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

Prvg.

New-Psychapharmd.

&Bid.

1998. Vol. 22. pp. 835844

Psychiat.

Copyfight 0 1998 Elsevier Science Inc. Printed in the USA. All rights resewed 0278-5846/98

ELSEVIER

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PI1 SO27S-5S46(9SlOOO43-S

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, Spain

Universidad

(Final form, March

de Malaga,

Malaga,

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. NeuroPsychopharmacol. & 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,

Abbreviations:

dopamine

gammahydroxybutyric

gamma-aminobutyric

acid (GABA),

(GHB)

835

acid, tiapride Gammahydroxybutyric

acid

+ .oO

J.F. Navarro et cd.

836

Introduction Gammahydroxybutyric (GABA)

which

acid (GHB) is a metabolite

is able

administration

to

micromolar

quantities

peripheral

traverse

(Tunnicliff,

organs

1992;

(Maitre,

et al, 1990), a decrease

bilaterally

synchronous

release

regions

including

spike wave discharges

as well

(Laborit,

(Navarro

a regulatory

influence

dopaminergic

neurons

on specific neuronal

on

evidence

GHB and dopamine

populations

via specific GHB receptors.

binding

sites

the regulation

of global

nigra.

dopaminergic

have demonstrated

as apomorphine-induced

activity

The regulating

for

that GHB

that GHB might exert especially

on

of a central

stereotypes

studies have focused in the nigrostriatal the presence

could

activity

support

systems

on the role

pathway.

For

the GHB action

of

that GHB participates

in

in the brain. Likewise, exhibit

to exert a

of GHB high-affinity

Hechler

an antidopaminergic

and hypothermia.

GHB and analogs

in rodents which appears to be dose-dependent. described

GHB-induced of NCS-382, properties

interaction

et al. activity

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

has been clearly

Moreover,

et al,

et al, 1987;

and mesolimbic

have also suggested

that GHB ligands

et al, 1993) and mice (Navarro

pathways

nigrostriatal

This result

These authors

using neuropharmacological also induce catalepsy

(Vayer

systems,

the existence

In this sense, several

in substantia

by admintstration

changes

(Banerjee

Thus, the GHB system appears

Hechler et al. (1992) have documented activity.

tests.

suggesting

receptor.

of dopaminergic

dopaminergic

immobility

neurotransmitter

action on the dopaminergic

of GHB as a regulator instance,

1996) and

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

There is experimental

(1993)

different

a wide

hypothermia

as well as brain mechanisms

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

neuromodulatory

produces 1964)

seizures

in

as in several

with behavioral

absence

brain receptor

peripheral

and Pedraza,

associated

acid

is present

and uptake provide a marked support to the hypothesis

may act as a neuromodulator

between

after

substance

GHB administration sedation

of aggression

of specific

barrier

This

investigated

of petit mal or generalized

1993). The existence synthesis,

1994).

1997). In rodents, effects,

(Kaufman

those

blood-brain

Cash,

in all brain

range of pharmacological

resembling

the

of gamma-aminobutyric

in rats (Snead

and Bearden,

et al, 1996) using different catalepsy

is reduced

a GHB receptor

of the endogenous

are a cause for the recent interest

types

This state of 1980; Hechler of behavioural

in a dose-dependent

antagonist GHB system

In synthetic

(Schmidt

of GHB

manner

et al, 1991).

on the dopaminergic

ligands acting specifically

Catalepsy induced by tiapride and GHB coadministration

at GHB receptors (Maitre,

of any role as metabolic

precursor

of GABA in brain

1997).

Tiapride affinity

and devoid

a37

is a benzamide

for other

possesses

(Peters

antiaggressive

properties catalepsy

with a specific antagonism

receptors

(Costall

(Navarro

et al, 1987).

in mice (Navarro

point of view, recommended

in

compared

at

as an anxiolytic

potentiate

and

risk

of Dz receptors

1994).

of

tiapride

and without

neuroleptic

drug

1997)

and

anxiolytic

is also

able

to induce

at high doses.

treatment

severe

From a clinical

to benzodiazepines

alcohol

withdrawal,

or being

drug in elderly patients (Steele et al, 1993).

data, it can be predicted

the neuroleptic-induced

that administration

catalepsy.

the effects of GHB (200 mg/kg) and tiapride

alone or in combination,

This

Manzaneque,

Furthermore,

as an alternative

patients

From these experimental perhaps

Faulds,

et al, 1997), especially

it is considered

chlormethiazole

and

on catalepsy

evaluated

For this purpose

of GHB will the authors

(175 and 200 mg/kg), either

by the bar and grid tests in male

mice.

Methods Animals 300 OF.1 strain albino male mice weighing de Animales

de Laboratorio”,

Granada,

25-30 g were obtained

Spain. Animals arrived

from “Servicio

in the laboratory

at

42 days of age and were housed in transparent

plastic cages (24 x 13.5 x 13 cm)

in groups

conditions

of five

under

constant

temperature

animals

underwent

experimental

standardized

and laboratory a seven-day

treatments

lighting

(light:

chow and tap water available adaptation

period

to the

20:00-8:00),

a

ad libitum. All

laboratory

before

began.

Druq Administration GHB and tiapride provide

appropriate

experimental

groups

(Sigma Laboratories, doses for injection

Madrid, Spain) were diluted

(i.p). Animals were assigned

(24-26 mice per group) receiving:

1. GHB (200 mg/kg) + saline

in saline to

to six different

J.F. Navarro et al.

838

2. Tiapride

(175mglkg)

3. Tiapride

(200 mglkg) + saline

+ saline

(175 mg/kg)

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

was measured

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

bar of 5 mm in diameter

forepaws

were

gently

was placed

4 cm above

the floor.

put on the bar and the time it took the animal

least one paw on the floor was measured.

If 1 min elapsed

Animals’

to place at

without movement,

the

test was interrupted. In the gnd test, mice were placed head down, approximately framed

(40 cm x 30 cm) wire grid at an angle of 45 degrees

Under

these

conditions,

within l-2 sec. Testing

normal

undrugged

was terminated

midway on a woodwith the table surface.

mice quickly

scurried

down

when any limb moved or when

usually

1 min had

passed. Successive minutes

behavioral

evaluations

after administration

of catalepsy

were carried

of drugs. Between determinations,

in their home cages. Individual

out 30 and 60

the mice were kept

animals were tested in a random order.

Data Analysis Nonparametric

Kruskal-Wallrs

were used to assess the variance

of catalepsy

Subsequently,

comparisons

over different

treatment

groups.

were

out using

Mann-Whitney

carried

different

treatment

groups.

U-tests

appropriate

paired

to contrast

the behavior

A value of ~~0.05 was considered

in the

to be statistically

significant.

Results Table

1 illustrates

after administration

medians

(with ranges) of catalepsy

of GHB, tiapride

or GHB + tiapride

scores shown by animals in both catalepsy

tests.

839

Catalepsy induced by tiapride and GHB coadministration

Kruskal-Wallis

analysis

showed

scores over different treatment When tested

at 30 min, paired

increased

significantly

grid tests,

as compared

significantly

catalepsy

treated

that there

following

variance

comparisons

revealed

acute injection

in catalepsy

with the control

that catalepsy

of GHB (pcO.01)

group.

Tiapride

also showed

a significant

scores

in both bar and

(200 mg/kg)

scores only in the bar test (~~0.05).

with GHB+tiapride

in comparison

was significant

groups (pcO.001).

increased

Both groups of animals

increase

in catalepsy

with saline group (p
scores,

with tiapride

and GHB groups (pcO.001). When tested

at 60 min, paired comparisons

bar and grid tests) increased

significantly

compared

(p
with saline

GHB+tiapride with saline

showed group

group

a significant

(pcO.Ol),

GHB (pcO.01). Furthermore, exhibited

significantly

GHB+saline

indicated

that catalepsy

scores

(in

after injection of both doses of tiapride, Likewise,

increase

both groups

in catalepsy

as well as in comparison

of mice treated

scores,

with animals

as with

in comparison receiving

only

when tested in grid test mice treated with GHB+tiapride

more catalepsy

than mice treated

with tiapride+saline

and

(pcO.01).

No significant

differences

mg/kg of tiapride

were found between

in both behavioural

mice treated

with 175 and 200

tests.

Discussion Tiapride carried

(175 and 200 mg/kg)

increased

out 60 min after injection.

Therefore,

that 02 receptors

has been demonstrated catalepsy

(Navarro

catalepsy

of mice, especially

in agreement are clearly

with previous

involved

of catalepsy

scores

at 30 min after injection.

concordance

with recent

studies

in which a dose-dependent

after GHB administration

were found to display produced

a marked

while tiapride

in the mediation

it of

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

an increase was described

at test

studies,

a different

(Navarro

time course

but short lasting catalepsy

produced

a catalepsy

tone did not seem to be different

This result

is also in

effect on catalepsy

et al, 1996). GHB and tiapride

in the induction

of catalepsy.

GHB

with a peak of action within 30 min,

state with a peak of action at 60 min. Muscular

in all groups examined.

J.F. Navarro et al.

840

Table 1 Median Scores of Catalepsy

(with ranges) after Treatment

(Ti : 175 mg/kg; T2: 200 mglkg), GHB+Tl

Tiapride

with GHB (200 mg/kg),

and GHB+T2. Tests at 30 and 60 min

after Injection.

Bar

Saline

GHB+sal

T 1+sal

T2+sal

GHB+Tl

GHB+T2

0

6.5**

0

(O-O)

(O-60)

(O-21)

2***

19.5*

60*

(O-60)

(O-60)

(O-60)

0

0

9

6 **

(O-O)

(O-60)

10**

8.5**

(O-60)

(O-60)

(O-60)

(O-60)

Saline

GHB+sal

Tl +sal

T2+sal

GHB+Tl

GHB+T2

0

6

(O-6)

(O-60)

0

0

31’

31*

(O-13)

(O-42)

(O-60)

(O-60)

0

2

5.5**

9**

18**

29’

(O-22)

(O-60)

(O-60)

(O-60)

(O-9)

(O-60)

test 30’

60’

Grid

**

test 30’

60’

**

____Differs from saline group on Mann-Whiney

U-tests, *pcO.OOl ; l * ~~0.01; ***p
Catalepsy induced by tiapride and GHB coadministration

This

cataleptogenic

neuroleptic-like activity could

effect

activity

of GHB

of this substance

of GHB agonists,

opening

and opiates

Therefore, release

induce

the GHB-induced of opioid

naltrexone

actions

Feigenbaum

cataleptic

effect

since

Thirty

scores

injection,

by acting as an opiate

significantly also evident Catalepsy

possible

separately.

is considered

naloxone

and

that GHB might produce

agonist

(Schmidt examined

et al, 1991). the effects of

and their findings and, consequently.

indicated it was not

of GHB + tiapride

produced

in bar and grid tests. As Table

increased following

in animals

treated

coadministration

a clear 1 shows,

with both drugs.

of GHB + tiapride

scores observed

This potentiation

as an appropriate

receiving

drugs

antipsychotics

and GHB a careful

utility

in the

In

was

after administration

of tiapride-induced

catalepsy

animal model for extrapyramidal (Sanberg

of withdrawal

symptoms

associated of patients

frequency

et al, 1988). Therefore,

caution

syndrome

produced

to narcolepsy simultaneously

should

it has been

because

effects.

Although

successfully

used

by alcohol and opiates

(Cash, 1994; Maitre, treated

simultaneously

be required

of extrapyramidal

of GHB is still limited,

treatment

reduced.

coadministration

of catalepsy

increase

therapeutic

catalepsy.

by increased

that

point of view, our data suggest that in patients treated

neuroleptic

tested

was

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

effects in humans

number

be produced

binding

higher than the sum of catalepsy

of GHB and tiapride

clinical

receptor

including

reported

(1996) have recently

on catalepsy

were markedly

fact, the induction

been

agonist.

of their actions

catalepsy

could

it has been

inactive at every dose examined

receptor

min after

potentiation

effects,

effect of GHB, suggesting

GHB on mu, delta and kappa-opioid a direct opiate

(or analogs)

GHB has alrealdy

of similar

and Simantov

that GHB was clearly

antipsychotic

that GHB agonists

a number

abolish the cataleptic

However,

the potential

and

patients (Levy et al, 1982; Schuls et al, 1981).

substances,

some of its central

an antidopaminergic

and underlies

Nevertheless,

success on schizophrenic

GHB

indicate

up the possibility

be used as antipsychotics.

without

can

841

sidefrom a with of a the in the

and to alleviate

1997). In any case, the

with both drugs

will be presumably

J.F. Navarro et al.

842

Conclusion Tiapride-induced mg/kg).

These

with central interaction

catalepsy

was clearly

results are in agreement

dopamine mechanisms

D2 transmission

between

potentiated

by GHB administration

with the view that GHB receptors Further

GHBergic

studies

are needed

and dopaminergic

(200 interact

to clarify the

systems.

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844

J.F.Navarro&al.

Inquiries

and reprint requests should be addressed

Dr. Jose Francisco

Navarro

Area de Psicobiologia, Campus

to’

de Teatinos,

Facultad

de Psicologia,

29071 Mtilaga,

Universidad

de MBlaga

Spain. E-mail: [email protected]