Tiapride-induced catalepsy is potentiated by gamma-hydroxybutyric acid administration

ELSEVIER

Prvg. New-Psychapharmd. &Bid. Psychiat. 1998. Vol. 22. pp. 835844

Copyfight 0 1998 Elsevier Science Inc. Printed in the USA. All rights resewed

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TIAPRIDE-INDUCED CATALEPSY IS POTENTIATED BY GAMMA-HYDROXYBUTYRIC ACID ADMINISTRATION

JOSE FRANCISCO NAVARRO, CARMEN PEDRAZA, MERCEDES MARTIN, JUAN M. MANZANEQUE, GUADALUPE DAVILA and ENRIQUE MALDONADO

Area de Psicobiologia, Facultad de Psicologia, Universidad de Malaga, Malaga, Spain

(Final form, March 1998)

Abstract

Navarro, Jose Francisco, Carmen Pedraza, Mercedes Martin, Juan M. Manzaneque, Guadalupe Davila and Enrique Maldonado: Tiapride-induced catalepsy is potentiated by gammahydroxybutiric acid administration. Prog. Neuro- Psychopharmacol. & Biol. Psychiat. 1998, 22. pp. 835-844. o 1998 Ek&er Science lnc.

1. The effect of administration of gammahydroxybutyrate (GHB) and tiapride, either alone or in combination, on catalepsy behavior was examined in male mice.

2. Catalepsy was measured by bar and grid tests. Two successive evaluations were carried out 30 and 60 min after injections.

3. Tiapride (175 and 200 mg/kg) and gammahydroxybutyrate (200 mg/kg) provoked an increase of catalepsy scores, exhibiting different time courses. GHB produced a marked but short lasting catalepsy with a peak of action at 30 min, while tiapride produced a catalepsy state with a peak of action at 60 min.

4. Tiapride-induced catalepsy was potentiated by gammahydroxybutyrate administration at 30 min (bar test) and 60 min (bar and grid tests).

5. These results underlie the view that GHB interacts with central dopamine Dz transmission.

Keywords: catalepsy, dopamine gammahydroxybutyric acid, tiapride

Abbreviations: gamma-aminobutyric acid (GABA), Gammahydroxybutyric acid

(GHB)

835

836 J.F. Navarro et cd.

Introduction

Gammahydroxybutyric acid (GHB) is a metabolite of gamma-aminobutyric acid

(GABA) which is able to traverse the blood-brain barrier after peripheral

administration (Tunnicliff, 1992; Cash, 1994). This substance is present in

micromolar quantities in all brain regions investigated as well as in several

peripheral organs (Maitre, 1997). In rodents, GHB administration produces a wide

range of pharmacological effects, including sedation (Laborit, 1964) hypothermia

(Kaufman et al, 1990), a decrease of aggression (Navarro and Pedraza, 1996) and

bilaterally synchronous spike wave discharges associated with behavioral changes

resembling those of petit mal or generalized absence seizures (Banerjee et al,

1993). The existence of specific brain receptor as well as brain mechanisms for

synthesis, release and uptake provide a marked support to the hypothesis that GHB

may act as a neuromodulator on specific neuronal populations (Vayer et al, 1987;

Hechler et al, 1992; Cash, 1994). In fact, it has been proposed that GHB might exert

a regulatory influence on different neurotransmitter systems, especially on

dopaminergic neurons (Diana et al, 1991; Hechler et al, 1993).

There is experimental evidence suggesting the existence of a central interaction

between GHB and dopamine receptor. Thus, the GHB system appears to exert a

neuromodulatory action on the dopaminergic nigrostriatal and mesolimbic systems

via specific GHB receptors. In this sense, several studies have focused on the role

of GHB as a regulator of dopaminergic activity in the nigrostriatal pathway. For

instance, Hechler et al. (1992) have documented the presence of GHB high-affinity

binding sites in substantia nigra. This result could support the GHB action of

dopaminergic activity. These authors have also suggested that GHB participates in

the regulation of global dopaminergic activity in the brain. Likewise, Hechler et al.

(1993) have demonstrated that GHB ligands exhibit an antidopaminergic activity

using neuropharmacological tests which can usually predict an anti-D2 profile, such

as apomorphine-induced stereotypes and hypothermia. GHB and analogs of GHB

also induce catalepsy in rodents which appears to be dose-dependent. This state of

immobility has been clearly described in rats (Snead and Bearden, 1980; Hechler

et al, 1993) and mice (Navarro et al, 1996) using different types of behavioural

tests. Moreover, GHB-induced catalepsy is reduced in a dose-dependent manner

by admintstration of NCS-382, a GHB receptor antagonist (Schmidt et al, 1991).

The regulating properties of the endogenous GHB system on the dopaminergic

pathways are a cause for the recent interest In synthetic ligands acting specifically

Catalepsy induced by tiapride and GHB coadministration a37

at GHB receptors and devoid of any role as metabolic precursor of GABA in brain

(Maitre, 1997).

Tiapride is a benzamide with a specific antagonism of Dz receptors and without

affinity for other receptors (Peters and Faulds, 1994). This neuroleptic drug

possesses antiaggressive (Navarro and Manzaneque, 1997) and anxiolytic

properties (Costall et al, 1987). Furthermore, tiapride is also able to induce

catalepsy in mice (Navarro et al, 1997), especially at high doses. From a clinical

point of view, it is considered as an alternative treatment to benzodiazepines or

chlormethiazole in patients at risk of severe alcohol withdrawal, being

recommended as an anxiolytic drug in elderly patients (Steele et al, 1993).

From these experimental data, it can be predicted that administration of GHB will

perhaps potentiate the neuroleptic-induced catalepsy. For this purpose the authors

compared the effects of GHB (200 mg/kg) and tiapride (175 and 200 mg/kg), either

alone or in combination, on catalepsy evaluated by the bar and grid tests in male

mice.

Methods

Animals

300 OF.1 strain albino male mice weighing 25-30 g were obtained from “Servicio

de Animales de Laboratorio”, Granada, Spain. Animals arrived in the laboratory at

42 days of age and were housed in transparent plastic cages (24 x 13.5 x 13 cm)

in groups of five under standardized lighting conditions (light: 20:00-8:00), a

constant temperature and laboratory chow and tap water available ad libitum. All

animals underwent a seven-day adaptation period to the laboratory before

experimental treatments began.

Druq Administration

GHB and tiapride (Sigma Laboratories, Madrid, Spain) were diluted in saline to

provide appropriate doses for injection (i.p). Animals were assigned to six different

experimental groups (24-26 mice per group) receiving:

1. GHB (200 mg/kg) + saline

838 J.F. Navarro et al.

2. Tiapride (175mglkg) + saline

3. Tiapride (200 mglkg) + saline

4. GHB (200 mg/kg)+ tiapride (175 mg/kg)

5. GHB (200 mg/kg) + tiapride (200 mg/kg)

6. Saline group. Mice were treated with two injections of 0.9 % NaCI.

Experimental Procedure

Catalepsy was measured by means of the bar and grid tests. In the bar test, an

aluminium bar of 5 mm in diameter was placed 4 cm above the floor. Animals’

forepaws were gently put on the bar and the time it took the animal to place at

least one paw on the floor was measured. If 1 min elapsed without movement, the

test was interrupted.

In the gnd test, mice were placed head down, approximately midway on a wood-

framed (40 cm x 30 cm) wire grid at an angle of 45 degrees with the table surface.

Under these conditions, normal undrugged mice quickly scurried down usually

within l-2 sec. Testing was terminated when any limb moved or when 1 min had

passed.

Successive behavioral evaluations of catalepsy were carried out 30 and 60

minutes after administration of drugs. Between determinations, the mice were kept

in their home cages. Individual animals were tested in a random order.

Data Analysis

Nonparametric Kruskal-Wallrs were used to assess the variance of catalepsy

over different treatment groups. Subsequently, appropriate paired comparisons

were carried out using Mann-Whitney U-tests to contrast the behavior in the

different treatment groups. A value of ~~0.05 was considered to be statistically

significant.

Results

Table 1 illustrates medians (with ranges) of catalepsy scores shown by animals

after administration of GHB, tiapride or GHB + tiapride in both catalepsy tests.

Catalepsy induced by tiapride and GHB coadministration 839

Kruskal-Wallis analysis showed that there was significant variance in catalepsy

scores over different treatment groups (pcO.001).

When tested at 30 min, paired comparisons revealed that catalepsy scores

increased significantly following acute injection of GHB (pcO.01) in both bar and

grid tests, as compared with the control group. Tiapride (200 mg/kg) increased

significantly catalepsy scores only in the bar test (~~0.05). Both groups of animals

treated with GHB+tiapride also showed a significant increase in catalepsy scores,

in comparison with saline group (p<O.OOi), as well as in comparison with tiapride

and GHB groups (pcO.001).

When tested at 60 min, paired comparisons indicated that catalepsy scores (in

bar and grid tests) increased significantly after injection of both doses of tiapride, as

compared with saline group (p<O.Ol). Likewise, both groups of mice treated with

GHB+tiapride showed a significant increase in catalepsy scores, in comparison

with saline group (pcO.Ol), as well as in comparison with animals receiving only

GHB (pcO.01). Furthermore, when tested in grid test mice treated with GHB+tiapride

exhibited significantly more catalepsy than mice treated with tiapride+saline and

GHB+saline (pcO.01).

No significant differences were found between mice treated with 175 and 200

mg/kg of tiapride in both behavioural tests.

Discussion

Tiapride (175 and 200 mg/kg) increased catalepsy of mice, especially at test

carried out 60 min after injection. Therefore, in agreement with previous studies, it

has been demonstrated that 02 receptors are clearly involved in the mediation of

catalepsy (Navarro et al, 1997). On the other hand, GHB (200 mg/kg) also provoked

an increase of catalepsy scores at 30 min after injection. This result is also in

concordance with recent studies in which a dose-dependent effect on catalepsy

was described after GHB administration (Navarro et al, 1996). GHB and tiapride

were found to display a different time course in the induction of catalepsy. GHB

produced a marked but short lasting catalepsy with a peak of action within 30 min,

while tiapride produced a catalepsy state with a peak of action at 60 min. Muscular

tone did not seem to be different in all groups examined.


Table 1

Median Scores of Catalepsy (with ranges) after Treatment with GHB (200 mg/kg),

Tiapride (Ti : 175 mg/kg; T2: 200 mglkg), GHB+Tl and GHB+T2. Tests at 30 and 60 min

after Injection.

Bar

test

Saline GHB+sal T 1 +sal T2+sal GHB+Tl GHB+T2

30’ 0 6.5** 0 2*** 19.5* 60*

(O-O) (O-60) (O-21) (O-60) (O-60) (O-60)

60’ 0 0 9 ** 6 ** 10** 8.5**

(O-O) (O-60) (O-60) (O-60) (O-60) (O-60)

Grid Saline GHB+sal Tl +sal T2+sal GHB+Tl GHB+T2

test

30’ 0 6 ** 0 0 31’ 31*

(O-6) (O-60) (O-13) (O-42) (O-60) (O-60)

60’ 0 2 5.5** 9** 18** 29’

(O-9) (O-22) (O-60) (O-60) (O-60) (O-60)

____-

Differs from saline group on Mann-Whiney U-tests, *pcO.OOl ; l * ~~0.01; ***p<O.O5


This cataleptogenic effect of GHB can indicate an antidopaminergic and

neuroleptic-like activity of this substance and underlies the potential antipsychotic

activity of GHB agonists, opening up the possibility that GHB agonists (or analogs)

could be used as antipsychotics. Nevertheless, GHB has alrealdy been tested

without success on schizophrenic patients (Levy et al, 1982; Schuls et al, 1981).

GHB and opiates induce a number of similar effects, including catalepsy.

Therefore, the GHB-induced cataleptic effect could be produced by increased

release of opioid substances, since it has been reported that naloxone and

naltrexone abolish the cataleptic effect of GHB, suggesting that GHB might produce

some of its central actions by acting as an opiate agonist (Schmidt et al, 1991).

However, Feigenbaum and Simantov (1996) have recently examined the effects of

GHB on mu, delta and kappa-opioid receptor binding and their findings indicated

that GHB was clearly inactive at every dose examined and, consequently. it was not

a direct opiate receptor agonist.

Thirty min after injection, coadministration of GHB + tiapride produced a clear

potentiation of their actions on catalepsy in bar and grid tests. As Table 1 shows,

catalepsy scores were markedly increased in animals treated with both drugs. In

fact, the induction of catalepsy following coadministration of GHB + tiapride was

significantly higher than the sum of catalepsy scores observed after administration

of GHB and tiapride separately. This potentiation of tiapride-induced catalepsy was

also evident 60 min after injection when mice were tested in the grid test.

Catalepsy is considered as an appropriate animal model for extrapyramidal side-

effects in humans receiving antipsychotics (Sanberg et al, 1988). Therefore, from a

clinical point of view, our data suggest that in patients treated simultaneously with

neuroleptic drugs and GHB a careful caution should be required because of a

possible increase in the frequency of extrapyramidal effects. Although the

therapeutic utility of GHB is still limited, it has been successfully used in the

treatment of withdrawal syndrome produced by alcohol and opiates and to alleviate

symptoms associated to narcolepsy (Cash, 1994; Maitre, 1997). In any case, the

number of patients simultaneously treated with both drugs will be presumably

reduced.


Conclusion

Tiapride-induced catalepsy was clearly potentiated by GHB administration (200

mg/kg). These results are in agreement with the view that GHB receptors interact

with central dopamine D2 transmission Further studies are needed to clarify the

interaction mechanisms between GHBergic and dopaminergic systems.

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844 J.F. Navarro &al.

Inquiries and reprint requests should be addressed to’

Dr. Jose Francisco Navarro

Area de Psicobiologia, Facultad de Psicologia, Universidad de MBlaga

Campus de Teatinos, 29071 Mtilaga, Spain. E-mail: [email protected]

Tiapride-induced catalepsy is potentiated by gamma-hydroxybutyric acid administration

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