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Baclofen-induced Catatonia: Modification by Serotonergic Agents
Neuropharmacology, Vol. 35, No. 5, pp. 595–598, 1996 Copyright01996 ElsevierScienceLtd.All rightsreserved Printedin GreatBritain 0028-3908/96$15.00 + 0.00
Pergamon
@ PII:SO028-3908(%)00025-1
Baclofen-induced Catatonia: Modification by Serotonergic Agents S. B. KASTURE,l S. N. MANDHANE2and C. T. CHOPDE2* IM. V. P. Samaj’s College of Pharmacy, Gangapur Road, Nashik 422002, India and 2Department of Pharmaceutical Sciences, Nagpur UniversiQ Campus, Nagpur 440010, India (Accepted 1 March 1996)
Summary-Baclofen, a GABA~receptor agonist can induce catatonia in rats. This catatonia may serve as a tool for the study of GABA~receptor function. Reciprocalinteractionsbetween serotonin(5-HT) and GABA~ receptors in the CNS are known to occur. In the present study we examined the effects of various agents that influence serotonergic neurotransmissionon baclofen-inducedcatatonia in rats. The catatonia was rated by means of a scoring method, accordingto the severityof motor symptomsproducedby baclofen (10-15 mg/kg, i.p.). All serotowgic drugswereinjectedintraperitoneally 30minpriortobaclofen,exceptthe5-HTsynthesis inhibitorp-chlorophenylalanine (PCPA),whichwasinjected72and48hrpriorto baclofen.The5-HTreleaser fenfluramine(10mgkg) andtheuptakeinhibitorfluoxetine(10mgkg) reversed,whereasthe5-HT1~agonist buspirone(3 mg,kg)potentiatedbaclofen-induced catatonia.The5-HTsynthesisinhibitorPCPA(150x 2 mg/ kg),thenon-specific5-HTantagonistcyproheptadine (5 mg/kg),the5-HTINIEJ antagonistpindolol(3 mg/kg) and the 5-HTzantagonistsulpiride(20 mgikg)enhancedbaclofen-induced catatonia.It is concludedthatthe manipulationsof centralserotonergicmechanismsmodulatebaclofen-induced catatonia.Copyright0 1996 ElsevierScienceLtd.
Keywords-GABA~receptors,baclofen,catatonia,serotonergicneurotransmission.
GABA-mimetic agents when injected into the nucleus accumbens(Pycock and Horton, 1979)or globuspallidus (Pycock et al., 1976) of rats cause behavioraldepression, such as reduction in locomotoractivity, akinesia,rigidity and catalepsy, a syndrome generally considered to be Parkinsonism-like.The GABAB analogue, baclofen @ chloro-fl-phenylGABA), which can penetratethe blood– brain barrier is used clinically as a muscle relaxant in spastic conditions (Faigle and Keberle, 1972). Baclofen and the agents that increase GABA activity have been shown to potentate the cataleptic effect of neuroleptics (Kaarianen, 1976;Keller et al., 1976).Further,peripheral administration of baclofen can induce catatonia in rats and this may serve as a model for the study of GABAB receptors, since this catatonia is mediated through GABABreceptors (Mehta and Ticku, 1987). Previousstudies have indicated an interactionbehveen serotonin (5-HT) and GABABreceptors in the CNS. For instance, in in vitro binding studies, applicationof either 5-HT (Segal, 1980)or baclofen (Inoe et al., 1985)to CA1 pyramidal cells causes large hyperpolarizations,due to a
*To whom correspondenceshould be addressed. Tel. No. 910712-222943,Fax No. 91-0712-521746.
selective increase in K+ conductance. It has been shown that both 5-HT and baclofen modulate the same K+ channels, although they act via distinct receptors (Andrade et al., 1986). Furthermore, GABA~ receptors have been shown to be involved in the control of 5-HT release (Gray et al., 1986b).Activationof these receptors by baclofen decreases the output of 5-HT from mammalian CNS (Bowery et al., 1980). Additionally, baclofenwas found to have an inhibitoryaction on 5-HTmediated head twitch response in rats (Gray et al., 1986a). However, it is not known whether the phenomenon of baclofen-induced catatonia can be modified by serotonergic manipulations. In order to examine this question, we tested the effects of various agents that affect 5-HT neurotransmission on baclofen-induced catatonia. METHODS Male albino Wistar rats (200-250 g) housed at a constant room temperature (25°C), on a 12:12 hr light/ dark cycle were used. The animals were allowed free access to food and water. All experiments were carried out at the same time each day (0900-1500 hr). (i-)Baclofen (Hindustan Ciba-Geigy Ltd., Bombay),
595
596
S. B. Kasture et al.
(+)pindolol (Sandoz Ltd., Bombay) and (+)sulpiride (Sigma Chemical Cov StLoui$ MO)were dissolvedina minimal quantity ofO.l N hydrochloricacid and brought to the final volume with saline. Fenfluramine HC1 (Wockhardt Ltd., Bombay), fluoxetine HC1 (Sun Pharmaceuticals, Bombay), buspirone HC1 (Cadila IAbs, ~medabad), cyproheptadine HC1 (Themis Pharmaceuticals, Bombay), DL-p-chlorophenylalaninemethyl ester HC1(PCPA) (Sigma Chemical Co.) were dissolved in 0.9% w/v NaC1.All drugs were injected intraperitoneally (i.p.). Catatoniawas inducedwith baclofen (10-15 mg/kg)in groups of rats (n= 6/dose). Separate groups of rats were pre-treated with 5-HT agonists/antagonistsin the experiments that examined the effects of these drugs on baclofen-induced catatonia. 5-HT agonists/antagonists were given 30 min prior to baclofen except PCPA which was given 72 and 48 hr prior. Saline (0.9%, 0.2 ml per animal, i.p.) was used as control. The catatonia was measured up to 3 hr followingbaclofen administrationby a scoring method (Kulkami et al., 1980), as described below. The rat moved when placed on the table, score= O;the rat moved only when touched or pushed, score = 0.5; the rat placed on the table with front paw set alternately on a 3 cm high block failed to correct the posture in 10 see, score = 0.5 for each paw with a total of 1 for this stage; the rat failed to move when the front paws were placed alternately on a 9 cm high block, score = 1 for each paw with a total score of 2 for this stage. Thus, for a singlerat, the maximum possible scores were 3.5 reflecting total catatonia.A lower scole would mean an apparentlylesser degree of catatonia. Data are presented as mean +- SEM for 6 rats per group.The resultswere statisticallyanalysedby Kruskal– Wallis one-way ANOVA. Differencesin catatoniascores of various treatment groups were compared using nonparametric Mann–WhitneyU-test (Siegel, 1956).A value of P <0.05 was considered to be statisticallysignificant. RESULTS
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Fig. 1.Effect of 5-HT agonistson baclofen-inducedcatatonia in rats. Catatoniawas inducedby baclofen (15 mg/kg, i.p.). Saline in the control group or 5-HT agonistswere i.p. injected 30 min before baclofen. Groups are: control (.), 10 mg/kg fenfluramine (+), 10 mg/kg fluoxetine (~) and 3 mg/kg buspirone (A). Data are presented as mean + SEM for 6 rats per group; P <0.05 (Mann–WhitneyU-test).
Effect of 5-HT antagonists
Prior administration of the tryptophan hydroxylase inhibitor (5-HT synthesis inhibitor) PCPA (150 mg/kg), the non-specific5-HT antagonist cyproheptadine(5 mg/ kg), the 5-HT1wl~receptorantagonistpindolol(3 mgkg) and the 5-HT2 antagonistsulpiride (20 mgilcg)enhanced baclofen-inducedcatatonia (Fig. 2). These 5-HT antagonists did not cause any catatonia or other motor impairmentwhen injected alone.
DISCUSSION
Baclofen, an agonist selective for GABAB receptor Administration of baclofen (10-15 mg/kg) induced catatonia in rats. The onset of effect was within 10 min (Hill and Bowery, 1981) has been shown to inhibit the and the maximum catatonia was seen at 60 min. The release of 5-HT from slices of frontal cortex of rat animals were recovered completely within 3 hr of the (Bowery et al., 1980) and mouse (Gray et al., 1986a). More recently, baclofen was shown to inhibit the headadministrationof baclofen. twitch responsemediated by 5-HT2 receptors, indicating Effect of 5-HT agonists the functional relationship between GABAB and 5-HT Figure 1 presents the effect of administration of receptors (Gray et al., 1986a). In our study, administravarious 5-HT receptor agonists on baclofen-induced tion of the 5-HT releaser fenfluramine and the 5-HT catatonia. The 5-HT releaser fenfluramine (10 mg/kg) uptake inhibitor fluoxetine significantly reversed the and the 5-HT uptake inhibitor fluoxetine (10 mg/kg) baclofen-inducedcatatonia suggesting that enhanced 5significantly reversed baclofen-induced catatonia. In HT neurotransmission reverses this GABAB mediated contrast to this, the 5-HTIA partial agonist buspirone (3 behavior. In contrast, the selective 5-HTIA receptor mg/kg) markedlypotentiatedbaclofen-inducedcatatonia. agonist buspirone (Glaser and Traber, 1983) markedly These 5-HT agonists were devoid of cataleptogenic potentiatedbaclofen-inducedcatatonia.5-HTIAreceptors are known to be locatedboth pre-synaptically,where they activity when injected alone.
5-HT in baclofen-inducedcatatonia 35r
3
2.5t 2
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597
induced catatonia. The effect of 5-HT appears to be mediatedby the interactionsat several receptor subtypes. Although the location of these receptors remains to be determined, these interactions may have important clinical implications, in view of therapeutic use of baclofen and serotonergic agents (e.g. buspirone or fluoxetine).
~
are grateful to Mr Sunil Jaiswal for
Acknowledgement—We
artwork.
REFERENCES AndradeR.; MalenkaR. C. and Nicoll R. A. (1986)A Gprotein couples serotonin and GABA~ receptors to the same channels in hippocampus.Science 234: 1261–1265. 1 1 I t I I o“ BoweryN. G., Hill D. R., HudsonA. L., Doble A., Middlemiss 160 10 20 30 180 60 90 120 D. N., Shaw J. and Turnbull M. J. (1980) (–) Baclofen TIME (rein) decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283: Fig. 2. Effect of 5-HT antagonists on baclofen-induced 92-94. catatonia in rats. Catatonia was induced by baclofen (10 mg/ kg, i.p.). Saline in the control group or 5-HT antagonists Dourish C. T., Hutson P. H. and Curzon G. (1986) Putative anxiolytics 8-OH-DPAT, buspirone and TVX Q7821 are (except PCPA), were i.p. injected 30 min prior to baclofen. agonists at 5-HTIAautoreceptorsin the raphe nuclei. Trends PCPA was injected 72 and 48 hr prior to baclofen. Groupsare: Pharmac, Sci. 7: 212–214. control (.), 150 x 2 mg/kg PCPA (A), 5 mg/kg cyproheptaFaigle J.W. and Keberle H. (1972) The chemistry and kinetics dine (~), 3 mgkg pindolol (Y) and 20 mg/kg sulpiride (+). Postgrad. Med. J. 48 (Suppl 5): 9–13. of Lioresal. Data are presented as mean + SEM for 6 rats per group; Glaser T. and Traber J. (1983) Buspirone:Action on serotonin P c 0.05 (Mann–WhitneyU-test). receptors in calf hippocampus. Eur. J. Pharmac. 88: 137– A
1
138.
function as somatodendritic autoreceptors and at postsynaptic terminals (Verge et al., 1986). Behavioral response produced by the activation of 5-HTIAreceptors may arise from receptorswith eitherpre-synapticor postsynaptic localization (Lucki, 1990). Moreover, there is evidence to suggest the inhibition of 5-HT neurotransmission by buspirone (VanderMaelen and Wilderman, 1984) most likely via 5-HTIA autoreceptor stimulation (Dourish et al., 1986). The overall balance between inhibitory and facilitator effects of 5-HTIA partial agonist on 5-HT neurotransmissionmay vary in different areas of brain. In view of these reports, it is apparent that the potentiationof catatonia by buspironemay be due to the activation of pre-synapticreceptors that inhibit 5-HT synthesis and release. This fact was further substantiated by the observationthat inhibitionof 5-HT neurotransmission with the tryptophan hydroxylase inhibitor PCPA potentiated baclofen-inducedcatatonia. If facilitation of serotonergic neurotransmission attenuates catatonia, it would be expected that 5-HT receptorantagonists,which act at post-synapticreceptors, would exacerbate it. The present findings are in agreement with this prediction. The non-specific 5-HT antagonist cyproheptadine, the 5-HTIWIB antagonist pindolol and the 5-HT2 antagonistsulpiride significantly enhanced the baclofen-inducedcatatonia. In conclusion, increasing 5-HT neurotransmission attenuates whereas decreasing it exacerbates baclofen-
Gray J. A., Metz A., GoodwinG. M. and Green A. R. (1986a) The effect of the GABA mimetic drugs, progabide and baclofen, on the biochemistry and function of 5-hydroxytryptamine and noradrenaline.Neuropharmacology 25: 711– 716.
Gray J. A., Green A. R. and Molyneux S. G. (1986b)Effect of baclofen on the release of endogenous 5-HT from mouse cortex slices. Br. J. Pharmac. 87: 149p. Hill D. R. and BoweryN. G. (1981)3H-baclofenand 3H-GABA binds to bicuculline-insensitive GABA~ sites in rat brain. Nature 290: 149-152.
Inoe M., Matsuo T. and Ogata N. (1985) Baclofen activates voltage-dependent and 4-aminopyridine sensitive K+ conductance in guinea-pig hippocampal pyramidal cells maintained in vitro. Br. J. Pharmacol. 85: 833-841. Kaarianen I. (1976) Effects of amino-oxyacetic acid and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol in rats. Acta Pharmacol. Toxicol. 39: 393-401. Keller H. H., SchaffnerR. and Haefely W. (1976)Interactionof benzodiazepines with neuroleptics at central dopamine neurons. Naunyn-Schmiedeb. Arch. Pharmacol. 294: 1–9. Kulkami S. K., Arzi A. and Kaul P. N. (1980) Modificationof drug-inducedcatatonia and tremors by quipazine in rats and mice. Jap. J. Pharmac. 30: 129–135. Lucki I. (1990)Behavioral responsesassociatedwith serotonin receptors.Adv. Behav. Pharmac. 7: 119–148. Mehta A. K. and Ticku M. K. (1987) Baclofen induces catatonia in rats. Neuropharmacology 26: 1419–1423. Pycock C. J., Horton R. W. and Marsden C. D. (1976) The behavioral effects of manipulating GABA function in the globus pallidus. Brain Res. 116: 353-359.
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S. B. Kasture et al.
Pycock C. J. and Horton R. W. (1979) Dopamine dependent hyperactivity in rat following manipulation of GABAmechanism in the region of nucleus accumbens. J. Neural Transm. 45: 17–33.
Segal M. (1980)The action of serotoninin the rat hippocampal slice preparation. J. Physiol. 330: 423440. Siegel S. (1956) Nonparametric Statistics for the Behavioral Sciences (Harlow, H. F., Ed.), pp. 116-127. McGraw Hill Kogakusha,Tokyo.
VanderMaelenC. P. and Wilderman R. C. (1984) Buspirone,a non-benzodiazepine anxiolytic drug, causes inhibition of serotonergicdorsal raphe neurons in the rat brain slice. Soc. Neurosci. 10: 259. Verge D., Daval G., Marcinkeiwicz M., Patey A., El MestikawyS., Gozlan H. and Hamon M. (1986)Quantitative autoradiographyof multiple 5-HTIAreceptor subtypes in the brain of control or 5,7-dihydroxytryptamine-treatedrats. J. Neurosci. 6: 3474-3482.
Pergamon
@ PII:SO028-3908(%)00025-1
Baclofen-induced Catatonia: Modification by Serotonergic Agents S. B. KASTURE,l S. N. MANDHANE2and C. T. CHOPDE2* IM. V. P. Samaj’s College of Pharmacy, Gangapur Road, Nashik 422002, India and 2Department of Pharmaceutical Sciences, Nagpur UniversiQ Campus, Nagpur 440010, India (Accepted 1 March 1996)
Summary-Baclofen, a GABA~receptor agonist can induce catatonia in rats. This catatonia may serve as a tool for the study of GABA~receptor function. Reciprocalinteractionsbetween serotonin(5-HT) and GABA~ receptors in the CNS are known to occur. In the present study we examined the effects of various agents that influence serotonergic neurotransmissionon baclofen-inducedcatatonia in rats. The catatonia was rated by means of a scoring method, accordingto the severityof motor symptomsproducedby baclofen (10-15 mg/kg, i.p.). All serotowgic drugswereinjectedintraperitoneally 30minpriortobaclofen,exceptthe5-HTsynthesis inhibitorp-chlorophenylalanine (PCPA),whichwasinjected72and48hrpriorto baclofen.The5-HTreleaser fenfluramine(10mgkg) andtheuptakeinhibitorfluoxetine(10mgkg) reversed,whereasthe5-HT1~agonist buspirone(3 mg,kg)potentiatedbaclofen-induced catatonia.The5-HTsynthesisinhibitorPCPA(150x 2 mg/ kg),thenon-specific5-HTantagonistcyproheptadine (5 mg/kg),the5-HTINIEJ antagonistpindolol(3 mg/kg) and the 5-HTzantagonistsulpiride(20 mgikg)enhancedbaclofen-induced catatonia.It is concludedthatthe manipulationsof centralserotonergicmechanismsmodulatebaclofen-induced catatonia.Copyright0 1996 ElsevierScienceLtd.
Keywords-GABA~receptors,baclofen,catatonia,serotonergicneurotransmission.
GABA-mimetic agents when injected into the nucleus accumbens(Pycock and Horton, 1979)or globuspallidus (Pycock et al., 1976) of rats cause behavioraldepression, such as reduction in locomotoractivity, akinesia,rigidity and catalepsy, a syndrome generally considered to be Parkinsonism-like.The GABAB analogue, baclofen @ chloro-fl-phenylGABA), which can penetratethe blood– brain barrier is used clinically as a muscle relaxant in spastic conditions (Faigle and Keberle, 1972). Baclofen and the agents that increase GABA activity have been shown to potentate the cataleptic effect of neuroleptics (Kaarianen, 1976;Keller et al., 1976).Further,peripheral administration of baclofen can induce catatonia in rats and this may serve as a model for the study of GABAB receptors, since this catatonia is mediated through GABABreceptors (Mehta and Ticku, 1987). Previousstudies have indicated an interactionbehveen serotonin (5-HT) and GABABreceptors in the CNS. For instance, in in vitro binding studies, applicationof either 5-HT (Segal, 1980)or baclofen (Inoe et al., 1985)to CA1 pyramidal cells causes large hyperpolarizations,due to a
*To whom correspondenceshould be addressed. Tel. No. 910712-222943,Fax No. 91-0712-521746.
selective increase in K+ conductance. It has been shown that both 5-HT and baclofen modulate the same K+ channels, although they act via distinct receptors (Andrade et al., 1986). Furthermore, GABA~ receptors have been shown to be involved in the control of 5-HT release (Gray et al., 1986b).Activationof these receptors by baclofen decreases the output of 5-HT from mammalian CNS (Bowery et al., 1980). Additionally, baclofenwas found to have an inhibitoryaction on 5-HTmediated head twitch response in rats (Gray et al., 1986a). However, it is not known whether the phenomenon of baclofen-induced catatonia can be modified by serotonergic manipulations. In order to examine this question, we tested the effects of various agents that affect 5-HT neurotransmission on baclofen-induced catatonia. METHODS Male albino Wistar rats (200-250 g) housed at a constant room temperature (25°C), on a 12:12 hr light/ dark cycle were used. The animals were allowed free access to food and water. All experiments were carried out at the same time each day (0900-1500 hr). (i-)Baclofen (Hindustan Ciba-Geigy Ltd., Bombay),
595
596
S. B. Kasture et al.
(+)pindolol (Sandoz Ltd., Bombay) and (+)sulpiride (Sigma Chemical Cov StLoui$ MO)were dissolvedina minimal quantity ofO.l N hydrochloricacid and brought to the final volume with saline. Fenfluramine HC1 (Wockhardt Ltd., Bombay), fluoxetine HC1 (Sun Pharmaceuticals, Bombay), buspirone HC1 (Cadila IAbs, ~medabad), cyproheptadine HC1 (Themis Pharmaceuticals, Bombay), DL-p-chlorophenylalaninemethyl ester HC1(PCPA) (Sigma Chemical Co.) were dissolved in 0.9% w/v NaC1.All drugs were injected intraperitoneally (i.p.). Catatoniawas inducedwith baclofen (10-15 mg/kg)in groups of rats (n= 6/dose). Separate groups of rats were pre-treated with 5-HT agonists/antagonistsin the experiments that examined the effects of these drugs on baclofen-induced catatonia. 5-HT agonists/antagonists were given 30 min prior to baclofen except PCPA which was given 72 and 48 hr prior. Saline (0.9%, 0.2 ml per animal, i.p.) was used as control. The catatonia was measured up to 3 hr followingbaclofen administrationby a scoring method (Kulkami et al., 1980), as described below. The rat moved when placed on the table, score= O;the rat moved only when touched or pushed, score = 0.5; the rat placed on the table with front paw set alternately on a 3 cm high block failed to correct the posture in 10 see, score = 0.5 for each paw with a total of 1 for this stage; the rat failed to move when the front paws were placed alternately on a 9 cm high block, score = 1 for each paw with a total score of 2 for this stage. Thus, for a singlerat, the maximum possible scores were 3.5 reflecting total catatonia.A lower scole would mean an apparentlylesser degree of catatonia. Data are presented as mean +- SEM for 6 rats per group.The resultswere statisticallyanalysedby Kruskal– Wallis one-way ANOVA. Differencesin catatoniascores of various treatment groups were compared using nonparametric Mann–WhitneyU-test (Siegel, 1956).A value of P <0.05 was considered to be statisticallysignificant. RESULTS
3.5 I
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-I=JJ “+%y~”
1
●
●
●
0.5
●
*
*
01
●
,
10 20 30
1
I
I
80
90
*Lln
TIME
.
3SII
.
-
.-n
(rein)
Fig. 1.Effect of 5-HT agonistson baclofen-inducedcatatonia in rats. Catatoniawas inducedby baclofen (15 mg/kg, i.p.). Saline in the control group or 5-HT agonistswere i.p. injected 30 min before baclofen. Groups are: control (.), 10 mg/kg fenfluramine (+), 10 mg/kg fluoxetine (~) and 3 mg/kg buspirone (A). Data are presented as mean + SEM for 6 rats per group; P <0.05 (Mann–WhitneyU-test).
Effect of 5-HT antagonists
Prior administration of the tryptophan hydroxylase inhibitor (5-HT synthesis inhibitor) PCPA (150 mg/kg), the non-specific5-HT antagonist cyproheptadine(5 mg/ kg), the 5-HT1wl~receptorantagonistpindolol(3 mgkg) and the 5-HT2 antagonistsulpiride (20 mgilcg)enhanced baclofen-inducedcatatonia (Fig. 2). These 5-HT antagonists did not cause any catatonia or other motor impairmentwhen injected alone.
DISCUSSION
Baclofen, an agonist selective for GABAB receptor Administration of baclofen (10-15 mg/kg) induced catatonia in rats. The onset of effect was within 10 min (Hill and Bowery, 1981) has been shown to inhibit the and the maximum catatonia was seen at 60 min. The release of 5-HT from slices of frontal cortex of rat animals were recovered completely within 3 hr of the (Bowery et al., 1980) and mouse (Gray et al., 1986a). More recently, baclofen was shown to inhibit the headadministrationof baclofen. twitch responsemediated by 5-HT2 receptors, indicating Effect of 5-HT agonists the functional relationship between GABAB and 5-HT Figure 1 presents the effect of administration of receptors (Gray et al., 1986a). In our study, administravarious 5-HT receptor agonists on baclofen-induced tion of the 5-HT releaser fenfluramine and the 5-HT catatonia. The 5-HT releaser fenfluramine (10 mg/kg) uptake inhibitor fluoxetine significantly reversed the and the 5-HT uptake inhibitor fluoxetine (10 mg/kg) baclofen-inducedcatatonia suggesting that enhanced 5significantly reversed baclofen-induced catatonia. In HT neurotransmission reverses this GABAB mediated contrast to this, the 5-HTIA partial agonist buspirone (3 behavior. In contrast, the selective 5-HTIA receptor mg/kg) markedlypotentiatedbaclofen-inducedcatatonia. agonist buspirone (Glaser and Traber, 1983) markedly These 5-HT agonists were devoid of cataleptogenic potentiatedbaclofen-inducedcatatonia.5-HTIAreceptors are known to be locatedboth pre-synaptically,where they activity when injected alone.
5-HT in baclofen-inducedcatatonia 35r
3
2.5t 2
●
T
597
induced catatonia. The effect of 5-HT appears to be mediatedby the interactionsat several receptor subtypes. Although the location of these receptors remains to be determined, these interactions may have important clinical implications, in view of therapeutic use of baclofen and serotonergic agents (e.g. buspirone or fluoxetine).
~
are grateful to Mr Sunil Jaiswal for
Acknowledgement—We
artwork.
REFERENCES AndradeR.; MalenkaR. C. and Nicoll R. A. (1986)A Gprotein couples serotonin and GABA~ receptors to the same channels in hippocampus.Science 234: 1261–1265. 1 1 I t I I o“ BoweryN. G., Hill D. R., HudsonA. L., Doble A., Middlemiss 160 10 20 30 180 60 90 120 D. N., Shaw J. and Turnbull M. J. (1980) (–) Baclofen TIME (rein) decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283: Fig. 2. Effect of 5-HT antagonists on baclofen-induced 92-94. catatonia in rats. Catatonia was induced by baclofen (10 mg/ kg, i.p.). Saline in the control group or 5-HT antagonists Dourish C. T., Hutson P. H. and Curzon G. (1986) Putative anxiolytics 8-OH-DPAT, buspirone and TVX Q7821 are (except PCPA), were i.p. injected 30 min prior to baclofen. agonists at 5-HTIAautoreceptorsin the raphe nuclei. Trends PCPA was injected 72 and 48 hr prior to baclofen. Groupsare: Pharmac, Sci. 7: 212–214. control (.), 150 x 2 mg/kg PCPA (A), 5 mg/kg cyproheptaFaigle J.W. and Keberle H. (1972) The chemistry and kinetics dine (~), 3 mgkg pindolol (Y) and 20 mg/kg sulpiride (+). Postgrad. Med. J. 48 (Suppl 5): 9–13. of Lioresal. Data are presented as mean + SEM for 6 rats per group; Glaser T. and Traber J. (1983) Buspirone:Action on serotonin P c 0.05 (Mann–WhitneyU-test). receptors in calf hippocampus. Eur. J. Pharmac. 88: 137– A
1
138.
function as somatodendritic autoreceptors and at postsynaptic terminals (Verge et al., 1986). Behavioral response produced by the activation of 5-HTIAreceptors may arise from receptorswith eitherpre-synapticor postsynaptic localization (Lucki, 1990). Moreover, there is evidence to suggest the inhibition of 5-HT neurotransmission by buspirone (VanderMaelen and Wilderman, 1984) most likely via 5-HTIA autoreceptor stimulation (Dourish et al., 1986). The overall balance between inhibitory and facilitator effects of 5-HTIA partial agonist on 5-HT neurotransmissionmay vary in different areas of brain. In view of these reports, it is apparent that the potentiationof catatonia by buspironemay be due to the activation of pre-synapticreceptors that inhibit 5-HT synthesis and release. This fact was further substantiated by the observationthat inhibitionof 5-HT neurotransmission with the tryptophan hydroxylase inhibitor PCPA potentiated baclofen-inducedcatatonia. If facilitation of serotonergic neurotransmission attenuates catatonia, it would be expected that 5-HT receptorantagonists,which act at post-synapticreceptors, would exacerbate it. The present findings are in agreement with this prediction. The non-specific 5-HT antagonist cyproheptadine, the 5-HTIWIB antagonist pindolol and the 5-HT2 antagonistsulpiride significantly enhanced the baclofen-inducedcatatonia. In conclusion, increasing 5-HT neurotransmission attenuates whereas decreasing it exacerbates baclofen-
Gray J. A., Metz A., GoodwinG. M. and Green A. R. (1986a) The effect of the GABA mimetic drugs, progabide and baclofen, on the biochemistry and function of 5-hydroxytryptamine and noradrenaline.Neuropharmacology 25: 711– 716.
Gray J. A., Green A. R. and Molyneux S. G. (1986b)Effect of baclofen on the release of endogenous 5-HT from mouse cortex slices. Br. J. Pharmac. 87: 149p. Hill D. R. and BoweryN. G. (1981)3H-baclofenand 3H-GABA binds to bicuculline-insensitive GABA~ sites in rat brain. Nature 290: 149-152.
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