) Atypical anxiolytic profile of buspirone and a
390
G. Griebel
related drug, SM-3997. in a modified forced swim test employing 46: 647-65
straw suspension.
Pharmac.
B&hem.
Behar.
1.
Njung’e, K. (1990) Effects of some 5-hydroxytryptamine and related ligands in anxiety models. Ph.D. Thesis, Aston University, Birmingham, U.K. Njung’e, K. and Handley, S. L. (1991 a) Evaluation of marble-burying behavior as a model of anxiety. Pharmac. Biochem.
Behar.
38: 63-67.
Njung’e, K. and Handley, S. L. (199lb) Effects of 5-HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Br. .I. Pharmac. 104: 105-l 12. Nogueira, R. L. and Graeff, F. G. (1991) 5-HT mediation of the antiaversive effect of isamoltane injected into the dorsal periaqueductal grey. Behav. Pharmac. 2: 73377. Oakley, N. R. and Jones, B. J. (1983) Buspirone enhances [ZH]flunitrazepam binding in riro. Eur. J. Pharmac. 87: 4999500.
types and anxiety. In: Target Receptorsfor Anxiolytics and Hypnotics: From Molecular Pharmacology to Therapeutics. International Academy of Biomedical Drug Research. Vol. 3, pp. 1 l-23, Mendlewicz, J. and Racagni, G. (eds) Karger, Basel.
Oakley, N. R. and Tyers, M. B. (1992) 5-HT receptor
Ogawa, N., Hara, C. and Takaki, S. (1993) Anxiolytic activity of SC-48274 compared with those of buspirone and diazepam in experimental anxiety models. Jap. J. Pharmac. 61: 1155121. Olds, M. E. and Olds, J. (1962) Approach-escape interactions in rat brain. Am. .I. Physiol. 203: 8033810. Olivier, B., Mos, J., van der Heyden, J. and Hartog, J. (1989) Serotonergic modulation of social interactions in isolated male mice. PsychopharmacoIogy 97: 154-l 56. Olivier. B., Mos, J., Tulp, M. T. M. and van der Poel, A. M. (1992) Animal models of anxiety and aggression in the study of serotonergic agents. In: Serotonin Subtypes: Pharmacological Signtficance und Clinical Implications, Vol. 1, pp. 67-79, Langer, S. Z.. Brunello, N. and Mendlewicz, J. (eds) Karger, Basel. Onaivi. E. S. (1993) The anxiolytic profile of buspirone can be detected in the elevated plus-maze test following r,-stimulation by dexmedethomidine. Sot. Neurosci. Abstr. 19: 755. Onaivi, E. S. and Martin, B. R. (1989) Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety. Prog. Nemo-Psy~chopharmac.
biol. Psychiat.
13: 9633976.
Palacios. J. M., Mengod, G., Hoyer, D., Waeber, C., Pompeiano, M., Niclou, S. and Bruinvels, A. (1992) Autoradiographic localization of 5-HT receptor subtypes. In: Serotonin. CNS Receptors and Brain Function. pp. 61-72, Bradley, P. B., Handley, S. L., Cooper, S. J., Key, B. J., Barnes, N. M. and Coote. J. H. (eds) Pergamon Press, Oxford. Panickar, K. S. and McNaughton, N. (1991) Doseeresponse analysis of the effects of buspirone on rearing in rats. J. Psychopharmuc. 5: 72276. Papp, M. (1988) Similar effects of diazepam and the 5-HTI receptor antagonist ICS 205-930 on place aversion conditioning. Eur. .I. Pharmac. 151:321-324. Papp, M. and Przegalinski, E. (1989) The 5-HT, receptor antagonist ICS 205-930 and GR38032F, putative anxiolytic drugs, differ from diazepam in their pharmacological profile. J. Psychopharmac. 3: 14-20. Patel, J. B. and Malick, J. B. (1980) Effects of isoproterenol and chlordiazepoxide on drinking and conflict behaviors in rats. Pharmac. Biochem. Behao. 12: 819-821. Pazos, A., Hoyer, D. and Palacios, J. M. (1984) The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur. J. Pharmac. 106: 5399546. Pellow, S. and File, S. E. (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmac. Biochem. Behar. 24: 5255529. Pellow, S., Chopin. P., File, S. E. and Briley, M. (1985) Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J. Neurosci. Meth. 14: 1499167. Pellow, S.. Johnston, A. L. and File, S. E. (1987) Selective agonists and antagonists for 5-hydroxytryptamine receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plus-maze test in the rat. J. Phnrm.
Pharmac.
39: 917-928.
Peroutka, S. J. (1986) Pharmacological differentiation and characterization of 5-HT,,, 5-HT,,, 5-HTic binding sites in rat frontal cortex. J. Neurochem. 47: 5299540. Peroutka. S. J. and Hamik, A. (1988) [‘H]Quipazine labels 5-HT1 recognition sites in rat cortical membranes. Erlr. J. Phurmuc~. 148: 297-299. Peroutka. S. J., Hamik, A., Harrington, M. A., Hoffman, A. J., Mathis, C. A., Pierce, P. A. and Wang, S. S. H. ( 1988) (R)-( ~ )-[“Br]4-Bromo-2,5-dimethoxy-amphetamine labels a novel 5-hydroxytryptamine binding site in brain membranes. Molec. Pharmac. 34: 5377542. Petersen, E. N. and Lassen, J. B. (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmncology
75: 236-239.
Pith, E. M. and Samanin, R. ( 1986) Disinhibitory, effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: possible role of dopamine. PsychopharmacoIogy~ 89: 125-130. Pigott, T. A., Hill, J. L., Grady, T. A., L’Heureux, F., Bernstein, S., Rubenstein, C. S. and Murphy, D. L. (1993) A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to IV mCPP. Biol. Psych&. 33: 3-14. Piper, D. C., Upton, N., Thomas, D. and Nicholson, J. (1988) The effects of 5-HTI receptor antagonists BRL 43694 and GR 38032F in animal behavioural models of anxiety. Br. .I. Pharmac. 94 (Suppl.): 314P. Piper, D. C., Kenney. C. A., Jenkins, E., Blackburn, T. P. and Hughes, H. C. (1992) A comparison of the
5-HT-interacting anxiolytic
activity
international
of BRL46470A,
Symposium
ondansetron
on SEROTONIN,
.from
and
drugs
391
diazepam
Cell Biology
in the cynomolgus
to Pharmacology
monkey.
and Therapeutics,
In: 2nd p. 16,
Houston, 15-1&h September. Plaznik, A., Stefanski, R. and Kostowski, W. (1991) The role of 5-HTIA- and 5-HT1-receptors within the nucleus accumbens and the hippocampus in the rat emotional behavior. In: SEROTONIN 1991, 5-Hydroxytryptamine-CNS Receptors and Brain Function, p. 190, Birmingham, 14-17th July. Pollard, G. T. and Howard, J. L. (1991) Cork gnawing in the rats as a screening method for buspirone-like anxiolytics. Drug Dev. Res. 22: 179-187. Pollard, G. T., Nanry, K. P. and Howard, J. L. (1992) Effects of tandospirone in three behavioral tests for anxiolytics. Eur. J. Pharmac. 221: 297-305. Porsolt, R. D., Lenegre. A., Caignard, D. H., Pfeiffer, B., Mocaer, E. and Guardiola-Lemaitre, B. (1992) Psychopharmacological profile of a new chroman derivative with 5-hydroxytryptaminelA agonist properties: S 20499 (+). Drug Dev. Res. 27: 389-402. Prather, P. L., Rezazaden, S. M., Lane, J. D., Rowan, G. A., Hooper, M. L., Lytle, D. A., Emmettoglesby, M. W. and Lal, H. (1993) Conflicting evidence regarding the efficacy of ondansetron in benzodiazepine withdrawal. J. Pharmac. exp. Ther. 264: 622-630. Przegalinski, E., Chojnacka-Wojcik, E. and Filip, M. (1992) Stimulation of postsynaptic 5-HTIA receptors is responsible for the anticonflict effect of ipsapirone in rats. J. Pharm. Pharmac. 44: 780-782. Redfern, W. S. and Williams, A. (1989) Acute of centrally-acting drugs on the behaviour of rats in an elevated X-maze and a partially-shaded holeboard. Br. J. Pharmac. 98 (Suppl.): 683P. Redfern, W. S., Clague, R. U. and Spedding, M. (1989) Anxiogenic-like properties of RS-30199 in the rat. Br. J. Pharmac. 98 (Suppl.): 682P. Rex, A., Fink, H., Ott, T. and Stephens, D. N. (1991) A sensitive and simple screen for anxiolytic drugs. In: SEROTONIN 1991,5-Hvdroxytryptamine-CNS Receptorsand Brain Function, p. 147, Birmingham, 14-17th July. Rezazadeh, S. M., Prather, P. L. and Lal, H. (1993) Sensitization to 5-HTlc receptor agonist in rats observed following withdrawal from chronic ethanol. Alcohol 10: 281-283. Rhodes, K. F., Middlefell, V. C., Lattimer, N., Brammer, N. T., Coleman, J., Taylor, A. P., Saville, L. and Ward, T. J. (1993) WAY 100289: pharmacological profile of a new .5-HTz receptor antagonist. Drug. Der. Res. 28: 128-140.
Richards, S-HT,
G., Schoch, P. and Jenck, F. (1991) Benzodiazepine Antagonists
and Benzodiazepines,
Their Comparative
receptors
and their ligands. In: 5-HTla Agonists, Pharmacology, pp. l-30, Rodgers,
Behavioural
R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Robichaud, R. C. and Sledge, K. L. (1969) The effects of p-chlorophenylalanine on experimentally induced conflict in the rat. L@ Sci. 8: 965-969. Rocha, B., Di Scala, G. and Sandner, G. (1992) Differential effect of 5,7_dihydroxytryptamine lesions on conditioned place aversions produced by FG-7 142 or mianserin in rats. In: The Role of Serotonin in Psychiatric Disorders, Castres, 24-26th June. Rocha, B., Di Scala, G., Jenck, F., Moreau, J.-L. and Sandner, G. (1993a) Conditioned place aversion induced by S-HTlc receptor antagonists. Behav. Pharmac. 4: 101-106. Rocha, B., Di Scala, G., Rigo, M., Hoyer, D. and Sandner, G. (1993b) Effect of 5,7_dihydroxytryptamine lesion on mianserin-induced conditioned place aversion and on 5hydroxytryptamine,c receptors in the rat brain. Neuroscience
56: 687-693.
Rodgers, R. J., Cole, J. C., Cobain, M. R., Daly, P., Doran, P. J., Eells, J. R. and Wallis, P. (1992) Anxiogenic-like effects of fluprazine and eltoprazine in the mouse elevated plus-maze: profile comparisons with 8-OH-DPAT, CGS 12066B, TFMPP and mCPP. Behav. Pharmac. 3: 621-634. Rodgers, R. J., Cole, J. C. and Davies, A. (1993) Anxiolytic and motoric effects of buspirone and flexinoxan in the murine elevated plus-maze. Sot. Neurosci. Abstr. 19: 756. Rutter, J. J. and Auerbach, S. B. (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J. Pharmac. exp. Ther. 265: 1319-1324. Saldivar, A., Rios, C. and Fernandez-Guasti, A. (1991) Differential role of serotonin and noradrenaline on anxiety reduction after ejaculation in the rat. Pharmac. Biochem. Behav. 38: 807-812. Sanders-Bush, E. (1988) 5-HT receptors coupled to phosphoinositide hydrolysis. In: The Serotonin Receptors, pp. 181-198, Sanders-Bush, E. (ed.) Humana Press, Clifton. Sanger, D. J. (1990) Effects of buspirone and related compounds on suppressed operant responding in rats. J. Pharmac.
exp.
Ther.
254: 420-426.
Sanger, D. J. (1991) Animal models of anxiety and the screening and development of novel anxiolytic drugs. In: Neuromethods, Vol. 19: Animal Models in Psychiatry, Vol. II, pp. 147-198, Boulton, A., Baker, G. and Martin-Iverson, M. (eds) The Humana Press, Clifton. Sanger, D. J. (1992) Increased rates of punished responding produced by buspirone-like compounds in rats. J. Pharmac.
exp.
Ther.
261: 513-517.
Sanger, D. J. and Joly, D. (1989-1990) Performance of a passive avoidance response is disrupted by compounds acting at 5-HT,, receptors. Behac. Pharmac. 1: 235-240. Sanger, D. J., Joly, D. and Zivkovic, B. (1985) Behavioural effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. J. Pharmac. e.yp, Ther. 232: 831-837.
392
G. Griebel
Sanger, D. J., Joly, D. and LePichon, M. (1989) Buspirone, gepirone and ipsapirone disrupt both active and passive avoidance responding in rats. Behaz,. Pharmac. I: 1533160. Schefke, D. M., Fontana, D. J. and Commissaris, R. L. (I 989) Anti-conflict efficacy of buspirone following acute versus chronic treatment. Psychopharmacology 99: 4277429. Schipper. J., van der Poel, A. M., Mos, J., van der Heyden, J. A. M. and Olivier, B. (1991) Flesinoxan: anxiolytic activity in animal models. In: SEROTONIN 1991, 5-H!,dro.u?,tr!,ptamine-CNS Receptors and Brain Function, p. 138, Birmingham, l4-17th July. Schlicker. E.. Finck, K., Gothert, M., Hoyer. D.. Molderings, G., Roschke, I. and Schoeffter, P. (1989) The pharmacological properties of the presynaptic serotonin autoreceptor in the pig brain cortex conform to the 5-HT,,, receptor subtype. NaunJn-Schmiedeberg’s Arch. Pharmuc. 340: 45551. Schmidt, A. W. and Peroutka, S. J. (1990) Quantitative molecular analysis predicts 5-HT1 receptor binding affinity. Molec. Phnrmac. 38: 51 l-516. Schoeffter. P. and Hoyer, D. (1989) 5-Hydroxytryptamine 5-HT,, and 5-HT,, receptors mediating inhibition of adenylate cyclase activity. Pharmacological comparison with special reference to the effects of yohimbine. rauwolscine and some beta-adrenoceptor antagonists. Nnuny-Schmiedeberg’s Arch. Phurmuc. 340: 285.-292. Schoenfeld, R. I. (1976) Lysergic acid diethylamideand mescaline-induced attenuation of the effect of punishment in the rat. Science 192: 8Oll803. Schreiber. R. and de Vry, J. (1993) 5-HTlh receptor ligands in animal models of anxiety, impulsivity and depression: multiple mechanisms of action? Prog. Neuro-Ps.l’~hopharmac. biol. Psychint. 17: 877104. Schreur, P. J. K. D. (1988) The face to face test for anxiolytics: a social interaction test in mice. Sot,. Neurosci. Ab.s/r. 14: 520. Schreur. P. J. K. D., Stone. M. P., Nichols, N. F., Lin. C.-H. and Haadsma Svensson, S. R. (1993) U-93385: an orally active anxiolytic with selective 5-HT,, agonist activity. Sot,. Neurosci. Ahstr. 19: 1867. Schiitz. M. T. B.. de Aguiar. J. C. and Graeff, F. G. (1985) Anti-aversive role of serotonin in the dorsal periaqueductal grey matter. P.s~~cl~ophurnluc~~)l~~g~ 85: 340--345. Schuurman. T., Spencer. D. G. and Traber, J. (1986) Behavioural effects of the 5-HT,, receptor l&and ipsapirone (TVXQ 7821): a comparison with X-OH-DPAT and diazepam. P.s~~c~hophurmacolog~~ 89: S54. Schweizer, E. and Rickels, K. (1991) Serotonergic anxiolytics: a review of their clinical efficacy. In: 5-HT,,, Agonists, 5-HT, Antagonists and Benzodiuzepines, Their Compnrutice Behurioural Phurmuc~ology, pp. 365-376, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Sepinwall, J. and Cook, L. (1978) Behavioral pharmacology of anti-anxiety drugs. In: Handbook of Ps~c~hophurn~crcolog~, Vol. 13. pp. 3455393, Iversen. L. L., Iversen, S. D. and Snyder. S. H. (eds) Plenum Press. New York. Sepinwall, J. and Cook. L. (1980) Mechanisms of action of the benzodiazepines: behavioral aspect. Fedn Proc. 39: 30244303 I. Shephard, R. A., Buxton, D. A. and Broadhurst. P. L. (1982) Drug interactions do not support reduction in serotonin turnover as the mechanism of action of benzodiazepines. N~,uropizclnnuco/~~g~ 21: 102771032. Shepherd, J. K.. Flores, T.. Rodgers, R. J., Blanchard, R. J. and Blanchard, D. C. (1992) The anxiety/defense test battery: influence of gender and ritanserin treatment on antipredator defensive behavior. Ph~xiol. Behac. 51: 277m285. Shepherd, J. K., Rodgers, R. J., Blanchard, R. J., Magee, L. K. and Blanchard, D. C. (1993) Ondansetron, gender and antidepredor defensive behaviour. J. Ps~ehophurmnc. 7: 72-8 1. Shimizu, H.. Hirose. A., Tatsuno. T., Nakamura. M. and Katsube, J. (1987) Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate. Jup. J. Phurmuc. 45: 493. 500. Shimizu. H.. Kumasaka, Y., Tanaka, H., Hirose. A. and Nakamura, M. (1992a) Anticonllict action of tandospirone in a modified Geller-Seifter conflict test in rats. Jup. J. Phurma~~. 58: 2833289. Shimizu. H., Tatsuno, T.. Tanaka, H., Hirose, A.. Araki, A. and Nakamura. M. (1992b) Serotonergic mechanisms in anxiolytic effect of tandospirone in the Vogel conflict test. Jup. J. Pharmuc~. 59: 1055112. Siiderpalm. B. and Engel, J. A. (1989) Does PCPA induced anticonflict effect involve activation of the GABA,‘benzodiazepine chloride ionophore receptor complex? J. Neural Trunsm. 76: 1455153. Soderpalm, B. and Engel, J. A. (1991) Involvement of the GABA,!benzodiazepine chloride ionophore receptor complex in the 5,7-DHT induced anticonflict effect. L@ Sci. 49: 139-I 53. Soderpalm. B. and Engel. J. A. (1992) The 5,7-DHT-Induced anticonflict effect is dependent on intact adrenocortical function. Li/e Sci. 51: 3 15- 326. Siiderpalm. B.. Hjorth. S. and Engel. J. A. (1989) Effects of 5-HT li\ receptor agonists and L-5-HTP in Montgomery’s conflict test. Phurmnc. Biochem. Behrn. 32: 2599265. Shderpalm. B., Lundin, B. and Hjorth, S. (1993) Sustained 5-hydroxytryptamine release-inhibitory and anxiolytic-like action of the partial 5-HTIA receptor agonist, buspirone. after prolonged chronic administration. Eur. J. Phurmuc. 239: 69%73. Sommermeyer. H., Schreiber, R., Greuel. J. M., de Vry. J. and Glaser, T. (1993) Anxiolytic effects of the 5-HT,, receptor agonist ipsapirone in the rat: neurobiological correlates. Eur. J. Pharmtrc. 240: 29937. Soubrie. P. (1989) 5-HT,, receptors: a bridge between anxiety and depression. In: Behuriourul Phurmuc~olog~ of’5-HT. pp. 3377352. Bevan, P., Cools, A. R. and Archer. T. (eds) Erlbaum. Hillsdale. Soubrie. P. and Thiebot, M. H. (1986) Some pre-clinical observations with buspirone: its effects ofanimal models of anxiety, depression and impulse control. In: Proc,. 151l7 C.I.N.P. Congress. p. 153. Puerto Rico. Stefanski. R.. Palejko. W.. Kostowski, W. and Plaznik, A. (1992a) The comparison of benzodiazepine
S-HT-interacting
drugs
393
derivatives and serotonergic agonists and antagonists in two animal models of anxiety. NeuropharmacologJ 31: 1251-1258. Stefanski, R., Plaznik, A., Palejko, W. and Kostowski, W. (1992b) The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. Pharmac. Res. 25 (Suppl.): 79980. Stefanski, R., Palejko. W., Bidzinski A., Kostowski, W. and Plaznik, A. (1993a) Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of midazolam and S-HT,, receptor agonists. Neuropharmacology 32: 9777985. Stefanski, R., Palejko, W.. Bidzinski A., Kostowski, W. and Plaznik, A. (1993b) Serotonergic innervation of the hippocampus and nucleus accumbens septi and the anxiolytic-like action of the S-HTI receptor antagonists. Neuropharmacology 32: 9877993. Stein, L., Wise. C. D. and Berger, B. D. (1973) Anti-anxiety action of benzodiazepines: decrease in activity of serotonin neurons in the punishment system. In: The Benzodiusepines, pp. 299-326, Costa, E. and Greengard, P. (eds) Raven Press. New York. Stein, L., Wise C. D., and Belluzzi, J. D. (1975) Effects of benzodiazepines on central serotonergic mechanisms. In: Mechanisms ofAction ofBenzodiazepines, pp. 29-44, Costa, E. and Greengard, P. (eds) Raven Press, New York. Stutzmann, J. M., Eon, B., Darche, F., Lucas, M., Rataud, J., Blanchard, J. C. and Laduron, P. M. (1991) Are S-HTz antagonists endowed with anxiolytic properties in rodents? Neurosci. Lett. 128: 4-8. Sudak, H. S. and Maas. J. W. (1964) Central nervous system serotonin and norepinephrine localization in emotional and non-emotional strains in mice. Nature 203: 1254-1256. Sullivan, J. W., Keim, K. L. and Sepinwall, J. (1983) A preclinical evaluation of buspirone in neuropharmacologic, EEG and anticonflict test procedures. Sot. Neurosci. Abstr. 9: 434. Sullivan, J. W., Gold, L. and Sepinwall, J. (1985) Anticonflict effects ofthree compounds having antiserotonergic activity: metergoline, mianserin, and clozapine. Sot. Neurosci. Abstr. 11: 1187. Svensson. L. (198.5) Effects of 8-OH-DPAT, lisuride and some ergot-related compounds on the acoustic startle response in the rat. Psychopharmacology 85: 469-475. Svensson, L. and Ahlenius, S. (1983) Enhancement by the putative S-HT receptor agonist 8-OH-2-(di-n-propylamino)tetralin of the acoustic startle response in the rat. Psychopharmacology 7% 104-107.
Takao. K., Nagatani, T., Kasahara, K.-I. and Hashimoto, S. (1992) Role of the central serotonergic system in the anticonflict effects of d-AP159. Pharmac. Biochem. Behav. 43: 503-508. Taylor. D. P., Eison, M. S., Riblet, L. A. and van der Maelen, C. P. (1985) Pharmacological and clinical effects of buspirone. Pharmac. Biochem. Behar:. 23: 687-694. Tenen, S. S. (1967) The effects of p-chlorophenylalanine. a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychophurmacologiu 10: 2044219. Thiebot. M.-H., Hamon. M. and Soubrie, P. (1982) Attenuation of induced-anxiety in rats by chlordiazepoxide: role of raphe dorsalis benzodiazepine binding sites and serotoninergic neurons. Neuroscience 7: 2287-2294.
Thiebot, M.-H., Hamon. M. and Soubrie. P. (1983) The involvement of nigral serotonin innervation in the control of punishment-induced behavioral inhibition in rats. Phurmac. Biochem. Behau. 19: 225-229. Thiebot. M.-H., Soubrie. P., Hamon, M. and Simon, P. (1984) Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat. Psychopharmacology 82: 355-359. Thiebot, M.-H., Dangoumau, L., Charrier. D. and Puech, A. J. (1990) Interaction ofbuspirone with ‘anxiogenic’ drugs in a safety signal withdrawal paradigm of conflict. Psychopharmacology 101:S57. Thiebot, M.-H.. Dangoumau, L., Richard, G. and Puech. A. J. (1991) Safety signal withdrawal: a behavioural paradigm sensitive to both ‘anxiolytic’ and ‘anxiogenic’ drugs under identical experimental conditions. Ps~~cllopilrrrnlucolog~ 103: 4 1S-424. Thomas. D. R., Nelson. D. R. and Johnson, A. M. (1987) Biochemical effects of the antidepressant paroxetine, a specific S-hydroxytryptamine uptake inhibitor. Psychopharmacology 93: 193-200. Tokuyama. S.. Takahashi, M. and Kaneto, H. (1993) Involvement of serotonergic receptor subtypes in the production of antinociception by psychological stress in mice. Jup. J. Pharmac. 61: 237-242. Tomkins, D. M.. Costall. B. and Kelly, M. E. (1990) Action of ritanserin and DO1 on the elevated X-maze. P~~~~~12opharnlrccolog~101:S57. Traber, J., Davies. M. A., Dompert, W. U., Glaser, T., Shuurman, T. and Seidel, P.-R. (1984) Brain serotonin receptors as a target for the putative anxiolytic TVXQ 7821. Bruin Res. Bull. 12: 741-744. Treit. D. (1985) Animal models for the study of anti-anxiety agents: a review. Neurosci. Biobehnr. Rer. 9: 2033222.
and 5-HTIA agonists: animal models. In: 5-HT,,, Agonists, Behurioural Pharmacology, pp. 107-I 32, Rodgers, R. J. and Cooper, S. J. (eds) John Wiley, Chichester. Treit, D. and Fundytus. M. (1988) A comparison of buspirone and chlordiazepoxide in the shock-probe/burying test for anxiolytics. Pharmuc. Biochem. Behar. 30: 1071~1075. Treit, D.. Robinson, A., Rotzinger, S. and Pesold, C. (1993) Anxiolytic effects of serotonergic interventions in the shock-probe burying test and the elevated plus-maze test. Behar. Bruin Res. 54: 23-34. Tye, N. C., Everitt, B. J. and Iversen, S. D. (1977) 5-Hydroxytryptamine and punishment. Nature 268: 741-743. Treit, D. (1991) Anxiolytic 5-HT,
Antngonistsnnd
effects of benzodiazepines
Ben~odiuzepines,
Their Comparative
G. Griebel
394
Tye, N. C., Iversen, S. D. and Green, A. R. (1979) The effects of benzodiazepines and serotonergic manipulations on punished responding. Neuropharmacology 18: 689-695. Tyers, M. B. (1989) A review of the evidence supporting the anxiolytic potential of 5-HT, receptor antagonists. In: Behavioural Pharmacology of5-HT, pp. 3533359, Bevan, P.. Cools, A. R. and Archer, T. (eds) Erlbaum, Hillsdale. Tyers, M. B., Costall, B., Domeney, A., Jones, B. J., Kelly, M. E., Naylor, R. J. and Oakley, N. R. (1987) The anxiolytic activities of 5HTI antagonists in laboratory animals. Neurosci. Left. 29 (Suppl.): S68. Upton, N. and Blackburn, T. P. (1991) Anxiolytic-like activity of the selective 5-HT, receptor antagonist, BRL 46470A, in the rat elevated X-maze test. Br. J. Pharmac. 102 (Suppl.): 253P. Van Dijken, H. H., Tilders, F. J. H., Olivier, B. and Mos, J. (1992) Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats. Ps_ychopharmacology
109: 395-402.
Van Praag, H. M. (1988) Serotonin disturbances in psychiatric disorders: functional versus nosological interpretation. Ado. Biol. Psychiat. 17: 52-57. Van Riezen, H., Pinder, R. M., Nickolson, V. J., Hobbelen, P., Zayed, I. and Van der Veen, F. (198 1) Mianserin. In: Pharmacological and Biochemical Properties of Drug Substances, Vol. 3, pp. 56-93, Goldberg, M. E. (ed.) American Pharmaceutical Association, Washington. Van Wijngaarden, I., Tulp, M. T. and Soudijn, W. (1990) The concept of selectivity in 5-HT receptor research. Eur. J. Pharmac.
188: 301-312.
Vasar, E., Peuranen, E., &pik, T., Harro, J. and Minnistii, P. T. (1993) Ondansetron, an antagonist of 5-HT, receptors, antagonizes the anti-exploratory effect of caerulein, an agonist of CCK receptors, in the elevated plus-maze. Psychopharmacology 110:2 13-2 18. Vivian, J. A. and Miczek, K. A. (1993) Antagonism ofdiazepam withdrawal by gepirone startle and ultrasounds. Sot. Neurosci. Abstr. 19: 756. Wada, T. and Fukada, N. (1991) Effects of DN-2327; a new anxiolytic, diazepam and buspirone on exploratory activity of the rat in an elevated plus-maze. Psychopharmacology 104: 4444450. Walters, J. K., Davis, M. and Sheard, M. H. (1979) Tryptophan-free diet: effects on the acoustic startle reflex in rats. Psychopharmacology 62: 103-l 09. Weissman, B. A., Barrett, J. E., Brady, L. S., Witkin, J. M., Mendelson, W. B., Paul, S. M. and Skolnick, P. (1984) Behavioural and neurochemical studies on the anticonflict actions of buspirone. Drug Dec. Res. 4: 83-93.
in anxiety and related disorders. In: 2nd International Symposium on and Therapeutics, p. 24, Houston, 15-18th September. Westenberg, H. G. M. and den Boer, J. A. (1988) Clinical and biochemical effects of selective serotonin-uptake inhibitors in anxiety disorders. Adv. Biol. Psychiat. 17: 84-99. Wettstein, J. G. (1988) Behavioral effects of acute and chronic buspirone. Eur. J. Pharmac. 151: 341-344. Wettstein, J. G. (1992) 5-HT, receptor ligands as potential anxiolytics. In: Central and Peripheral 5-HTj Receptors, pp. 257-274, Hamon, M. (ed.) Academic Press, London. Whitton, P. and Curzon, G. (1990) Anxiogenic-like effect ofinfusing I-(3-chlorophenyl) piperazine (mCPP) into the hippocampus. Psychopharmacology 100: 1388140. Wiley, J. L., Compton, A. D. and Porter, J. H. (1993) Effects of four antipsychotics on punished responding in rats. Pharmac. Biochem. Behav. 45: 263-267. Williams, J. H., Meara, J. R. and Azmitia, E. C. (1990) Effects of 5,7_dihydroxytryptamine injections in the fornix-fimbria on locomotor activity in photocell cages and the open field. Behac. Brain Res. 40: 37-44. Winslow, J. T. and Insel, T. R. (1991a) Infant rat separation is a sensitive test for novel anxiolytics. Prog. Neuro-Psychopharmac. biol. Psychiat. 15: 745-757. Winslow, J. T. and Insel, T. R. (1991b) Serotonergic modulation, of the rat pup ultrasonic isolation call: studies with 5HT, and 5HT2 subtype-selective agonists and antagonists. Psychopharmacology 105: 513-520. Winter, J. C. (1972) Comparison of chlordiazepoxide, methysergide, and cinanserin as modifiers of punished behavior and as antagonists of N,N-dimethyltryptamine. Arch. Int. Pharmacodyn. 197: 1477159. Wise, C. D., Berger, B. D. and Stein, L. (1972) Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain. Science 177: 180-183. Witkin, J. M. and Barrett, J. E. (1986) Interaction of buspirone and dopaminergic agents on punished behavior of pigeons. Pharmac. Biochem. Behao. 24: 751-756. Witkin, J. M. and Perez, L. A. (1989-1990) Comparison of effects of buspirone and gepirone with benzodiazepines and antagonists of dopamine and serotonin receptors on punished behavior of rats. Behav. Pharmac. 1: 247-254. Witkin, J. M., Mansbach, R. S., Barrett, J. E., Bolger. G. T., Skolnick, P. and Weissman, B. (1987) Behavioral studies with anxiolytic drugs. IV. Serotonergic involvement in the effects of buspirone on punished behavior of pigeons. J. Pharmac. exp. Ther. 243: 970-977. Wojnicki, F. H. E. and Barrett, J. E. (1993) Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response. Psychopharmacology 112: 26633. Wong, E. H. F., Wu, I., Eglen, R. M. and Whiting, R. L. (1992) Labelling of species variants of 5-hydroxytryptaminez (5-HT,) receptors by a novel 5-HTI receptor ligand [ZH]RS-42358197. Br. J. Pharmac. 105 (Suppl.): 33P. Wright, I. K., Heaton, M., Upton, N. and Marsden, C. A. (1992a) Comparison of acute and chronic treatment Westenberg,
Serotonin,
H. G. M. (1992) Serotonin
from
Cell Biology
to Pharmacology
5-HT-interacting of
various
serotonergic
Psychopharmacology
agents
with
those
of
drugs
diazepam
395 and
idazoxan
in
the
elevated
X-maze.
107: 405-414.
Wright, I. K., Upton, N. and Marsden, C. A. (1992b) Effects of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. Psychopharmacology
109: 338-346.
Yagaloff, K. A. and Hartig, P. R. (1985) [“‘I]LSD binds to a novel serotonergic site on rat choroid plexus epithelial cells. J. Neurosci. 5: 3 178-3 183. Ybema, C. E., Slangen, J. L., Olivier, B. and Mos, J. (1992) Discriminative stimulus of the serotonergic compound eltoprazine. J. Pharmac. exp. Ther. 260: 1045-1051. Young, R. and Johnson, D. N. (1988) Comparative effects of zacopride, GR 38032F. buspirone and diazepam in the mouse light/dark exploratory model. Sot. Neurosci. Abstr. 14: 207. Young, R. and Johnson, D. N. (1991a) Anxiolytic-like activity of R( +)- and S( -)-zacopride in mice. Eur. J. Pharmac.
201:
151-155.
Young, R. and Johnson, D. N. (1991b) Comparison of routes of administration and time course effects of zacopride and buspirone in mice using and automated light/dark test. Pharmac. Biochem. Behat>. 40: 733-737. Young, R. and Johnson, D. N. (1991~) A fully automated light/dark apparatus useful for comparing anxiolytic agents. Pharmac. Biochem. Behac. 40: 739-743. Young, R., Urbancic, A.. Emrey, T. A., Hall, P. C. and Metcalf. G. (1987) Behavioral effects of several new anxiolytics and putative anxiolytics. Eur. J. Pharmac. 143: 361-371. Zhang, H. T. and Luo, Z. P. (1993) Potentiating effect of clonidine on anxiolytic action of buspirone in rats. Acta pharmac.
sin. 14: 354-357.