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Cataleptogenic and anticataleptic activity produced by cholecystokinin octapeptides in mice
Neuropeptides
6,
CATALEPTOGENIC CHOLECYSTOI
\
Gyula
Telegdy
Department University (Reprint
259-268,
1985
AND ANTICATALEPTIC OCTAPEPTIDES IN Lot-ant
Borda,
of Pathophysiology, Medical School, requests to GT)
Botond
ACTIVITY MICE Penke
“Department H-6701 Szeged,
f
PRODUCED
, Kalmdn
BY
Kovacs
of Medical P.O.B. 531,
*
, and
Chemistry, Hungary
ABSTRACT The catalepsy induced by subcutaneously (SC.) and intracerebroventricularly (icv.) administered cholecystokinin octapeptide sulfate ester (Ccl<-8-SE) and desulfated cholecystokinin and the effects of CCK-8-SE and Ccl<-8-NS octapeptide (Ccl<-8-NS), were investigated in mice. The on haloperidol-induced catalepsy, results demonstrate the bimodal effect of CCK octapeptides in a Ccl<-8-SE in the doses of catalepsy test, With SC. administration but not CCK-8-NS at any dose, induced cata0.4 or 0.8 pmole/kg, the catalepsy induced by CCK-8-SE was of Furthermore, lepsy. administration only 40 pmole Ccl<-~-NS short duration. With icv. induced significant catalepsy. When 0.2, 0.4 and 0.8 pmole/kg SC. doses of Ccl<-8-NS or 0.4 pmole icv. dose of Ccl<-8-SE or CCK-8-NS was given in combination with intraperitoneal (ip.) administration of 1.0 mg/kg haloperidol, the total d’uration of catalepsy was suppressed. Finally, CCK-8-SE SC. when given in combination with haloperidol ip., exerted a biphasic, synergistic-antagonistic effect on the haloperidol-induced catalepsy. INTRODUCTION In the past few years, an increasing number of papers have demonstrated different neuropharmacological actions of cholecystokinin octapeptide (Ccl<-8) and the CCK-related peptide ceruletide, and have pointed to their possible therapeutic value. Ccl<-8 and/or ceruletide have been reported to have analgesic, sedative (1, 2, 3), anticonvulsive (4, 5, 6, 7) and memory (8, 9, 10, 11) effects, and a large proportion of the papers have described their neuroleptic-like properties, i.e. antistereotypic (2, 12), antiavoidance (10, 12, 13, 14), antidopaminergic (15), and ptotic (16) effects. A few papers have recently been published on the antipsychotic action of CCI< and ceruletide, which improved the mental state of schizophrenic patients (17,18,1g).
The induction of catalepsy in experimental animals is a characteristic feature of classical neuroleptic drugs, and is a screening test widely used to evaluate the neuroleptic potency of new compounds (20). The cataleptogenic potency of neucorrelates well with the appearence of roleptics, however, pseudoparkinsonism in human therapy, i.e. with a nigrostriatal Cataiepsy could be induced by side-effect of the drugs (21). Ccl<-related peptides in mice after peripheral administration (2, 16), but no such effect was observed in rats (12). In the present study gate whether the sulfated and to elucidate catalepsy, genie action of haloperidol.
an attempt has been and desulfated forms how they influence
made to investiof Ccl<-8 induce the catalepto-
METHODS Male CFLP mice weighing 25-35 g were Ikept under standard conditions with free access to commercial food and tap water. All animals were used only once. All drugs were dissolved in saline, and were injected for peripheral treatment in a volume of 0.10 ml/10 g body weight. Haloperidol was injected intraperitoneally (ip. ), and peptide solutions were injected subcutaneously (SC. ) or intracerebroventricularly (icv. ). treatment a guide cannula was implanted into the For icv. lateral brain ventricle of mice under pentobarbital anesthesia (35 mg/l
statistical Multiple accepted
analyses, Range test. as statistically
one-way ANOVA was A probability level significant.
Cholecystokinin octapeptide sulfate desulfated cholecystokinin octapeptide synthetized by the method of (23).
260
followed of less
ester (CCK-8-SE) (Ccl<-8-NS) were
by than
and
Haloperidol
(Gedeon
Richter,
Budapest)
was
also
used.
RESULTS 0.4 or 0.8 pmole/l
CCK-8-
SE TOTAL
SeC
70.
1
---
CONTROL 0.2 pmolelkg Q4 pmolelkg 0.8 pmolel kg
*a-v_.
60-
-*-
50CO3020. lo-
5
15
30
45
60
90
120 min
c
a2 Ok 0.6 pmol I kg
Fig. 1. Effect of CCK-8-SE SC. in a combined catalepsy test. Left: abscissa : time following sc. injection (indicated by arrow) of CCK-8-SE in three doses or saline; ordinate: catalepsy in sec. In the control group, mean + SEM are shown, In the peptide-treated groups the presence of-standard error bars indicates statistically significant differences. Right: mean + SEM of total duration of catalepsy obtained after summaiion of scores individually. xx: p(o.01
261
CCK-8-X
set
set
180 I 1
TOTAL I
1260-
---
CONTROL 0.2 pmolelkg -* - Q4 pmolel kg
60
..‘.... 0.8 pmolel kg
5
15
30
45
60
90
120 min
C 0.2 0.4 0.8 pmole/
2. Effect Fig. in a combined tide or saline) Further details
kg
of Ccl<-8-SE SC, on haloperidol-induced catalepsy catalepsy test. Left: arrows indicate SC, (pepand ip. (1 mg/l
The effects of CCI< octapeptides on the catalepsy induced by a high dose (1 mg/l
262
CCK-8-NS TOTAL
--- .-
5 15
30
45
60
a2 pmolelkg 04 pmolel kg
90
120 min
C 0.2 0.40.8
pmolelkg
Fig. 3. Effect in a combined details as in
of Ccl<-8-NS SC. on haloperidol-induced catalepsy test. x: p 0.05; xx: p 0.01. Fig. 1 and Fig. 2.
TABLE
I
of intracerebroand anticataleptic activity administered Ccl<-8-SE and Ccl<-8-NS in mice
Cataleptogenic ventricularly
TOTAL TREATMENT Saline
catalepsy Further
DURATION Single'
icv.
OF
CATALEPSY
(set)
Combined'
186
+
45
(8)
1040
+
38
(12)
Ccl<-8-SE
0.4
pmole
icv.
122
+
16
(8)
441
+
63b(ll)
Ccl<-8-NS
0.4
pmole
icv.
122
+
33
(7)
497
2
71b(13)
141
+
39
(18)
1080
2
46
(15)
Saline
icv.
Ccl<-8-SE
4.0
pmole
icv.
225
2
62
(11)
944
2
57
(11)
Ccl<-8-NS
4.0
pmole
icv.
294
+
50
(11)
1010
+
54
(10)
Ccl<-8-X
40
132
2
39
(11)
1042
+
78
(9)
1105
+
54
(9)
Ccl<-8-NS
40
pmole pmole
icv. icv.
381
+
8ga(ll)
1: single treatment with individual Mean + SEM are shown. 2: combined treatment with individual peptides peptiaes icv.; ip.; a: ~(0.05; b: p
263
TOTAL
500
..~
I 5
15
30
45
-a-
CCK-8-SE
--
CCK -8-NS
60
90
4. Effects of Ccl<-8-SE Fig. on haloperidol-induced pmole icv. catalepsy test. Left: arrows and ip, (1 mg/kg haloperidol) Fig. 1.
0.2 pmole/l
dose of at every
and
l2Ollkl
C
SE
NS
Ccl<-8-NS in a dose of 0.4 catalepsy in a combined indicate icv, (peptide or saline) injections. Further details as
Ccl<-8-NS time-point.
of
significantly
lowered
the
in
cata-
After icv. administration of a 4.0 or 40 pmole dose of the peptides showed no inhibition of Ccl<-8-SE or Ccl<-8-NS, haloperidol-induced catalepsy (Table I)> but a very strong antagonistic action was observed after the smallest, 0.4 pmole Figure 4 demonstrates that, besides dose of each octapeptide. the total duration of catalepsy being halved by 0.,4 pmole Ccl<-~-SE or Ccl<-~-NS as compared to the icv. saline-treated the catalepsy score was also highly significantly reduced group, at every time-point during testing. DISCUSSION administered Ccl<-~-SE induced catalepsy in the Only sc. same manner as described by Zetler (2) for Ccl<-8-SE and ceruletide. After icvo treatment, Ccl<-8-SE induced a slight, insignificant catalepsy in the 4,O pmole dose, and only the effect of 40 pmole Ccl<-8-NS was significant. Another difference was that the effect of Ccl<-8-SE SC. could be observed only in the first 30 min, whereas that of 40 pmole Ccl<-8-NS icv. persisted much longer. The shorter duration of catalepsy after peripheral treatment and the lack of effect of Ccl<-8-SE icv. might indicate that the cataleptogenic potency of SC. adminis-
264
tered CCI<-~-SE is mediated through a mechanism of peripheral similarly to arousal inhibition and open-field inhibiorigin, tion associated with the satiety effect (24,25,26), but it might be a peripherally mediated neuroleptic-like effect as well. It whether a centrally mediated or a periphis not clarified yet, erally mediated neuroleptic-like effect of peripherally administered CCI< or caerulein is the more important for the therapy 27 and 28 for the behavioral effects of periph(eg, cf. refs. erally administered caerulein after vagotomy). A tendency to antagonism in the interaction of the effects of peripherally administered ceruletide and haloperidol on catalepsy was first observed by Zetler (16), In the present biphasic synergistic-antagonistic experiments a time-dependent, administered doses of interaction was revealed between SC. Ccl<-8-SE and 1 mg/kg haloperidol. In addition, a dose-dependent, bimodal anticataleptic-cataleptogenic effect of centrally administered Ccl<-8-NS (and a mainly anticataleptic effect of The present results indicate, that CCK-~-SE) was also observed. the anticataleptic activity of CCI< octapeptides is purely centrally mediated. In rats, no cataleptogenic action of CCK-8-SE was observed after peripheral administration (12). This finding was confirmed after the icvo administration of Ccl<-8-SE or CCK-8-NS, and extended to the demonstration of the antagonism of haloperidol-induced catalepsy by both octapeptides, Ccl<-8-NS displaying the higher anticataleptic activity (KidAtet al., submitted). Van Ree et al. (11) observed a slight immobility in various grip tests in rats, but after much higher icv. doses of CCK-8-SE and CCK-8-NS. It was stated in Section 1 that CCK-like peptides exert potent neuroleptic-like effects considered to be mediated through dopaminergic transmission. As a mechanism, the presynaptic inhibition of dopamine release in the terminal areas of the mesolimbic dopaminergic system is the most obvious, since the inhibition of dopamine release by CCK-8-SE has been demonstrated in the nucleus accumbens both in vitro (29) and in vivo @), and Ccl<-8-SE and ceruletide are more active against methylphenydate-induced than against apomorphine-induced stereotypies (2,12). To complicate the picture, excitatory effects on dopaminergic transmission have also been reported (11,31). I
265
tivity of Ccl<-8-SE and Ccl<-8-NS. aleptic-cataleptogenic action of in addition to tho octapeptides, tance of the dose-dependence and for Ccl<-~-NS can be suggested, Besides the pseudoparkinsonism-like in the treatment
theoretical of
state Parkinson’s
Because of the double anticatcentrally administered Ccl< locus-specificity, the imporof certain specific actions
implications, can have diseasse.
the antagonism of a therapeutical implications
ACKNOWLEDGEMENTS This Hungarian
work was Ministry
supported of Health
by the Scientific (16/4-10/502/T).
Research
Council,
REFERENCES 1.
Zetler, G., 1980 and cholecystokinin 19, 415-422.
, Analgesia
and
octapeptide
ptosis (Ccl<-8),
caused by caerulein Neuropharmacology,
2.
depressant effects Zetler, G., 1981 , Central and cholecystokinin octapeptide (Ccl<-8) differ of diazepam and haloperidol, Neuropharmacology,
of caerulein from those 20, 277-283,
3.
I
of choleby thythe rat,
4.
Zetler, G, , 1980 . Ccl<-8 compared with 65 a 297-300.
5.
l
6.
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7.
I
8.
K&d&r, passive cular
Jpn.
Anticonvulsant effects of caerulein and those of diszepam, European J. Pharmacol.
G.
Toth, M. Zarandi and G. and dose - effect relapicrotoxin-induced seizures fragments and analogues 1223-1229.
T., M. Fekete and G. Telegdy, avoidance behaviour of rats administration of cholecystokinin
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1981, Modulation by intracerebroventrioctapeptide,
of Acta
,
physiol. 9.
l
Acad.
Sci.
hung.
58,
269-274.
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8. Penke, I<. I
10.
Fekete, M., A. Lengyel, B. Hegedus, B. Penke, MS Zarandy, 1983, Further analysis of the G.I<. Toth, and G. Telegdy, effects of cholecystokinin octapeptides on avoidance behaviour in rats, European J. Pharmacol. 98, 79-91.
11.
0. Gaffori and D. De Van Ree, 3.) behavioral profile of CCK-8-related of antipsychotic agents, European
12.
Cohen, S.L., M. i
13.
Fekete, M., A. Szabo, M. Balazs, Effect of intraventricular 1981 cystol:inin octapeptide sulfate cystokinin octapeptide on active feeding behaviour of rats, Acta 58, 39-45.
14.
Telegdy in the
15,
Itoh, S. and C. Katsuura, 1981, Suppressive action cystokinin octapeptide on the behavioral effects in the rat, European J. Pharmacol, 75, 313-316.
, G., brain,
C.A.
M. Fekete and Int. Med. 2,
B. Penke and G, Telegdy, administration of choleester and unsulfated choleavoidance and conditioned physiol, Acad. Sci. hung.
T. Udar, 2-5.
1982,
Zetler, G., stereotypic pharmacology,
17.
Moroji, T., N. Watanabe, N. Aoki and S. psychotic effects of ceruletide (caerulein) schizophrenia, Arch. Gen.. Psychiatry 39,
18.
Nair, N.P., D.M. appears to have Psychopharmacol.
19.
Nair, N.P., Therapeutic -resistant 134-136. Worms, cificity Pharmac,
21,
Btirki, Ther.
P.,
Differential of caerulein 681-686.
Bloom and J. antipsychotic Biol. Psychiat.
D.M. Bloom, efficacy of schizcphrenic
Cholecystokinin
cataleptogenic and haloperidol,
of
and
of choleL-DOPA
antiNeuro-
Itoh,
1982, Antion chronic 485-488,
Nestoros, 1982, Cholecystokinir properties, Prog. Neuro6, 509-512.
J.N. Nestoros and G. Schwartz, cholecystokinin in neurolepticsubjects, Psychopharmacol, Bull.
and K.G. Lloyd, 1979, of behavioral screening Ther. 5, 445-450.
H.R., 1979, 5, 525-534,
In rats, the resembles that 93, 63-75.
Tamminga and T.N, Chase, 1982, effects on conditioned avoidand catalepsy, European J.
16.
20.
1981 effecis 20,
Wied, 1983, peptides J. Pharmacol,
Extrapyramidal
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Predictability tests for side-effects,
and speneuroleptics, Pharmac.
1983, 19,
22.
De Ryck, M., T. versus haloperidol sis of postural
Schallert and P. Teitelbaum, 1980, Morphine catalepsy in the rat: A behavioral analysupport mechanisms, Brain Res. 201, 143-172.
23.
Penke, B., G.I<. A new synthesis methionine, in: Coppenhagen) p.
Toth, M. Zarandi, of tyrosine-O-sulfated Peptides 1980, 253-257.
A.
Nagy and peptides I<. Brunfeldt
ed.
24.
S.M. Paul Crawley, J.N., S.E. Hays, Cholecystokinin reduces exploratory Behav. 27, 407-411.
25.
Crawley, abolishes exploratory
26.
I
27.
Moroji, Effects effects Neurosci.
T. of of
28.
Ibii N, graphic caerulein
Yamamoto I<. (1984) Behavioral studies of a cholecystokinin (883-S), in animals. J.
29.
Hokfelt, T., M. Schultzberg, 515-521.
30.
Voigt , M.M. mine in the cholecystokinin,
31.
Kovacs, Effects metabolism climbing
32.
Fekete, 1981, ester Transm,
33.
Telegdy , G., transmitter Experimentalis,
Received Accepted
J.N., the
and F.I<. behavior
I<.
I
1981,
1981 , Physiol.
Goodwin, in mice,
S.E. Hays, and S,M. Paul, 1981 a Vagotomy inhibitory effects of cholecystokinin on rat behavior. European J. Pharmacol. 74, 379-380, Telegdy, 1985 and novel envi;onment octapeptide.
Hagino Y, Nonake R-I, Watanabe N, Hagino bilateral abdominal vagotomy on central caerulein : A behavioral pharmacological Lett. S13, S120,
0.
Johansson, A. 1980, Peptidergic
I<. (1983) depressant study.
and electroencephalo(Ccl<)-related substance, Pharm. Dyn. 7, S41.
Ljundahl, J.M. Lundberg neurons, Nature 284,
and R.Y. Wang, 1984, nucleus accumbens of Brain Res. 296,
In vivo the rat: 189-193.
release of modulation
and
dopaby
B. Penke and G. Telegdy, 1981, G. L., G. Szabo, of cholecystokinin octapeptide on striate1 dopamine and on apomorphine-induced stereotyped cagein mice, European J. Pharmacol. 69, 313-319.
M. , T, I
d/2/85 20/3/85
268
Kovacs and G. Telegdy, octapeptide sulfate in rats, J. Neural
alteration function,
in brain Endocrinologia
6,
CATALEPTOGENIC CHOLECYSTOI
\
Gyula
Telegdy
Department University (Reprint
259-268,
1985
AND ANTICATALEPTIC OCTAPEPTIDES IN Lot-ant
Borda,
of Pathophysiology, Medical School, requests to GT)
Botond
ACTIVITY MICE Penke
“Department H-6701 Szeged,
f
PRODUCED
, Kalmdn
BY
Kovacs
of Medical P.O.B. 531,
*
, and
Chemistry, Hungary
ABSTRACT The catalepsy induced by subcutaneously (SC.) and intracerebroventricularly (icv.) administered cholecystokinin octapeptide sulfate ester (Ccl<-8-SE) and desulfated cholecystokinin and the effects of CCK-8-SE and Ccl<-8-NS octapeptide (Ccl<-8-NS), were investigated in mice. The on haloperidol-induced catalepsy, results demonstrate the bimodal effect of CCK octapeptides in a Ccl<-8-SE in the doses of catalepsy test, With SC. administration but not CCK-8-NS at any dose, induced cata0.4 or 0.8 pmole/kg, the catalepsy induced by CCK-8-SE was of Furthermore, lepsy. administration only 40 pmole Ccl<-~-NS short duration. With icv. induced significant catalepsy. When 0.2, 0.4 and 0.8 pmole/kg SC. doses of Ccl<-8-NS or 0.4 pmole icv. dose of Ccl<-8-SE or CCK-8-NS was given in combination with intraperitoneal (ip.) administration of 1.0 mg/kg haloperidol, the total d’uration of catalepsy was suppressed. Finally, CCK-8-SE SC. when given in combination with haloperidol ip., exerted a biphasic, synergistic-antagonistic effect on the haloperidol-induced catalepsy. INTRODUCTION In the past few years, an increasing number of papers have demonstrated different neuropharmacological actions of cholecystokinin octapeptide (Ccl<-8) and the CCK-related peptide ceruletide, and have pointed to their possible therapeutic value. Ccl<-8 and/or ceruletide have been reported to have analgesic, sedative (1, 2, 3), anticonvulsive (4, 5, 6, 7) and memory (8, 9, 10, 11) effects, and a large proportion of the papers have described their neuroleptic-like properties, i.e. antistereotypic (2, 12), antiavoidance (10, 12, 13, 14), antidopaminergic (15), and ptotic (16) effects. A few papers have recently been published on the antipsychotic action of CCI< and ceruletide, which improved the mental state of schizophrenic patients (17,18,1g).
The induction of catalepsy in experimental animals is a characteristic feature of classical neuroleptic drugs, and is a screening test widely used to evaluate the neuroleptic potency of new compounds (20). The cataleptogenic potency of neucorrelates well with the appearence of roleptics, however, pseudoparkinsonism in human therapy, i.e. with a nigrostriatal Cataiepsy could be induced by side-effect of the drugs (21). Ccl<-related peptides in mice after peripheral administration (2, 16), but no such effect was observed in rats (12). In the present study gate whether the sulfated and to elucidate catalepsy, genie action of haloperidol.
an attempt has been and desulfated forms how they influence
made to investiof Ccl<-8 induce the catalepto-
METHODS Male CFLP mice weighing 25-35 g were Ikept under standard conditions with free access to commercial food and tap water. All animals were used only once. All drugs were dissolved in saline, and were injected for peripheral treatment in a volume of 0.10 ml/10 g body weight. Haloperidol was injected intraperitoneally (ip. ), and peptide solutions were injected subcutaneously (SC. ) or intracerebroventricularly (icv. ). treatment a guide cannula was implanted into the For icv. lateral brain ventricle of mice under pentobarbital anesthesia (35 mg/l
statistical Multiple accepted
analyses, Range test. as statistically
one-way ANOVA was A probability level significant.
Cholecystokinin octapeptide sulfate desulfated cholecystokinin octapeptide synthetized by the method of (23).
260
followed of less
ester (CCK-8-SE) (Ccl<-8-NS) were
by than
and
Haloperidol
(Gedeon
Richter,
Budapest)
was
also
used.
RESULTS 0.4 or 0.8 pmole/l
CCK-8-
SE TOTAL
SeC
70.
1
---
CONTROL 0.2 pmolelkg Q4 pmolelkg 0.8 pmolel kg
*a-v_.
60-
-*-
50CO3020. lo-
5
15
30
45
60
90
120 min
c
a2 Ok 0.6 pmol I kg
Fig. 1. Effect of CCK-8-SE SC. in a combined catalepsy test. Left: abscissa : time following sc. injection (indicated by arrow) of CCK-8-SE in three doses or saline; ordinate: catalepsy in sec. In the control group, mean + SEM are shown, In the peptide-treated groups the presence of-standard error bars indicates statistically significant differences. Right: mean + SEM of total duration of catalepsy obtained after summaiion of scores individually. xx: p(o.01
261
CCK-8-X
set
set
180 I 1
TOTAL I
1260-
---
CONTROL 0.2 pmolelkg -* - Q4 pmolel kg
60
..‘.... 0.8 pmolel kg
5
15
30
45
60
90
120 min
C 0.2 0.4 0.8 pmole/
2. Effect Fig. in a combined tide or saline) Further details
kg
of Ccl<-8-SE SC, on haloperidol-induced catalepsy catalepsy test. Left: arrows indicate SC, (pepand ip. (1 mg/l
The effects of CCI< octapeptides on the catalepsy induced by a high dose (1 mg/l
262
CCK-8-NS TOTAL
--- .-
5 15
30
45
60
a2 pmolelkg 04 pmolel kg
90
120 min
C 0.2 0.40.8
pmolelkg
Fig. 3. Effect in a combined details as in
of Ccl<-8-NS SC. on haloperidol-induced catalepsy test. x: p 0.05; xx: p 0.01. Fig. 1 and Fig. 2.
TABLE
I
of intracerebroand anticataleptic activity administered Ccl<-8-SE and Ccl<-8-NS in mice
Cataleptogenic ventricularly
TOTAL TREATMENT Saline
catalepsy Further
DURATION Single'
icv.
OF
CATALEPSY
(set)
Combined'
186
+
45
(8)
1040
+
38
(12)
Ccl<-8-SE
0.4
pmole
icv.
122
+
16
(8)
441
+
63b(ll)
Ccl<-8-NS
0.4
pmole
icv.
122
+
33
(7)
497
2
71b(13)
141
+
39
(18)
1080
2
46
(15)
Saline
icv.
Ccl<-8-SE
4.0
pmole
icv.
225
2
62
(11)
944
2
57
(11)
Ccl<-8-NS
4.0
pmole
icv.
294
+
50
(11)
1010
+
54
(10)
Ccl<-8-X
40
132
2
39
(11)
1042
+
78
(9)
1105
+
54
(9)
Ccl<-8-NS
40
pmole pmole
icv. icv.
381
+
8ga(ll)
1: single treatment with individual Mean + SEM are shown. 2: combined treatment with individual peptides peptiaes icv.; ip.; a: ~(0.05; b: p
263
TOTAL
500
..~
I 5
15
30
45
-a-
CCK-8-SE
--
CCK -8-NS
60
90
4. Effects of Ccl<-8-SE Fig. on haloperidol-induced pmole icv. catalepsy test. Left: arrows and ip, (1 mg/kg haloperidol) Fig. 1.
0.2 pmole/l
dose of at every
and
l2Ollkl
C
SE
NS
Ccl<-8-NS in a dose of 0.4 catalepsy in a combined indicate icv, (peptide or saline) injections. Further details as
Ccl<-8-NS time-point.
of
significantly
lowered
the
in
cata-
After icv. administration of a 4.0 or 40 pmole dose of the peptides showed no inhibition of Ccl<-8-SE or Ccl<-8-NS, haloperidol-induced catalepsy (Table I)> but a very strong antagonistic action was observed after the smallest, 0.4 pmole Figure 4 demonstrates that, besides dose of each octapeptide. the total duration of catalepsy being halved by 0.,4 pmole Ccl<-~-SE or Ccl<-~-NS as compared to the icv. saline-treated the catalepsy score was also highly significantly reduced group, at every time-point during testing. DISCUSSION administered Ccl<-~-SE induced catalepsy in the Only sc. same manner as described by Zetler (2) for Ccl<-8-SE and ceruletide. After icvo treatment, Ccl<-8-SE induced a slight, insignificant catalepsy in the 4,O pmole dose, and only the effect of 40 pmole Ccl<-8-NS was significant. Another difference was that the effect of Ccl<-8-SE SC. could be observed only in the first 30 min, whereas that of 40 pmole Ccl<-8-NS icv. persisted much longer. The shorter duration of catalepsy after peripheral treatment and the lack of effect of Ccl<-8-SE icv. might indicate that the cataleptogenic potency of SC. adminis-
264
tered CCI<-~-SE is mediated through a mechanism of peripheral similarly to arousal inhibition and open-field inhibiorigin, tion associated with the satiety effect (24,25,26), but it might be a peripherally mediated neuroleptic-like effect as well. It whether a centrally mediated or a periphis not clarified yet, erally mediated neuroleptic-like effect of peripherally administered CCI< or caerulein is the more important for the therapy 27 and 28 for the behavioral effects of periph(eg, cf. refs. erally administered caerulein after vagotomy). A tendency to antagonism in the interaction of the effects of peripherally administered ceruletide and haloperidol on catalepsy was first observed by Zetler (16), In the present biphasic synergistic-antagonistic experiments a time-dependent, administered doses of interaction was revealed between SC. Ccl<-8-SE and 1 mg/kg haloperidol. In addition, a dose-dependent, bimodal anticataleptic-cataleptogenic effect of centrally administered Ccl<-8-NS (and a mainly anticataleptic effect of The present results indicate, that CCK-~-SE) was also observed. the anticataleptic activity of CCI< octapeptides is purely centrally mediated. In rats, no cataleptogenic action of CCK-8-SE was observed after peripheral administration (12). This finding was confirmed after the icvo administration of Ccl<-8-SE or CCK-8-NS, and extended to the demonstration of the antagonism of haloperidol-induced catalepsy by both octapeptides, Ccl<-8-NS displaying the higher anticataleptic activity (KidAtet al., submitted). Van Ree et al. (11) observed a slight immobility in various grip tests in rats, but after much higher icv. doses of CCK-8-SE and CCK-8-NS. It was stated in Section 1 that CCK-like peptides exert potent neuroleptic-like effects considered to be mediated through dopaminergic transmission. As a mechanism, the presynaptic inhibition of dopamine release in the terminal areas of the mesolimbic dopaminergic system is the most obvious, since the inhibition of dopamine release by CCK-8-SE has been demonstrated in the nucleus accumbens both in vitro (29) and in vivo @), and Ccl<-8-SE and ceruletide are more active against methylphenydate-induced than against apomorphine-induced stereotypies (2,12). To complicate the picture, excitatory effects on dopaminergic transmission have also been reported (11,31). I
265
tivity of Ccl<-8-SE and Ccl<-8-NS. aleptic-cataleptogenic action of in addition to tho octapeptides, tance of the dose-dependence and for Ccl<-~-NS can be suggested, Besides the pseudoparkinsonism-like in the treatment
theoretical of
state Parkinson’s
Because of the double anticatcentrally administered Ccl< locus-specificity, the imporof certain specific actions
implications, can have diseasse.
the antagonism of a therapeutical implications
ACKNOWLEDGEMENTS This Hungarian
work was Ministry
supported of Health
by the Scientific (16/4-10/502/T).
Research
Council,
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