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5-HT-1A receptor-mediated effects of antidepressants
CRITICAL REVIEWS AND THEORETICAL ARTICLES
Pmg. N-Psycfwphamuzm4. Printed
III Great
Brltatn.
& Bid All rights
Psychfat
0278
1993. Vol. 17. PP. 1-19
0 1992
reselved
5-HT-1A RECEPTOR-MEDIATED OF ANTIDEPRESSANTS MICHAEL E. NEWMAN', BERNARD LERER'
- 5846/93 Peganon
$15.00 Press
Ltd
EFFECTS
and
BARUCH SHAPIRA'
'Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah University Hospital, and 'Depression Treatment Unit, Ezrath Nashim (Herzog) Hospital, Jerusalem, Israel. (Final form, February 1992) Contents 1. 2. 3. 4. 5. 6.
Abstract Introduction Behavioral Studies in Animals Electrophysiological Studies in Animals Receptor Binding and Second Messenger Studies in Animals Human Studies and Clinical Effects of 5-HT-la Agonists Conclusions Acknowledgements References
1 2 2 4 5 12 14 14 14
Abstract Newman, Michael E., Bernard Lerer and Baruch Shapira. Receptor-Mediated Prog. Effects of Antidepressants. Psychopharmacol. & Biol. Psychiat. 1993, 17(l): l-19.
5-HT-la Neuro-
1. Antidepressant (AD) drugs in general induce subsensitivity of of 5-HT-la beavioural functions associated with activation receptors in animals. 2. Electrophysiological studies in animals in general indicate increased serotonergic transmission after AD administration, mediated partly by increased functioning of post-synaptic 5-HT-la receptors in the hippocampus. 3. Binding studies have in general shown no change in 5-HT-la receptor number either pre-or post-synaptically, while results of second messenger studies (inhibition of adenylate cyclase) indicate subsensitivity after AD administration. 4. Human studies also indicate subsensitivity of 5-HT-la receptors after ADS. Keywords: adenylate cyclase, antidepressant, receptor, serotonin
M.E.NewmanetaL
2
Abbreviations: acetylcholine (ACh), adenocorticotrophic hormone (ACTH) r antidepressant (AD), desmethylimipramine (DMI), dorsal raphe nucleus 5,7_dihydroxytryptamine (5,7-DHT), (DHN), hydroxytryptamine (HT), 8-hydroxy-(di-n-propylamino)tetralin (8OH-DPAT), electroconvulsive shock (ECS), monoamine oxidase (MAO), obsessive convulsive disorder (OCD), p-chloroamphetamine (pCA), pchloro-phenylalanine (pCPA).
1.
Evidence
Introduction
implicating 5-HT-la receptors in the pathophysiology
of depression and mechanism of action of antidepressant
(AD) drugs
has been obtained from a variety of sources, including biochemical, behavioural and electrophysiological studies in animals and, to a lesser extent, human studies involving strategies such as hormone challenge
tests
antidepressants.
in
patients
before
and
after
treatment
with
These various approaches have not always yielded
comparable results and in some cases opposite conclusions have been reached. The purpose of this review is to examine data obtained on the functioning of 5-HT-la receptors using each of these approaches and to attempt to identify ways in which these apparent contradictions
could be resolved.
2.
Behavioral Studies in Animals
Interest in the 5-HT-la receptor as a possible mediator of AD action was boosted by the findings of Goodwin et al. (1985) of a reduction
in the hypothermic effect of the 5-HT-la agonist 8-OH-
DPAT in mice after a wide range of AD treatments. These included the tricyclics amitriptyline and desipramine (DMI), the 5-HT uptake blockers
zimelidine
tranylcypromine,
and
mianserin,
the
HA0
inhibitor
and electroconvulsive shock (ECS). The effect of
ECS was striking in that it persisted for up to 24 days after the last of a series of shocks given over 10 days. The effect of ECS to induce subsensitivity
of the hypothermic response
contrasted
with its actions on 5-HT-2 receptors, where ECS has been shown to increase receptor number and function while these parameters are generally decreased by ADS (Kellar et al., 1981). Further studies
5-I-IT-1A
3
receptorsandantidepressants
from the same laboratory showed that in mice administration of Li for 14 days also resulted in attenuation of the hypothermic effect of 8-OH-DPAT, while in rats a similar effect was obtained after chronic administration of DMI, zimelidine or tranylcypromine, and also after chronic ECS. Another group (Wozniak et al., 1988) also showed reduced hypothermia in rats in response to 8-OH-DPAT after chronic administration
of the MAO inhibitor clorgyline,
after DMI or clomipramine.
In another recent report
al., 1991), reduction in hypothermia
but not
(Hensler et
in rats was obtained after
chronic administration of the MAO inhibitors clorgyline, phenelzine and tranylcypromine, and after the 5-HT uptake blockers sertraline and citalopram, but not after DMI or trazadone. The serotonergic syndrome
induced by 8-OH-DPAT in the rat, consisting of forepaw
treading, flat posture and other manifestations, was also reduced following
a
variety
of
ADS
including
ECS,
but
was
increased
following Li (reviewed by Goodwin, 1989). Another
line of evidence implicating the 5-HT-la receptor in
AD action derives from studies of the behavioral effects of 5-HTla agonists. buspirone
An
and
"AD-like" action of 8-OH-DPAT
and
ipsapirone to reduce stress-induced
its analogs decreases
in
locomotor activity and increases in defaecation in rats was shown after both single and repeated administration of these agents by Kennett et al (1987 a,b). Both single and repeated administration of 5-HT-la agonists also resulted in attenuation of the hypothermic and hyperphagic responses to 8-OH-DPAT administered the next day, as well as impairment of the 8-OH-DPAT -induced reduction in raphe 5-HIAA levels (Kennett et al., 1987b, Beer et al., 1990, Larsson et al., 1990). 5-HT-la agonists also showed activity in experiments using two other animal models of depression, the forced swim test and the learned helplessness paradigm
(Cervo and Samanin,
1987;
Wieland and Lucki, 1990, Martin et al., 1990, 1991). In
order
behavioural messengers
to
relate
effects
observed
with
these
various
tests to the studies on receptor binding and second discussed below, some understanding of the anatomical
4
M.E.Newman et&
basis
of
these
paradigms
is
necessary.
The
location
of
the
hypothermic effect induced by 5-HT-la agonists has now been shown to differ between rats and mice (Bill et al., 1991). In mice the response is attenuated by lesioning of central 5-HT neurones with the neurotoxin 5,7_dihydroxytryptamine 5-HT synthesis
(5,7-DHT) or by use of the
inhibitor p-chlorophenylalanine
(pCPA), while
in
rats these treatments do not affect the response. The hypothermia thus appears to be mediated by presynaptic autoreceptors, located in the raphe nuclei, in the mouse, and by postsynaptic receptors in the rat. The situation regarding the "AD-like" effects of 5-HTla agonists is still confusing. Cervo and Samanin (1987) found the effect of 8-OH-DPAT, given in three doses over a 24-hour period, in the forced swim test to be blocked by 5,7-DHT, indicating a presynaptic
action.
Similarly,
buspirone
and
8-OH-DPAT
reduced
immobility time in the open field only when given into the dorsal raphe nucleus showed
pCPA
(Cervo et al., 1988). Beer et al. (1990) similarly to
prevent
the
reversal
of
stress-induced
the
locomotion deficit caused by 8-OH-DPAT. However, Wieland and Lucki (1990) found that pCPA did not reduce the immobility time in the forced swim test and did not affect the reduction caused by 8-OHDPAT, while Martin et al. (1990, 1991) found that the actions of buspirone and 8-OH-DPAT to reverse helpless behaviour induced by chronic inescapable footshocks were still observed when 5,7-DHT was injected
into the
helpless
behaviour
raphe nuclei. These was
reversed
agonists by microinjection nucleus.
Further
data
by
authors
also
administration
found of
that
5-HT-la
into the septum but not into the raphe
supporting
a post-synaptic
location
was
provided by Chojnacka-Wojcik et al (1991), who found no effect of either pCPA or the serotonergic neurotoxin p-chloroamphetamine
on
the anti-immobility effect of a single dose of gepirone. 3. A
large
ElectroDhvsioloaical Studies in Animals body
(reviewed by Blier
of
work
et al.,
from
the
laboratory
1990) has provided
of
de
Montigny
a comprehensive
analysis of the effects of ADS on serotonergic transmission, based
5
5-HT-1Areceptorsand antidepressants
both on measurements
of the firing rate of 5-HT neurons
in the
dorsal raphe, and on the effects of electrical stimulation of the 5-HT pathway on the firing activity of postsynaptic neurons in the hippocampus. pyramidal
The
postsynaptic
receptors
on
the
hippocampal
neurons which mediate changes in the firing rate have
been shown to be of the 5-HT-la type. This work has led to the conclusion that all classes of AD treatment enhance serotonergic transmission,
but do so in different ways. Tricyclic ADS and ECS
have no presynaptic effects but sensitize postsynaptic neurons to 5-HT, while MAO inhibitors enhance the availability of releasable 5-HT,
and
5-HT
uptake
blockers
increase
the
efficacy
of
5-HT
neurons by desensitizing 5-HT autoreceptors located presynaptically on the nerve terminals. The actions of 5-HT-la agonists and Li can also be encompassed by this scheme. Like 5-HT uptake blockers, the agonists
desensitize
presynaptic
receptors
thus
leading
to
an
increase in the tonic activation of postsynaptic 5-HT-la receptors. The effect of Li
to enhance 5-HT transmission has been shown both
by the electrophysiological
experiments of de Montigny
(Blier et
al., 1987) and by direct measurements of 5-HT release, where Li has been shown to inhibit autoreceptor activity 1988,
Wang
and
Friedman,
1988).
This
(Hotta and Yamawaki,
action
of
Li
is
thus
consistent with its behavioural effect in the rat, namely increased manifestation
of
the
postsynaptically
mediated
serotonergic
syndrome, while the electrophysiological effects of ADS and ECS are not consistent with their effects on the postsynaptically mediated hypothermic and behavioural effects in the rat. It should be noted, however, that results from another group (Rowan and Anwyl, 1985), have shown a change in the opposite direction, namely a reduction in postsynaptic neuronal responsiveness to 5-HT in the hippocampal slice preparation of the rat after chronic administration of either imipramine or DMI. 4. Recewtor Bindins and Second Messenger Studies in Animals The electrophysiological and behavioralresults
discussed above
are only partly consistent with the results of receptor binding
M.E.NewmanetaL.
studies
shown
in
Tables
1
and
2.
Thus,
the
tricyclic
AD
amitriptyline increased 5-HT-la receptor number in the hippocampus (Welner et al., 1989), while having no effect in raphe nucleus, while both the selective 5-HT uptake blocker fluoxetine and the 5HT-la agonist gepirone had no effect on postsynaptic binding but reduced
the number of 5-HT-la receptors in the dorsal raphe. A
similar reduction in dorsal raphe binding was shown by Beer et al. (1990)
after
administration
a
single
dose
of buspirone
of
8-OH-DPAT,
and
after
chronic
(Gobbi et al., 1991). However,
the
results of Hensler et al. (1991), who found no effects of any of a range of ADS on binding in any brain area, and Schechter et al. (1990) who similarly found no effects with ipsapirone, are
5-HT
5-Hr
n 1 5-HT-1 A
5-HT
ACh
’
8 -HT-1 A
Fig. 1. Diagrammatic representation of 5-HT-la receptor-G proteineffector complex. Gs = G protein stimulatory to adenylate cyclase, Gi = G protein inhibitory to adenylate cyclase, Go= G protein linked to K+ channels or phospholipase C sensitive to pertussis toxin, Gq = G protein linked to phospholipase C insensitive to pertussis toxin, PLC = phospholipase C, AC = adenylate cyclase, ACh = acetylcholine.
5-I-IT-1A
receptorsandantidepressants
Table 1 Effects of Chronic Antidepressant Treatment on 5-HT-1A Receptor Number and Function in Rat Brain TREATMENT
Imipramine DMI
ECS
Clorqyline
DOSE
AUTHORS
20 mq/kq 15 mqlkq
Mizuta 1988 Newman 1991
lo 10 15 8
Newman 1990 Pandey 1991 Varrault 1991 Lund 1992
mqlkq mq/kq mqlkq mq/kq
Xl0 x14 x10 x10
Newman 1988 Pandey 1991 Varrault 1991 Nowak 1991
1 mqlkq II 8,
Sleight 1988 Hensler 1991 Varrault 1991
Amitriptyline
3H-8-OH-DPAT BINDING CYCLASE Cortex Hip DRN (Hippocampus)
49
.L 0
.L
0 0
L
0
1
0
I ,&
0 & .I
T L 0
0
0
L
lOmq/kq Welner 1989
t
Q
0
4
10 mq/kq II 15 mqlkq
Welner 1989 Varrault 1991 Newman 1992
2 meq/kq 0.1% 0.2%
Mizuta 1988 Odaqaki 1990 Newman 1990
0 0 0
.L
Citalopram
20 mq/kq
Hensler 1991
0
0
0
Sertraline
5 mq/kq
Hensler 1991
0
0
0
Phenelzine
5 mq/kq
Hensler 1991
0
0
0
Tranylcypromine
5 mqlkq II
Sleight 1988 Hensler 1991
0
0
0
Seleqiline
1 mq/kq
Sleight 1988
0
Fluoxetine
Lithium
0 .L
A
.L
L
Maprotiline
15 mq/kq
Newman 1992
J
Iprindole
15 mq/kq
Newman 1992
0
8
M.E.Newman etal.
Table 2 Effects of Administration of 5-HT-1A Agonists on 5-HT-1A Receptor Number and Function in Rat Brain TREATMENT 8-OH-DPAT
DOSE 1 1 1 4 1
mg/kg mgfkg mg/kg mgfkg mg/kg
AUTHORS xl x7 xl xl x8
3H-8-OH-DPAT BINDING CYCLASE Cortex Hip DRN (Hip)
Beer 1990 Larsson 1990 Newman 1992 II II
0
0
0
0
-L 0 :
Gepirone
10 mg/kg 3wk
Weiner 1989
Ipsapirone
5 mgfkg 2wk 10 mg/kg 3wk II Xl II x8
Schechter 1990 Varrault 1991 Newman 1992 II
Buspirone
10 mg/kg 3wk 4 mg/kg xl 8 mg/kg xl II X8
Gobbi 1991 Newman 1992 11 II
0
L
0
0
0
0
0
0 0 0 .L
J :
5
SALINE IPSAPIRONE
n
.
96
60 O
-9
-6 [
-7
-6
-5
5 - HT I, log M
Fig. 2. Effects of repeated daily injections of buspirone (4 mglkg), 8-OH-DPAT (1 mg/kg) and ipsapirone (10 mg/kg) for 8 days on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean of 6 observations. Post-hoc t tests showed significant effects of buspirone (p = 0.047), ipsapirone (p = 0.03) and 8-OH-DPAT (p = 0.02).
5-I-IT-1A
receptorsand antidepressants n
SALINE
l
ZIMELIDINE
.
MAPROTILINE
a5
a0
75
0
-9
-a [
5-HT
-7
-6
-5
I. log M
Fig. 3. Effects of chronic administration of zimelidine and maprotiline at 15 mg/kg daily for 3 weeks on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean + SEN. of at least 4 observations. Two-way analysis of variance showed an overall effect of treatment (p -C 0.002) and post-hoc t tests gave p = 0.001 for maprotiline and p < 0.001 for zimelidine.
100 A-_
“.&_-__-r---
--t
n
SALINE
l
IPRINDOLE
0
FLUOXETINE
\ . \ \
95
MIANSERIN \
\
90
a5
a0
751 0
-9
-a [
5-HT
-7
-6
-5
I, log M
Fig. 4. Effects of chronic administration of fluoxetine, iprindole and mianserin at 15 mg/kg daily for 3 weeks on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean of 10 observations. Two-way analysis of variance showed an overail effect of treatment (p = 0.015) and post hoc t tests showed a significant effect of fluoxetine ( p = 0.007).
9
10
M.E.Newman etal.
inconsistent
the
with
electrophysiological
work.
Conflicting
results have been obtained for the actions of imipramine and Li on 5-HT-la receptor binding. While Mizuta and Segawa (1988) found a reduction
in hippocampal
binding after both imipramine
and Li,
these findings could not be replicated in our laboratory et al.,
1990, 1991a). We similarly found no effects
(Newman
of DMI on
hippocampal binding, a finding confirmed by Pandey et al. (1991), although these authors did report a reduction in cortical binding. The latter finding was confirmed by Lund et al. (1992), who gave DMI to rats via drinking water. Conflicting results for the effects of chronic ECS on cortical binding have also been obtained, with both an increase (Nowak and Dulinski, 1991) and a decrease (Pandey et al., 1991) having been reported. Several second messenger systems have been proposed to be coupled to 5-HT-la receptors, and these are illustrated in Fig 1. The most widely characterised is inhibition of adenylate cyclase (de Vivo and Maayani, 1986), which has mainly been studied using forskolin as an activating agent for the enzyme but can also be measured by the use of Ca'* as activator (Mork and Geisler, 1990). Using this system, work from our laboratory and others (Newman and Lerer, 1988; Sleight et al., 1988; Newman et al., 1990, 1991a; Mork and Geisler, 1989; Varrault et al., 1991), has shown subsensitivity of the 5-HT-la response after ECS, DMI, imipramine, Li and MAO inhibitors.
This
work
receptor
agonists
repeated
administration
and
has
recently
5-HT uptake of
been
extended Fig
blockers.
8-OH-DPAT,
buspirone
to
2
5-HT-la
shows
or
that
ipsapirone
reduced the degree of inhibition of forskolin-stimulated adenylate cyclase
obtained
administration
with
of
the
5-HT, drugs.
an
action
not
Similarly,
seen
the
after
uptake
single
blockers
fluoxetine, zimelidine and maprotiline reduced activity, although no effect was seen with either mianserin or iprindole (Fig 3, 4). It should be noted that, despite our earlier suggestion (Newman et cyclase situated al., 1990) that the adenylate may be presynaptically
on
nerve
terminals
in the
hippocampus,
recent
evidence has conclusively demonstrated a postsynaptic site for this
11
5-HT-1Areceptorsandantidepressants
enzyme (Hamon et al., 1990; Yocca and Maayani, 1990; Newman et al. 1991a). This subsensitivity of the cyclase after AD administration is thus
in agreement with the reduction
behavioural increased
effects
seen
in
the
rat,
sensitivity
postsynaptic
in the hypothermic but
of
contrasts
and
with
the
neurons
hippocampal
demonstrated electrophysiologically. The lack of concordance between the results of receptor binding and second messenger
experiments
suggests the possibility
of a
"post-receptor" effect of the AD treatments, possibly an action at the G protein level. Direct measurement of G proteins by the use of
3H-GTP
binding
(Avissar
pertussis
toxin-induced
Hsaio
al.,
et
1992)
et
al.,
1988),
ADP-ribosylation
or
assays
using
cholera
toxin
or
(Kawamoto et al, 1991, antibodies
specific
for
particular G protein sub-units (Lesch et al., 1991a, Colin et al., 1991) have shown effects of Li at this level. Two explanations for the lack of agreement between the majority of the electrophysiological results
of
adenylate
experiments discussed
cyclase
experiments
can
above and the
be
put
forward.
Firstly, 5-HT-la receptors are also coupled to K+ channels (Andrade et
al.,
1986),
hippocampal
and
these
may
mediate
the
effects
of
5-HT
on
neuron electrical activity. Secondly, a recent study
(Sijbesma et al., 1991) showed that i.p. injection of 8-OH-DPAT increased rather than decreased hippocampal cyclic AMP levels as measured
by
microdialysis.
If
the
in vivo
effect
of
5-HT-la
receptor stimulation is mediated by increased cyclic AMP levels, an AD-induced
decrease in the degree of inhibition of adenylate
cyclase
lead to an increased signal at the post-synaptic
would
level. Stimulation of adenylate cyclase by 5-HT in the hippocampus has indeed been described
(Barbaccia et al., 1983), and has been
shown to be mediated by 5-HT-la receptors (Markstein et al., 1986; Shenker et al., 1987;
De Vivo and Maayani, 1990). Furthermore,
Hotta and Yamawaki (1986) showed that the stimulatory effect of 5HT on hippocampal chronic
adenylate cyclase activity was potentiated
Li administration.
Although
by
it is not clear under what
12
M. E.Newman etal
circumstances activation of 5-HT-la receptors leads to stimulation or to inhibition of adenylate cyclase, measurements unit
activity
treatments
have
shown
reductions
after
a
of Gi-alpha
variety
of
AD
(Lesch et al., 1991b). These reductions are consistent
with the reduced inhibitions of cyclase seen in our experiments. Further
experiments
will be necessary to show whether
both the
stimulatory and inhibitory pathways are functional in vivo or not, and what the relationship between them is. It should also be noted that another second messenger
system
coupled to 5-HT-la receptors has recently been described. Claustre et al.
(1988, 1991) showed 8-OH-DPAT to selectively
carbachol-induced hippocampal studies
on
preliminary
slices AD
inhibit the
increase in inositol phosphate (IP) formation in from
effects
immature on
this
rats.
Although
process
have
no
been
extensive published,
results from our laboratory showed abolition of this
effect after chronic Li administration (Newman et al., 1991b). This effect
of
adenylate
Li
was
cyclase
thus
in accordance
with
its
system. The negative coupling
action
on
the
of the 5-HT-la
receptor to the phosphatidylinositol hydrolysis system appears to be mediated by a G protein different from that involved either in inhibition of adenylate cyclase or opening of K* channels, since both
these
actions
are
blocked
inhibition of carbachol-stimulated
by
pertussis
toxin,
IP formation is not
whereas (Claustre
et al., 1991). If the effect of ADS and Li on the 5-HT-la system does not take place at the receptor level, as suggested
by the
general lack of effect of these treatments on receptor number, it would thus appear necessary to postulate actions of ADS and Li on several different G proteins in order to account for the multiple effects seen at the functional level. 5. Human Studies and Clinical Effects of 5-HT-la Asonists Although the 5-HT-la agonists buspirone, ipsapirone and gepirone were
initially
marketed
as
anxiolytic
agents,
recent
results
involving both open trials (Schweitzer et al., 1986; Amsterdam et
13
5-I-IT-1AreceptorsandanUdepressants
al.,
1987) and controlled
clinical trials
(Kurtz et al.,
1990;
Robinson et al., 1990) have shown them to have AD-like effects. One apparent
relates
problem
substances
to
the
administered.
are
time
The
period
studies
for
of
which
Kennett
these et
al.
(1987a,b) implied that single administration of 5-HT-la agonists to rats was enough to produce an AD-like effect in an animal model of
depression,
while
other
authors
(Cervo and
Samanin,
1987;
Wieland and Lucki, 1990) used three doses only given over a 24-hour period.
These findings would appear to contradict the need for
chronic administration in order to observe an AD effect in humans, although
a rapid onset of the clinical effect of ipsapirone
in
neurotic depressive patients, with a significant effect at 3 days, has been observed
(Spencer et al., 1990). Beer et al. (1990) have
suggested that this apparent discrepancy may result from the doses administered to rats being much higher than those used clinically. Our experiments on subsensitivity of 5-HT-mediated
inhibition of
adenylate cyclase (Fig 2) showed an effect of 5-HT-la agonists only after 7 days administration, although with a high dose of buspirone (8 mg/kg) an effect was observed after a single dose. There have been few studies on the actions of 5-HT-la agonists on biochemical and physiological parameters in humans. Lesch et al. (1990) showed a reduction in the hypothermic response to ipsapirone in depressed patients after treatment with amitriptyline, a finding complementary to those obtained in rodents discussed above. Another parameter studied by the same group is the neuroendocrine challenge test
in which
the
adrenocorticotrophic
ability hormone
of
ipsapirone
to
induce
release
of
(ACTH) and cortisol is measured.
In
patients with obsessive-compulsive disorder (OCD), subsensitivity of both the hypothermia and hormone release induced by ipsapirone was observed during chronic treatment with the 5-HT uptake blocker fluoxetine
(Lesch
et
al.,
1991c).
There
was
no
significant
correlation between the degree of subsensitivity of the responses and the fluoxetine-induced
improvement in OCD symptoms. However
these results are important in that they provide a human correlate of the subsensitivity phenomenon observed in both biochemical and
M. E.Newman etal.
14
behavioural
experiments
animals
in
after
5-HT-la
agonist
administration. 6.
It is clear
Conclusions
from the above that at the present
time
it is
impossible to say that AD treatment unequivocally affects 5-HT-la receptor
function
in a single direction.
In order to obtain an
overall picture of 5-HT-la receptor function it will be necessary to
integrate
the
results
obtained
with
the
various
approaches
outlined above into a scheme which encompasses both pre- and postsynaptic
elements,
and both receptor-mediated
and post-receptor
changes. While changes in parameters such as receptor number may be adaptive responses and secondary to, for example, changes in the firing
rate
important
of
in
presynaptic
that
they
neurons,
affect
any
these response
changes
are
dependent
still on
the
functioning of postsynaptic neurons. Thus, analysis of behavioural or other physiological responses known to involve 5-HT-la receptors may provide the best means of assessing the effects of AD treatment on this
system.
This
approach
pathways,
possibly
contribute
to the neuronal
involving
is however
risky
in that
other
other
sequence
neurotransmitters, may leading to the behavioural
response. Acknowledsements The experimental
work described herein was performed
Research Laboratory, Ezrath Nashim
at the
(Herzog) Hospital, Jerusalem,
and was supported by grant MH 43873 from the National Institutes of Health, U.S.A. References AMSTERDAM, J.D, BERWISH, N., POTTER, L., and RICKELS, K. (1987) Open trial of gepirone in the treatment of major depressive disorder. Curr. Therap. Res. 41: 185-193. ANDRADE, R., MALENKA, R.L. and NICOLL, R.A. (1986) A G protein couples serotonin and GABA, receptors to the same channels
5-HT-1Areceptorsand antldepressants in hippocampus. Science 234: 1261-1265. AVISSAR, S., SCHREIBER, G., DANON, A. and BELMAKER, R.H. (1988) Lithium inhibits adrenerqic and cholinerqic increases in GTP binding in rat cortex. Nature 331: 440-442. BARBACCIA, M.L., BRUNELLO, N., CHUANG, D.-M. and COSTA, E. (1983) Serotonin-elicited amplification of adenylate cyclase activity in hippocampal membranes from adult rat. J. Neurochem. 40: 1671-1679. BEER, M., KENNETT, G.A. and CURZON, G. (1990) A single dose of 8 -OH-DPAT reduces raphe binding of (3H]8-OH-DPAT and increases the effect of raphe stimulation on 5-HT metabolism. Eur. J. Pharmacol. 178: 179-187. BILL, D.J., KNIGHT, M., FORSTER, E.A. and FLETCHER, A. (1991) Direct evidence for an important species difference in the mechanism of 8-OH-DPAT -induced hypothermia. Br. J. Pharmacol. 103: 1857-1864. BLIER, P., DE MONTIGNY, C. and CHAPUT, Y. (1987) Modifications of the serotonin system by antidepressant treatments; implications for the therapeutic response in major depression. J. Clin. Psychopharmacol. 7: 24s-35s. BLIER, P., DE MONTIGNY, C. and CHAPUT, Y. (1990) A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. J. Clin. Psychiatry 51: 14 -20. CERVO, L. and SAMANIN, R. (1987) Potential antidepressant properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin -la receptor agonist. Eur. J. Phaf-macol. 144: 223-229. CERVO, L., GRIGNASCHI, G. and SAMANIN, R. (1988) 8-hydroxy2-(di-n-propylamino)tetralin, a selective serotonin,, receptor agonist, reduces the immobility of rats in the forced swimming test by acting on the nucleus raphe dorsalis. Eur. J. Pharmacol. 158: 53-59. CHOJNACKA-WOJCIK, E., TATARCZYNSKA, E., GOLEMBIOWSKA, K. and PRZEGALINSKI, E. (1991) Involvement of 5-HT,,,receptors in the antidepressant-like activity of qepirone in the forced swimming test in rats. Neuropharmacoloqy 30: 711-717. CLAUSTRE, Y., BENAVIDES, J. and SCATTON, B. (1988) 5-HT,, receptor agonists inhibit carbachol-induced stimulation of phosphoinositide turnover in the rat hippocampus. Eur. J. Pharmacol. 149: 149-153. CLAUSTRE, Y., BENAVIDES, J. and SCATTON, B. (1991) Potential mechanisms involved in the negative coupling between serotonin 5-HT,, receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. J. Neurochem. 56: 1276-1285. COLIN, S.F., CHANG, H.-C., MOLLNER,S., PFEUFFER, T., REED, R.R. DUMAN, R.S. and NESTLER, E.R. (1991) Chronic lithium regulates the expression of adenylate cyclase and Gi-protein alpha -subunit in rat cerebral cortex. Proc. Natl. Acad. Sci. U.S.A. 88: 10634-10637. DE VIVO, M. and MAAYANI, S. (1986) Characterization of the 5 -hydroxytryptamine-la receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea-pig and rat hippocampal membranes. J. Pharmacol. exp. Ther. 238:
15
16
M. E. Newman etal. 248-253. and inhibition of DE VIVO, M. and MAAYANI, S. (1990) Stimulation adenylate cyclase by distinct 5-hydroxytryptamine receptors. Biochem. Pharmacol. 40: 1551-1558. GOBBI, M., CAVANUS, S., MIARI, A and MENNINI, T. (1991) Effect of acute and chronic administration of buspirone on serotonin and benzodiazepine receptor subtypes in the rat brain: an autoradiographic study. Neuropharmacology 30: 313-321. GOODWIN, G-M., DE SOUZA, R.J. and GREEN, A.R. (1985) Presynaptic serotonin receptor-mediated response in mice attenuated by antidepressant drugs and electroconvulsive shock. Nature 317: 531-533. treatments and GOODWIN, G.M. (1989) The effects of antidepressant lithium upon 5-HT-la receptor function. Prog. Neuro -Psychopharmacol. & Biol. Psychiat. 13: 445-451. HAMON, M., GOZLAN, H., EL MESTIKAWY, S., EMERIT, M.B., BOLANOS, F. and SCHECHTER, L. (1990) The central 5-HT-la receptors: pharmacological, biochemical, functional and regulatory properties. Ann. N.Y. Acad. Sci. 600: 114-131. HENSLER, J-G., KOVACHICH, G.B. and FRAZER, A. (1991) A quantitative autoradiographic study of serotonin,, receptor regulation. Effect of 5,7_dihydroxytryptamine and Neuropsychopharmacology 4: 131-144. antidepressant treatments. HOTTA, I. and YAMAWAKI, S. (1986) Lithium decreases 5-HT-1 receptors but increases 5-HT-sensitive adenylate cyclase activity in rat hippocampus. Biol. Psychiatry 21: 1382-1390. of HOTTA, I. and YAMAWAKI, S. (1988) Possible involvement presynaptic 5-HT autoreceptors in the effect of lithium on 5-HT release in hippocampus of rat. Neuropharmacology 27: 987-992. HSAIO, J.K., MANJI, H.K., CHEN, G., BITRAN, J.A., RISBY, E.D. and POTTER, W.Z. (1992) Lithium administration modulates platelet Gi in humans. Life Sci. 50: 227-234. KAWAMOTO,H., WATANABE,Y., IMAIZUMI, T., IWASAKI, T. and YOSHIDA, H. (1991) Effects of lithium ion on ADP-ribosylation of inhibitory GTP-binding protein by pertussis toxin, islet activating protein. Eur. J. Pharmacol. 206: 33-37. KELLAR, K.J., CASCIO, C.S., BUTLER, J.A. and KURTZE, R.N. (1981) Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain. 69: 515-518 Eur. J. Pharmacol. KENNETT, G.A., DOURISH, C.T. and CURZON, G. (1987a) Antidepressant-like action of 5-HT-la agonists and conventional antidepressants in an animal model of depression. Eur. J. Pharmacol. 134: 265-274. KENNETT, G.A., MARCOU, M., DOURISH, C.T. and CURZON, G. (1987b) Single administration of 5-HT,, agonists decreases 5-HT,, presynaptic, but not postsynaptic receptor-mediated responses: relation to antidepressant-like action. Eur.J. Pharmacol. 138: 53-60. KURTZ, N.M., KEPPEL-HESSELINK, J., BENEKE, M. and HELLER,A. (1990) Preliminary studies of 5-HT-la agonists in depression. 13: (Suppl.2) 95-96. Clin. Neuropharmacol. LARSSON, L.-G., RENYI, L., ROSS, S.B., SVENSSON, B. AND
5-HT-IA
receptorsand antidepressants
ANGEBY-MOLLER, K. (1990) Different effects on the responses of functional pre- and postsynaptic 5-HT-la receptors by repeated treatment of rats with the 5-HT-la receptor agonist 8-OH-DPAT. Neuropharmacology 29: 85-91. LESCH, K.P., DISSELKAMP-TIETZE, J. and SCHMIDTKE, A. (1990) 5-HT-la receptor function in depression: effect of chronic amitriptyline treatment. J. Neural Transm. 80: 157-161. LESCH, K.P., AULAKH, C.S., TOLLIVER, T.J., HILL, J.L., WOLOZIN,B.L. and MURPHY,D.L (1991a) Differential effects of lonq-term lithium and carbamazepine administration on G_ protein in rat brain. Eur. J. Pharmacol. D -yg,
:““,“,,“$a$$~
LESCH, K.P., AULAKH, C.S., TOLLIVER, T.J., HILL, J.L. and MURPHY,D.L (1991b) Regulation of G proteins by chronic antidepressant drug treatment in rat brain; tricyclics but not clorgyline increase Go-alpha subunits. Eur. J. Pharmacol. 207: 361-364. LESCH, K.P., HOH, A., SCHULTE, A.M., OSERHEIDER, M. and MULLER, T. (1991c) Long-term fluoxetine treatment decreases 5-HT-la receptor sensitivity in obsessive-compulsive disorder. Psychopharmacology 105: 415-4.20. LUND, A., MJELLEM-JOLY, N. and HOLE, K. (1992) Desipramine, administered chronically, influences 5_hydroxytryptamine,! receptors,as measured by behavioural treets and receptor binding in rats. Neuropharmacology 31: 25-32. MARKSTEIN, R., HOYER, D. and ENGEL,G. (1986) 5-HT,, -receptors mediate stimulation of adenylate cyclase in rat hippocampus. Naunyn-Schmiedeberg's Arch. Pharmacol. 333: 335-341. MARTIN, P., BENINGER, R.J., HAMON, M. and PUECH, A.J. (1990) Antidepressant-like action of 8-OH-DPAT, a 5-HT-la agonist, in the learned helplessness paradigm: evidence for a postsynaptic mechanism. Behav. Brain Res. 38: 135-144. MARTIN, P., TISSIER, M.-H., ADRIEN, J. and PUECH, A.J. (1991) Antidepressant-like effects of buspirone mediated by the -5-HTlA post-synaptic receptors in the learned helplessness paradigm. Life Sci. 48: 2505-2511. MIZUTA, T. and SEGAWA, T. (1988) Chronic effects of imipramine and lithium on postsynaptic 5-HT-la and 5-HT-lb sites and on presynaptic 5-HT-3 sites in rat brain. Japan J. Pharmacol. 47: 107-113. MORK, A. and GEISLER, A. (1989) Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase in rat brain. Eur. J. Pharmacol. 168: 347-354. MORK, A. and GEISLER, A. (1990) 5-hydroxytryptamine receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat. Eur. J. Pharmacol. 175: 237-244. NEWMAN, M.E. and LERER, B. (1988) Chronic electroconvulsive shock and desimipramine reduce the degree of inhibition by 5-HT and carbachol of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Eur. J. Pharmacol. 148: 257-260. NEWMAN, M.E., DRUMMER, D. and LERER, B. (1990) Single and combined effects of desimipramine and lithium on serotonergic receptor number and second messenger function in rat brain. J.
17
18
M. E. Newman
el al.
Pharmacol. exp. Ther. 252: 826-831. NEWMAN, M.E., BEN-ZEEV, A. and LERER, B. (1991a) Chloroamphetamine did not prevent the effects of chronic antidepressants on 5 -hydroxytryptamine inhibition of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Eur. J. Pharmacol. 207: 209-213. NEWMAN, M.E., SHAPIRA, B. and LERER, B. (1991b) Effects of lithium and desimipramine on second messenger responses in rat hippocampus: relation to G protein effects. Neuropharmacology, 30: 1297-1301. NEWMAN,M.E., SHAPIRA, B. and LERER, B. (1992) Regulation of 5 -hydroxytryptamine-la receptor function in rat hippocampus by of 5-hydroxytryptamine-la short- and long-term administration agonists and antidepressants. J. Pharmacol. exp. Ther. 260: 16-20. NOWAK, G. and DULINSKI, J. (1991) Effect of repeated treatment with electroconvulsive shock on serotonin receptor density and turnover in the rat cerebral cortex. Pharmacol. Biochem. Behav. 38: 691-694. R. and ODAGAKI, Y., KOYAMA, T., MATSUBARA, S., MATSUBARA, YAMASHITA, I. (1990) Effects of chronic lithium treatment on serotonin binding sites in rat brain. J. Psychiat. Res. 24: 271-277. PANDEY, S.C., ISAAC, L., DAVIS, J.M. and PANDEY, G.N. (1991) Similar effects of treatment with desipramine and electroconvulsive shock on 5_hydroxytryptamine,, receptors in rat brain. Eur. J. Pharmacol. 202: 221-225. ROBINSON, D.S., GAMMANS, R.E., SHROTIYA, R.C., JENKINS, S.W., ANDARY, J.J., ALMS, D.R. and MESSINA, M.E. (1990) Clinical effects of 5-HT-la partial agonists, buspirone and gepirone, in the treatment of depression. Clin. Neuropharmacol. 13 (suppl.2): 228-229. ROWAN, M.J.and ANWYL, R. (1985) The effect of prolonged treatment with tricyclic antidepressants on the actions of 5 -hydroxytryptamine in the hippocampal slice of the rat. Neuropharmacology 24: 131-137. SCHECHTER, L.E., BOLANOS, F.J., GOZLAN, H., LANFUMEY, L., HAJ -DAHMANE, S., LAPORTE, A.-M., FATTACCINI, C.-M. and HAMON, M. (1990) Alterations of central serotonergic and dopaminergic neurotransmission in rats chronically treated with ipsapirone; biochemical and electrophysiological studies. J. Pharmacol. exp. Ther. 255: 1335-1347. SCHWEITZER, E.E., AMSTERDAM, J.D., RICKELS, K., KAPLAN, M. and DROBA, M. (1986) Open trial of buspirone in the treatment of major depressive disorder. Psychopharmacol. Bull. 22: 183185. SHENKER, A., MAAYANI, S., WEINSTEIN, H. and GREEN, J.P. (1987) Pharmacological characterisation of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea-pig membranes. Mol. Pharmacol. 31: 357-367. hippocampal SIJBESMA, H., SCHIPPER, J., MOLEWIJK, H-E., BOSCH, A-1. and DE KLOET, E.R. (1991) B-hydroxy-2-(di-n-propylamino)tetralin increases the activity of adenylate cyclase in the hippocampus of freely-moving rats. Neuropharmacology 30: 967-975.
5-HT-IA
receptors and antidepressants
SLEIGHT, A.J., MARSDEN, C.A., PALFREYMAN, M.G., MIR, A.K. and LOVENBERG, W. (1988) Chronic MAO A and MAO B inhibition decreases the 5-HT-la receptor-mediated inhibition of forskolin -stimulated adenylate cyclase. Eur. J. Pharmacol. 154: 255-261. SPENCER, D.G.Jr., DE VRY, J., SCHREIBER, R. and TRABER, J. (1990) Pharmacology of 5-HT,, agonists. Clin. Neuropharmacol. 13 (Suppl.2): 93-94. VARRAULT, A., LEVIEL, V. and BOCKAERT, J. (1991) 5-HT,, -sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. J.Pharmacol. exp. Ther. 257: 433-438. WANG, H.-Y. and FRIEDMAN, E. (1988) Chronic lithium: desensitization of autoreceptors mediating serotonin release. Psychopharmacology 94: 312-314. WELNER, S.A., DE MONTIGNY, C., DESROCHES, J., DESJARDINS, P. and SURANYI-CADOTTE, B.E. (1989) Autoradiographic quantification of serotonin,, receptors in rat brain following antidepressant drug treatment. Synapse 4: 347-352. WIELAND, S. and LUCKI, I. (1990) Antidepressant-like activity of 5-HT-la agonists measured with the forced swim test. Psychopharmacology 101: 497-504. WOZNIAK, K.M., AULAKH, C.S., HILL, J.L. and MURPHY, D.L. (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol. Biochem. Behav. 30: 451-456. YOCCA, F.D. and MAAYANI, S. (1990) 5-HT receptors linked to adenylate cyclase activity in mammalian brain. Ann. N.Y. Acad. Sci. 600: 212-223. Inquiries and reprint requests should be sent to: Dr. Michael E. Newman Biological Psychiatry Laboratory Department of Psychiatry Hadassah-Hebrew University Medical Center P.O.B. 12000 Jerusalem 91120 Israel.
19
Pmg. N-Psycfwphamuzm4. Printed
III Great
Brltatn.
& Bid All rights
Psychfat
0278
1993. Vol. 17. PP. 1-19
0 1992
reselved
5-HT-1A RECEPTOR-MEDIATED OF ANTIDEPRESSANTS MICHAEL E. NEWMAN', BERNARD LERER'
- 5846/93 Peganon
$15.00 Press
Ltd
EFFECTS
and
BARUCH SHAPIRA'
'Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah University Hospital, and 'Depression Treatment Unit, Ezrath Nashim (Herzog) Hospital, Jerusalem, Israel. (Final form, February 1992) Contents 1. 2. 3. 4. 5. 6.
Abstract Introduction Behavioral Studies in Animals Electrophysiological Studies in Animals Receptor Binding and Second Messenger Studies in Animals Human Studies and Clinical Effects of 5-HT-la Agonists Conclusions Acknowledgements References
1 2 2 4 5 12 14 14 14
Abstract Newman, Michael E., Bernard Lerer and Baruch Shapira. Receptor-Mediated Prog. Effects of Antidepressants. Psychopharmacol. & Biol. Psychiat. 1993, 17(l): l-19.
5-HT-la Neuro-
1. Antidepressant (AD) drugs in general induce subsensitivity of of 5-HT-la beavioural functions associated with activation receptors in animals. 2. Electrophysiological studies in animals in general indicate increased serotonergic transmission after AD administration, mediated partly by increased functioning of post-synaptic 5-HT-la receptors in the hippocampus. 3. Binding studies have in general shown no change in 5-HT-la receptor number either pre-or post-synaptically, while results of second messenger studies (inhibition of adenylate cyclase) indicate subsensitivity after AD administration. 4. Human studies also indicate subsensitivity of 5-HT-la receptors after ADS. Keywords: adenylate cyclase, antidepressant, receptor, serotonin
M.E.NewmanetaL
2
Abbreviations: acetylcholine (ACh), adenocorticotrophic hormone (ACTH) r antidepressant (AD), desmethylimipramine (DMI), dorsal raphe nucleus 5,7_dihydroxytryptamine (5,7-DHT), (DHN), hydroxytryptamine (HT), 8-hydroxy-(di-n-propylamino)tetralin (8OH-DPAT), electroconvulsive shock (ECS), monoamine oxidase (MAO), obsessive convulsive disorder (OCD), p-chloroamphetamine (pCA), pchloro-phenylalanine (pCPA).
1.
Evidence
Introduction
implicating 5-HT-la receptors in the pathophysiology
of depression and mechanism of action of antidepressant
(AD) drugs
has been obtained from a variety of sources, including biochemical, behavioural and electrophysiological studies in animals and, to a lesser extent, human studies involving strategies such as hormone challenge
tests
antidepressants.
in
patients
before
and
after
treatment
with
These various approaches have not always yielded
comparable results and in some cases opposite conclusions have been reached. The purpose of this review is to examine data obtained on the functioning of 5-HT-la receptors using each of these approaches and to attempt to identify ways in which these apparent contradictions
could be resolved.
2.
Behavioral Studies in Animals
Interest in the 5-HT-la receptor as a possible mediator of AD action was boosted by the findings of Goodwin et al. (1985) of a reduction
in the hypothermic effect of the 5-HT-la agonist 8-OH-
DPAT in mice after a wide range of AD treatments. These included the tricyclics amitriptyline and desipramine (DMI), the 5-HT uptake blockers
zimelidine
tranylcypromine,
and
mianserin,
the
HA0
inhibitor
and electroconvulsive shock (ECS). The effect of
ECS was striking in that it persisted for up to 24 days after the last of a series of shocks given over 10 days. The effect of ECS to induce subsensitivity
of the hypothermic response
contrasted
with its actions on 5-HT-2 receptors, where ECS has been shown to increase receptor number and function while these parameters are generally decreased by ADS (Kellar et al., 1981). Further studies
5-I-IT-1A
3
receptorsandantidepressants
from the same laboratory showed that in mice administration of Li for 14 days also resulted in attenuation of the hypothermic effect of 8-OH-DPAT, while in rats a similar effect was obtained after chronic administration of DMI, zimelidine or tranylcypromine, and also after chronic ECS. Another group (Wozniak et al., 1988) also showed reduced hypothermia in rats in response to 8-OH-DPAT after chronic administration
of the MAO inhibitor clorgyline,
after DMI or clomipramine.
In another recent report
al., 1991), reduction in hypothermia
but not
(Hensler et
in rats was obtained after
chronic administration of the MAO inhibitors clorgyline, phenelzine and tranylcypromine, and after the 5-HT uptake blockers sertraline and citalopram, but not after DMI or trazadone. The serotonergic syndrome
induced by 8-OH-DPAT in the rat, consisting of forepaw
treading, flat posture and other manifestations, was also reduced following
a
variety
of
ADS
including
ECS,
but
was
increased
following Li (reviewed by Goodwin, 1989). Another
line of evidence implicating the 5-HT-la receptor in
AD action derives from studies of the behavioral effects of 5-HTla agonists. buspirone
An
and
"AD-like" action of 8-OH-DPAT
and
ipsapirone to reduce stress-induced
its analogs decreases
in
locomotor activity and increases in defaecation in rats was shown after both single and repeated administration of these agents by Kennett et al (1987 a,b). Both single and repeated administration of 5-HT-la agonists also resulted in attenuation of the hypothermic and hyperphagic responses to 8-OH-DPAT administered the next day, as well as impairment of the 8-OH-DPAT -induced reduction in raphe 5-HIAA levels (Kennett et al., 1987b, Beer et al., 1990, Larsson et al., 1990). 5-HT-la agonists also showed activity in experiments using two other animal models of depression, the forced swim test and the learned helplessness paradigm
(Cervo and Samanin,
1987;
Wieland and Lucki, 1990, Martin et al., 1990, 1991). In
order
behavioural messengers
to
relate
effects
observed
with
these
various
tests to the studies on receptor binding and second discussed below, some understanding of the anatomical
4
M.E.Newman et&
basis
of
these
paradigms
is
necessary.
The
location
of
the
hypothermic effect induced by 5-HT-la agonists has now been shown to differ between rats and mice (Bill et al., 1991). In mice the response is attenuated by lesioning of central 5-HT neurones with the neurotoxin 5,7_dihydroxytryptamine 5-HT synthesis
(5,7-DHT) or by use of the
inhibitor p-chlorophenylalanine
(pCPA), while
in
rats these treatments do not affect the response. The hypothermia thus appears to be mediated by presynaptic autoreceptors, located in the raphe nuclei, in the mouse, and by postsynaptic receptors in the rat. The situation regarding the "AD-like" effects of 5-HTla agonists is still confusing. Cervo and Samanin (1987) found the effect of 8-OH-DPAT, given in three doses over a 24-hour period, in the forced swim test to be blocked by 5,7-DHT, indicating a presynaptic
action.
Similarly,
buspirone
and
8-OH-DPAT
reduced
immobility time in the open field only when given into the dorsal raphe nucleus showed
pCPA
(Cervo et al., 1988). Beer et al. (1990) similarly to
prevent
the
reversal
of
stress-induced
the
locomotion deficit caused by 8-OH-DPAT. However, Wieland and Lucki (1990) found that pCPA did not reduce the immobility time in the forced swim test and did not affect the reduction caused by 8-OHDPAT, while Martin et al. (1990, 1991) found that the actions of buspirone and 8-OH-DPAT to reverse helpless behaviour induced by chronic inescapable footshocks were still observed when 5,7-DHT was injected
into the
helpless
behaviour
raphe nuclei. These was
reversed
agonists by microinjection nucleus.
Further
data
by
authors
also
administration
found of
that
5-HT-la
into the septum but not into the raphe
supporting
a post-synaptic
location
was
provided by Chojnacka-Wojcik et al (1991), who found no effect of either pCPA or the serotonergic neurotoxin p-chloroamphetamine
on
the anti-immobility effect of a single dose of gepirone. 3. A
large
ElectroDhvsioloaical Studies in Animals body
(reviewed by Blier
of
work
et al.,
from
the
laboratory
1990) has provided
of
de
Montigny
a comprehensive
analysis of the effects of ADS on serotonergic transmission, based
5
5-HT-1Areceptorsand antidepressants
both on measurements
of the firing rate of 5-HT neurons
in the
dorsal raphe, and on the effects of electrical stimulation of the 5-HT pathway on the firing activity of postsynaptic neurons in the hippocampus. pyramidal
The
postsynaptic
receptors
on
the
hippocampal
neurons which mediate changes in the firing rate have
been shown to be of the 5-HT-la type. This work has led to the conclusion that all classes of AD treatment enhance serotonergic transmission,
but do so in different ways. Tricyclic ADS and ECS
have no presynaptic effects but sensitize postsynaptic neurons to 5-HT, while MAO inhibitors enhance the availability of releasable 5-HT,
and
5-HT
uptake
blockers
increase
the
efficacy
of
5-HT
neurons by desensitizing 5-HT autoreceptors located presynaptically on the nerve terminals. The actions of 5-HT-la agonists and Li can also be encompassed by this scheme. Like 5-HT uptake blockers, the agonists
desensitize
presynaptic
receptors
thus
leading
to
an
increase in the tonic activation of postsynaptic 5-HT-la receptors. The effect of Li
to enhance 5-HT transmission has been shown both
by the electrophysiological
experiments of de Montigny
(Blier et
al., 1987) and by direct measurements of 5-HT release, where Li has been shown to inhibit autoreceptor activity 1988,
Wang
and
Friedman,
1988).
This
(Hotta and Yamawaki,
action
of
Li
is
thus
consistent with its behavioural effect in the rat, namely increased manifestation
of
the
postsynaptically
mediated
serotonergic
syndrome, while the electrophysiological effects of ADS and ECS are not consistent with their effects on the postsynaptically mediated hypothermic and behavioural effects in the rat. It should be noted, however, that results from another group (Rowan and Anwyl, 1985), have shown a change in the opposite direction, namely a reduction in postsynaptic neuronal responsiveness to 5-HT in the hippocampal slice preparation of the rat after chronic administration of either imipramine or DMI. 4. Recewtor Bindins and Second Messenger Studies in Animals The electrophysiological and behavioralresults
discussed above
are only partly consistent with the results of receptor binding
M.E.NewmanetaL.
studies
shown
in
Tables
1
and
2.
Thus,
the
tricyclic
AD
amitriptyline increased 5-HT-la receptor number in the hippocampus (Welner et al., 1989), while having no effect in raphe nucleus, while both the selective 5-HT uptake blocker fluoxetine and the 5HT-la agonist gepirone had no effect on postsynaptic binding but reduced
the number of 5-HT-la receptors in the dorsal raphe. A
similar reduction in dorsal raphe binding was shown by Beer et al. (1990)
after
administration
a
single
dose
of buspirone
of
8-OH-DPAT,
and
after
chronic
(Gobbi et al., 1991). However,
the
results of Hensler et al. (1991), who found no effects of any of a range of ADS on binding in any brain area, and Schechter et al. (1990) who similarly found no effects with ipsapirone, are
5-HT
5-Hr
n 1 5-HT-1 A
5-HT
ACh
’
8 -HT-1 A
Fig. 1. Diagrammatic representation of 5-HT-la receptor-G proteineffector complex. Gs = G protein stimulatory to adenylate cyclase, Gi = G protein inhibitory to adenylate cyclase, Go= G protein linked to K+ channels or phospholipase C sensitive to pertussis toxin, Gq = G protein linked to phospholipase C insensitive to pertussis toxin, PLC = phospholipase C, AC = adenylate cyclase, ACh = acetylcholine.
5-I-IT-1A
receptorsandantidepressants
Table 1 Effects of Chronic Antidepressant Treatment on 5-HT-1A Receptor Number and Function in Rat Brain TREATMENT
Imipramine DMI
ECS
Clorqyline
DOSE
AUTHORS
20 mq/kq 15 mqlkq
Mizuta 1988 Newman 1991
lo 10 15 8
Newman 1990 Pandey 1991 Varrault 1991 Lund 1992
mqlkq mq/kq mqlkq mq/kq
Xl0 x14 x10 x10
Newman 1988 Pandey 1991 Varrault 1991 Nowak 1991
1 mqlkq II 8,
Sleight 1988 Hensler 1991 Varrault 1991
Amitriptyline
3H-8-OH-DPAT BINDING CYCLASE Cortex Hip DRN (Hippocampus)
49
.L 0
.L
0 0
L
0
1
0
I ,&
0 & .I
T L 0
0
0
L
lOmq/kq Welner 1989
t
Q
0
4
10 mq/kq II 15 mqlkq
Welner 1989 Varrault 1991 Newman 1992
2 meq/kq 0.1% 0.2%
Mizuta 1988 Odaqaki 1990 Newman 1990
0 0 0
.L
Citalopram
20 mq/kq
Hensler 1991
0
0
0
Sertraline
5 mq/kq
Hensler 1991
0
0
0
Phenelzine
5 mq/kq
Hensler 1991
0
0
0
Tranylcypromine
5 mqlkq II
Sleight 1988 Hensler 1991
0
0
0
Seleqiline
1 mq/kq
Sleight 1988
0
Fluoxetine
Lithium
0 .L
A
.L
L
Maprotiline
15 mq/kq
Newman 1992
J
Iprindole
15 mq/kq
Newman 1992
0
8
M.E.Newman etal.
Table 2 Effects of Administration of 5-HT-1A Agonists on 5-HT-1A Receptor Number and Function in Rat Brain TREATMENT 8-OH-DPAT
DOSE 1 1 1 4 1
mg/kg mgfkg mg/kg mgfkg mg/kg
AUTHORS xl x7 xl xl x8
3H-8-OH-DPAT BINDING CYCLASE Cortex Hip DRN (Hip)
Beer 1990 Larsson 1990 Newman 1992 II II
0
0
0
0
-L 0 :
Gepirone
10 mg/kg 3wk
Weiner 1989
Ipsapirone
5 mgfkg 2wk 10 mg/kg 3wk II Xl II x8
Schechter 1990 Varrault 1991 Newman 1992 II
Buspirone
10 mg/kg 3wk 4 mg/kg xl 8 mg/kg xl II X8
Gobbi 1991 Newman 1992 11 II
0
L
0
0
0
0
0
0 0 0 .L
J :
5
SALINE IPSAPIRONE
n
.
96
60 O
-9
-6 [
-7
-6
-5
5 - HT I, log M
Fig. 2. Effects of repeated daily injections of buspirone (4 mglkg), 8-OH-DPAT (1 mg/kg) and ipsapirone (10 mg/kg) for 8 days on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean of 6 observations. Post-hoc t tests showed significant effects of buspirone (p = 0.047), ipsapirone (p = 0.03) and 8-OH-DPAT (p = 0.02).
5-I-IT-1A
receptorsand antidepressants n
SALINE
l
ZIMELIDINE
.
MAPROTILINE
a5
a0
75
0
-9
-a [
5-HT
-7
-6
-5
I. log M
Fig. 3. Effects of chronic administration of zimelidine and maprotiline at 15 mg/kg daily for 3 weeks on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean + SEN. of at least 4 observations. Two-way analysis of variance showed an overall effect of treatment (p -C 0.002) and post-hoc t tests gave p = 0.001 for maprotiline and p < 0.001 for zimelidine.
100 A-_
“.&_-__-r---
--t
n
SALINE
l
IPRINDOLE
0
FLUOXETINE
\ . \ \
95
MIANSERIN \
\
90
a5
a0
751 0
-9
-a [
5-HT
-7
-6
-5
I, log M
Fig. 4. Effects of chronic administration of fluoxetine, iprindole and mianserin at 15 mg/kg daily for 3 weeks on 5-HT inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes. Each point represents the mean of 10 observations. Two-way analysis of variance showed an overail effect of treatment (p = 0.015) and post hoc t tests showed a significant effect of fluoxetine ( p = 0.007).
9
10
M.E.Newman etal.
inconsistent
the
with
electrophysiological
work.
Conflicting
results have been obtained for the actions of imipramine and Li on 5-HT-la receptor binding. While Mizuta and Segawa (1988) found a reduction
in hippocampal
binding after both imipramine
and Li,
these findings could not be replicated in our laboratory et al.,
1990, 1991a). We similarly found no effects
(Newman
of DMI on
hippocampal binding, a finding confirmed by Pandey et al. (1991), although these authors did report a reduction in cortical binding. The latter finding was confirmed by Lund et al. (1992), who gave DMI to rats via drinking water. Conflicting results for the effects of chronic ECS on cortical binding have also been obtained, with both an increase (Nowak and Dulinski, 1991) and a decrease (Pandey et al., 1991) having been reported. Several second messenger systems have been proposed to be coupled to 5-HT-la receptors, and these are illustrated in Fig 1. The most widely characterised is inhibition of adenylate cyclase (de Vivo and Maayani, 1986), which has mainly been studied using forskolin as an activating agent for the enzyme but can also be measured by the use of Ca'* as activator (Mork and Geisler, 1990). Using this system, work from our laboratory and others (Newman and Lerer, 1988; Sleight et al., 1988; Newman et al., 1990, 1991a; Mork and Geisler, 1989; Varrault et al., 1991), has shown subsensitivity of the 5-HT-la response after ECS, DMI, imipramine, Li and MAO inhibitors.
This
work
receptor
agonists
repeated
administration
and
has
recently
5-HT uptake of
been
extended Fig
blockers.
8-OH-DPAT,
buspirone
to
2
5-HT-la
shows
or
that
ipsapirone
reduced the degree of inhibition of forskolin-stimulated adenylate cyclase
obtained
administration
with
of
the
5-HT, drugs.
an
action
not
Similarly,
seen
the
after
uptake
single
blockers
fluoxetine, zimelidine and maprotiline reduced activity, although no effect was seen with either mianserin or iprindole (Fig 3, 4). It should be noted that, despite our earlier suggestion (Newman et cyclase situated al., 1990) that the adenylate may be presynaptically
on
nerve
terminals
in the
hippocampus,
recent
evidence has conclusively demonstrated a postsynaptic site for this
11
5-HT-1Areceptorsandantidepressants
enzyme (Hamon et al., 1990; Yocca and Maayani, 1990; Newman et al. 1991a). This subsensitivity of the cyclase after AD administration is thus
in agreement with the reduction
behavioural increased
effects
seen
in
the
rat,
sensitivity
postsynaptic
in the hypothermic but
of
contrasts
and
with
the
neurons
hippocampal
demonstrated electrophysiologically. The lack of concordance between the results of receptor binding and second messenger
experiments
suggests the possibility
of a
"post-receptor" effect of the AD treatments, possibly an action at the G protein level. Direct measurement of G proteins by the use of
3H-GTP
binding
(Avissar
pertussis
toxin-induced
Hsaio
al.,
et
1992)
et
al.,
1988),
ADP-ribosylation
or
assays
using
cholera
toxin
or
(Kawamoto et al, 1991, antibodies
specific
for
particular G protein sub-units (Lesch et al., 1991a, Colin et al., 1991) have shown effects of Li at this level. Two explanations for the lack of agreement between the majority of the electrophysiological results
of
adenylate
experiments discussed
cyclase
experiments
can
above and the
be
put
forward.
Firstly, 5-HT-la receptors are also coupled to K+ channels (Andrade et
al.,
1986),
hippocampal
and
these
may
mediate
the
effects
of
5-HT
on
neuron electrical activity. Secondly, a recent study
(Sijbesma et al., 1991) showed that i.p. injection of 8-OH-DPAT increased rather than decreased hippocampal cyclic AMP levels as measured
by
microdialysis.
If
the
in vivo
effect
of
5-HT-la
receptor stimulation is mediated by increased cyclic AMP levels, an AD-induced
decrease in the degree of inhibition of adenylate
cyclase
lead to an increased signal at the post-synaptic
would
level. Stimulation of adenylate cyclase by 5-HT in the hippocampus has indeed been described
(Barbaccia et al., 1983), and has been
shown to be mediated by 5-HT-la receptors (Markstein et al., 1986; Shenker et al., 1987;
De Vivo and Maayani, 1990). Furthermore,
Hotta and Yamawaki (1986) showed that the stimulatory effect of 5HT on hippocampal chronic
adenylate cyclase activity was potentiated
Li administration.
Although
by
it is not clear under what
12
M. E.Newman etal
circumstances activation of 5-HT-la receptors leads to stimulation or to inhibition of adenylate cyclase, measurements unit
activity
treatments
have
shown
reductions
after
a
of Gi-alpha
variety
of
AD
(Lesch et al., 1991b). These reductions are consistent
with the reduced inhibitions of cyclase seen in our experiments. Further
experiments
will be necessary to show whether
both the
stimulatory and inhibitory pathways are functional in vivo or not, and what the relationship between them is. It should also be noted that another second messenger
system
coupled to 5-HT-la receptors has recently been described. Claustre et al.
(1988, 1991) showed 8-OH-DPAT to selectively
carbachol-induced hippocampal studies
on
preliminary
slices AD
inhibit the
increase in inositol phosphate (IP) formation in from
effects
immature on
this
rats.
Although
process
have
no
been
extensive published,
results from our laboratory showed abolition of this
effect after chronic Li administration (Newman et al., 1991b). This effect
of
adenylate
Li
was
cyclase
thus
in accordance
with
its
system. The negative coupling
action
on
the
of the 5-HT-la
receptor to the phosphatidylinositol hydrolysis system appears to be mediated by a G protein different from that involved either in inhibition of adenylate cyclase or opening of K* channels, since both
these
actions
are
blocked
inhibition of carbachol-stimulated
by
pertussis
toxin,
IP formation is not
whereas (Claustre
et al., 1991). If the effect of ADS and Li on the 5-HT-la system does not take place at the receptor level, as suggested
by the
general lack of effect of these treatments on receptor number, it would thus appear necessary to postulate actions of ADS and Li on several different G proteins in order to account for the multiple effects seen at the functional level. 5. Human Studies and Clinical Effects of 5-HT-la Asonists Although the 5-HT-la agonists buspirone, ipsapirone and gepirone were
initially
marketed
as
anxiolytic
agents,
recent
results
involving both open trials (Schweitzer et al., 1986; Amsterdam et
13
5-I-IT-1AreceptorsandanUdepressants
al.,
1987) and controlled
clinical trials
(Kurtz et al.,
1990;
Robinson et al., 1990) have shown them to have AD-like effects. One apparent
relates
problem
substances
to
the
administered.
are
time
The
period
studies
for
of
which
Kennett
these et
al.
(1987a,b) implied that single administration of 5-HT-la agonists to rats was enough to produce an AD-like effect in an animal model of
depression,
while
other
authors
(Cervo and
Samanin,
1987;
Wieland and Lucki, 1990) used three doses only given over a 24-hour period.
These findings would appear to contradict the need for
chronic administration in order to observe an AD effect in humans, although
a rapid onset of the clinical effect of ipsapirone
in
neurotic depressive patients, with a significant effect at 3 days, has been observed
(Spencer et al., 1990). Beer et al. (1990) have
suggested that this apparent discrepancy may result from the doses administered to rats being much higher than those used clinically. Our experiments on subsensitivity of 5-HT-mediated
inhibition of
adenylate cyclase (Fig 2) showed an effect of 5-HT-la agonists only after 7 days administration, although with a high dose of buspirone (8 mg/kg) an effect was observed after a single dose. There have been few studies on the actions of 5-HT-la agonists on biochemical and physiological parameters in humans. Lesch et al. (1990) showed a reduction in the hypothermic response to ipsapirone in depressed patients after treatment with amitriptyline, a finding complementary to those obtained in rodents discussed above. Another parameter studied by the same group is the neuroendocrine challenge test
in which
the
adrenocorticotrophic
ability hormone
of
ipsapirone
to
induce
release
of
(ACTH) and cortisol is measured.
In
patients with obsessive-compulsive disorder (OCD), subsensitivity of both the hypothermia and hormone release induced by ipsapirone was observed during chronic treatment with the 5-HT uptake blocker fluoxetine
(Lesch
et
al.,
1991c).
There
was
no
significant
correlation between the degree of subsensitivity of the responses and the fluoxetine-induced
improvement in OCD symptoms. However
these results are important in that they provide a human correlate of the subsensitivity phenomenon observed in both biochemical and
M. E.Newman etal.
14
behavioural
experiments
animals
in
after
5-HT-la
agonist
administration. 6.
It is clear
Conclusions
from the above that at the present
time
it is
impossible to say that AD treatment unequivocally affects 5-HT-la receptor
function
in a single direction.
In order to obtain an
overall picture of 5-HT-la receptor function it will be necessary to
integrate
the
results
obtained
with
the
various
approaches
outlined above into a scheme which encompasses both pre- and postsynaptic
elements,
and both receptor-mediated
and post-receptor
changes. While changes in parameters such as receptor number may be adaptive responses and secondary to, for example, changes in the firing
rate
important
of
in
presynaptic
that
they
neurons,
affect
any
these response
changes
are
dependent
still on
the
functioning of postsynaptic neurons. Thus, analysis of behavioural or other physiological responses known to involve 5-HT-la receptors may provide the best means of assessing the effects of AD treatment on this
system.
This
approach
pathways,
possibly
contribute
to the neuronal
involving
is however
risky
in that
other
other
sequence
neurotransmitters, may leading to the behavioural
response. Acknowledsements The experimental
work described herein was performed
Research Laboratory, Ezrath Nashim
at the
(Herzog) Hospital, Jerusalem,
and was supported by grant MH 43873 from the National Institutes of Health, U.S.A. References AMSTERDAM, J.D, BERWISH, N., POTTER, L., and RICKELS, K. (1987) Open trial of gepirone in the treatment of major depressive disorder. Curr. Therap. Res. 41: 185-193. ANDRADE, R., MALENKA, R.L. and NICOLL, R.A. (1986) A G protein couples serotonin and GABA, receptors to the same channels
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5-HT-IA
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ANGEBY-MOLLER, K. (1990) Different effects on the responses of functional pre- and postsynaptic 5-HT-la receptors by repeated treatment of rats with the 5-HT-la receptor agonist 8-OH-DPAT. Neuropharmacology 29: 85-91. LESCH, K.P., DISSELKAMP-TIETZE, J. and SCHMIDTKE, A. (1990) 5-HT-la receptor function in depression: effect of chronic amitriptyline treatment. J. Neural Transm. 80: 157-161. LESCH, K.P., AULAKH, C.S., TOLLIVER, T.J., HILL, J.L., WOLOZIN,B.L. and MURPHY,D.L (1991a) Differential effects of lonq-term lithium and carbamazepine administration on G_ protein in rat brain. Eur. J. Pharmacol. D -yg,
:““,“,,“$a$$~
LESCH, K.P., AULAKH, C.S., TOLLIVER, T.J., HILL, J.L. and MURPHY,D.L (1991b) Regulation of G proteins by chronic antidepressant drug treatment in rat brain; tricyclics but not clorgyline increase Go-alpha subunits. Eur. J. Pharmacol. 207: 361-364. LESCH, K.P., HOH, A., SCHULTE, A.M., OSERHEIDER, M. and MULLER, T. (1991c) Long-term fluoxetine treatment decreases 5-HT-la receptor sensitivity in obsessive-compulsive disorder. Psychopharmacology 105: 415-4.20. LUND, A., MJELLEM-JOLY, N. and HOLE, K. (1992) Desipramine, administered chronically, influences 5_hydroxytryptamine,! receptors,as measured by behavioural treets and receptor binding in rats. Neuropharmacology 31: 25-32. MARKSTEIN, R., HOYER, D. and ENGEL,G. (1986) 5-HT,, -receptors mediate stimulation of adenylate cyclase in rat hippocampus. Naunyn-Schmiedeberg's Arch. Pharmacol. 333: 335-341. MARTIN, P., BENINGER, R.J., HAMON, M. and PUECH, A.J. (1990) Antidepressant-like action of 8-OH-DPAT, a 5-HT-la agonist, in the learned helplessness paradigm: evidence for a postsynaptic mechanism. Behav. Brain Res. 38: 135-144. MARTIN, P., TISSIER, M.-H., ADRIEN, J. and PUECH, A.J. (1991) Antidepressant-like effects of buspirone mediated by the -5-HTlA post-synaptic receptors in the learned helplessness paradigm. Life Sci. 48: 2505-2511. MIZUTA, T. and SEGAWA, T. (1988) Chronic effects of imipramine and lithium on postsynaptic 5-HT-la and 5-HT-lb sites and on presynaptic 5-HT-3 sites in rat brain. Japan J. Pharmacol. 47: 107-113. MORK, A. and GEISLER, A. (1989) Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase in rat brain. Eur. J. Pharmacol. 168: 347-354. MORK, A. and GEISLER, A. (1990) 5-hydroxytryptamine receptor agonists influence calcium-stimulated adenylate cyclase activity in the cerebral cortex and hippocampus of the rat. Eur. J. Pharmacol. 175: 237-244. NEWMAN, M.E. and LERER, B. (1988) Chronic electroconvulsive shock and desimipramine reduce the degree of inhibition by 5-HT and carbachol of forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Eur. J. Pharmacol. 148: 257-260. NEWMAN, M.E., DRUMMER, D. and LERER, B. (1990) Single and combined effects of desimipramine and lithium on serotonergic receptor number and second messenger function in rat brain. J.
17
18
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el al.
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5-HT-IA
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SLEIGHT, A.J., MARSDEN, C.A., PALFREYMAN, M.G., MIR, A.K. and LOVENBERG, W. (1988) Chronic MAO A and MAO B inhibition decreases the 5-HT-la receptor-mediated inhibition of forskolin -stimulated adenylate cyclase. Eur. J. Pharmacol. 154: 255-261. SPENCER, D.G.Jr., DE VRY, J., SCHREIBER, R. and TRABER, J. (1990) Pharmacology of 5-HT,, agonists. Clin. Neuropharmacol. 13 (Suppl.2): 93-94. VARRAULT, A., LEVIEL, V. and BOCKAERT, J. (1991) 5-HT,, -sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. J.Pharmacol. exp. Ther. 257: 433-438. WANG, H.-Y. and FRIEDMAN, E. (1988) Chronic lithium: desensitization of autoreceptors mediating serotonin release. Psychopharmacology 94: 312-314. WELNER, S.A., DE MONTIGNY, C., DESROCHES, J., DESJARDINS, P. and SURANYI-CADOTTE, B.E. (1989) Autoradiographic quantification of serotonin,, receptors in rat brain following antidepressant drug treatment. Synapse 4: 347-352. WIELAND, S. and LUCKI, I. (1990) Antidepressant-like activity of 5-HT-la agonists measured with the forced swim test. Psychopharmacology 101: 497-504. WOZNIAK, K.M., AULAKH, C.S., HILL, J.L. and MURPHY, D.L. (1988) The effect of 8-OH-DPAT on temperature in the rat and its modification by chronic antidepressant treatments. Pharmacol. Biochem. Behav. 30: 451-456. YOCCA, F.D. and MAAYANI, S. (1990) 5-HT receptors linked to adenylate cyclase activity in mammalian brain. Ann. N.Y. Acad. Sci. 600: 212-223. Inquiries and reprint requests should be sent to: Dr. Michael E. Newman Biological Psychiatry Laboratory Department of Psychiatry Hadassah-Hebrew University Medical Center P.O.B. 12000 Jerusalem 91120 Israel.
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