_Journal of_

J NeuralTransm(1996) 103:1255-1263 Neural

Transmission
9 Springer-Verlag 1996
Printed in Austria

The GABAB-receptor antagonist, CGP 35348, antagonises

y-hydroxybutyrate- and baclofen-induced alterations in
locomotor activity and forebrain dopamine levels in mice

H. Nissbrandt 1 and G. Engberg 2

1Department of Pharmacology, Institute of Physiology and Pharmacology, GOteborg
University, G6teborg, and 2Division of Pharmacology, Department of Physiology and
Pharmacology, Karolinska Institute, Stockholm, Sweden

Accepted August 21, 1996

Summary. Previous studies have shown that administration of 7-

hydroxybutyric acid (GHBA) or baclofen is associated with a decrease in
locomotor activity as well as an increase of dopamine (DA) in brain. In the
present study we analyse whether these actions are related to activation of
GABAB-receptors utilising a GABAB-receptor antagonist, CGP 35348. Ad-
ministration of GHBA (200 or 800mg/kg, i.p.) or baclofen (4 or 16mg/kg, i.p,)
induced a marked and dose-dependent decrease in locomotor activity in mice,
that was antagonised by pretreatment with CGP 35348 (400mg/kg, i.p.).
Treatment with the highest doses of GHBA and baclofen produced clear-cut
increases in forebrain DA concentration. Also these effects were effectively
antagonised by pretreatment with CGP 35348. Treatment with the GABAB-
receptor antagonist alone did not influence the locomotor activity or brain
DA concentration. These results indicate that the behaviourally depressive
and DA increasing effects of GHBA and baclofen are mediated by activation
of GABAB-receptors.
Keywords: Baclofen, y-hydroxybutyric acid, CGP 35348, dopamine, GABAB
receptors, locomotor activity.

Abbreviations
CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid], G A B A 7-
aminobutyric acid, G H B A 7-hydroxybutyric acid, G B L 7-butyrolactone, D A
dopamine.

Introduction
y-Hydroxybutyric acid (GHBA), a structural analogue of y-aminobutyric acid
(GABA), is a naturally occurring compound in mammalian brain (Bessrnan
1256 H, Nissbrandt and G. Engberg

and Fishbein, 1963; Roth and Giarman, 1970; Vayer et al., 1987) whose
physiological significance is unknown. Systemic administration of GHBA or
its prodrug 7-butyrolactone (GBL) produces behavioural depression and
anaesthesia in animals and humans, but lack of analgesia have limited their
use as anaesthetics (see Snead, 1977; Tunnicliff, 1992). Recently, however,
novel applications for GHBA have emerged; clinical studies have shown that
the drug given orally in non-hypnotic doses suppresses ethanol consumption,
craving and withdrawal symptoms in alcoholics (see Biggio et al., 1992).
Animal experiments have revealed that GHBA suppresses specifically the
spontaneous firing rate of midbrain dopamine (DA) neurons (Roth et al.,
1973) and increases brain DA concentrations (Gessa et al., 1966); the latter
effect being attributed to the GHBA-induced reduction of DA release (Gessa
et al., 1968; Walters and Roth, 1972; Stock et al., 1973). Due to these proper-
ties, GHBA, or its prodrug GBL, frequently is used as a pharmacological tool
in studies on dopaminergic physiology and pharmacology.
The presence of membrane binding sites in the brain with high affinity for
GHBA and little affinity to G A B A or GABAergic agonists has initiated the
suggestion that the pharmacological actions of the drug are mediated by
activation of specific GHBA binding sites (Benavides et al., 1982; Maitre et
al., 1983). Recent findings, however, indicate that GHBA directly or indirectly
induces a stimulation of GABAB-receptors. Thus, it has been shown that all of
the following effects of GHBA, or its prodrug GBL, can be antagonised by
GABA~-receptor antagonists; (1) increase in D A synthesis rate (Waldmeier,
1991), (2) postsynaptic potentials in rat hippocampal slices (Xie and Smart,
1992a,b), (3) induction of absence-like seizures (Bernasconi et al., 1992), (4)
attenuation of GABA and glutamate release (Banarjee and Snead, 1995), and
(5) decrease of firing rate and regularisation of firing pattern of dopaminergic
substantia nigra neurons (Engberg and Nissbrandt, 1993; Engberg et al.,
1993).
So, although many of the central effects of GHBA seem to be mediated by
stimulation of central GABAB receptors the mechanisms for other effects of
the drug have not yet been established, Therefore, the aim of the present
study was to investigate whether also the behaviourally depressive and the
DA increasing effects of the drug are mediated by activation of GABAB-
receptors. As a comparison the effects of the GABAB-receptor agonist,
baclofen, were also investigated.

Materials and methods

Animals and drugs
Male albino mice of the NMRI strain (B&K International AB, Sollentuna, Sweden),
weighing 20-30g were used in all experiments. The animals were housed in cages under
controlled environmental conditions (temperature 25~ light 5 a.m.-7 p.m., dark 7 p.m.-
5 a.m.). Food and tap water were allowed ad libitum. The experimental procedures were
all carried out during daytime. The following drugs were used: D-L-baclofen (kindly
donated by Ciba, Basel, Switzerland), [3-aminopropyl(diethoxymethyl)phosphinicacid]
(CGP 35348, kindly donated by Ciba, Basel, Switzerland), and y-hydroxybutyric acid
sodium salt (GHBA; Sigma, St. Louis, MO, USA). All drugs were administered i.p.
 7-Hydroxybutyrate effects mediated by GABAB receptors 1257

Locomotor activity
The locomotor activity was measured by M/P 40 Fc Electronic Motility Meters (Motron
Products, Stockholm, Sweden), equipped with 40 photocells arranged in 5 rows of 8 cells
with a centre to centre distance of 40 mm. The motility meters were kept in sound- and
light-proof boxes and were connected to external electromechanical time-interval
counters. Saline or CGP 35348 was injected in the homecage 5rain before baclofen or
GHBA. Immediately following the injection of baclofen or GHBA the mice were placed
in the motility meters. One mouse was placed in each motron box. Mice were habituated
10rain before measurement.

Assay of dopamine
Following drug treatment and determination of locomotor activity the animals were
killed by decapitation by a guillotine (60rain after drug treatment). The brains were
rapidly taken out, placed on an ice-chilled petri dish and divided into two parts by means
of a frontal section at the level of the median eminence. The anterior part of the brains
were immediately frozen on dry ice and stored at -70~ until analysis. The forebrains
were homogenised with an Ultra-Turrax homogeniser in 0.1M H C 1 0 4 containing 4.5mM
Na2EDTA and 1.6mM reduced glutathione. Quantification of DA was performed by
means of reversed-phase high performance ion-pair liquid chromatography with electro-
chemical detection essentially according to standard procedures (Felice et al., 1978)
following injection of eluate after adsorption of the catecholamine onto aluminum oxide
(Anton and Sayre, 1962).

Results
Locomotor activity
Systemic administration of baclofen (4 or 16 mg/kg) or G H B A (200 or 800rag/
kg) inhibited dose-dependently the locomotor activity in habituated mice
(Fig. 1). The behavioral depression of the two drugs was similar in quality,
including ataxia, decreased muscle tone and hypnosis. The inhibitory effect of
the drugs on locomotor activity was antagonised by p r e t r e a t m e n t with C G P
35348 (400mg/kg, given 5rain before saline, baclofen or G H B A ) with excep-
tion for the highest dose of G H B A . Pretreatment with C G P 35348 in a lower
dose (200mg/kg) did not significantly antagonise the action of baclofen or
G H B A (data not shown). P r e t r e a t m e n t with C G P 35348 (400mg/kg) alone
did not significantly affect the locomotor activity w h e n c o m p a r e d to the saline
controls.

Brain dopamine concentration

The smaller doses of baclofen (4mg/kg) and G H B A (200mg/kg) did not
significantly affect the D A concentrations in the forebrain w h e n m e a s u r e d 1 h
after drug administration. However, the larger doses of baclofen (16mg/kg)
and G H B A (800mg/kg) increased the D A concentrations by 35% and 75%,
respectively (Fig. 2). The D A increasing effect induced by the drugs was
antagonised by p r e t r e a t m e n t with C G P 35348 (400mg/kg) while t r e a t m e n t
with C G P 35348 alone did not, in analogy to the behavioral result, influence
the D A concentrations.
1258 H. Nissbrandt and G. Engberg

180 F*l
t~
135 "+l
L
90 •
F+q
45

,,4 (6) (13) (6)

'4- Jr + +
+ +

+ +

Fig. 1. The effects of baclofen (Bac; 4 or 16mg/kg, i,p.), ~-hydroxybutyric acid (GHBA;
200 or 800mg/kg, i.p.) and CGP 35348 (CGP; 400mg/kg, i.p., given 5min before saline,
baclofen or GHBA) on locomotor activity in mice. Data, which represents the sum of
counts from 10-60min after administration of saline, baclofen or GHBA, are means _+
SEM for the numbers of animals given within brackets. Statistical significances between
groups were calculated utilising Mann-Whitney's U-test.; ***p < 0.01 vs. NaC1 + NaC1
treated group, + p < 0.05, + + p < 0.01

Discussion
The results of the present study indicate, for several reasons, that the
behavioural depression induced by G H B A is, at least partly, due to an activa-
tion of GABAB-receptors. Firstly, the quality of the behavioural depression
induced by G H B A is similar to that following administration of baclofen,
which is considered as a potent and specific GABAB-receptor agonist (see
Bowery, 1993; Misgeld et al., 1995). Both drugs induce a behavioural depres-
sion characterized by ataxia, decreased locomotor activity, decreased muscle
tone and hypnosis. The decrease in locomotor activity induced by G H B A or
baclofen in the present study is quantitatively similar to that observed by
previous investigators (Gianutsos and Moore, 1978; Wachtel and And~n,
1978). Secondly, and more important, the actions of the drugs on locomotor
activity were antagonised by pretreatment with the specific GABAB-receptor
antagonist CGP 35348 (Olpe et al., 1990). However, CGP 35348 did not
antagonise the hypoactivity produced by the highest dose of G H B A . This may
be related to a putative relatively weak affinity of the antagonist at GABAB-
receptor sites. Alternatively, at higher doses of G H B A other mechanisms of
actions than GABAB-receptor agonism are responsible for the inhibition of
locomotor activity.
 y-Hydroxybutyrate effects mediated by GABAB receptors 1259
+
r
3000-
I
2500-

2000-
I I I
$1
I
1500-

'ff 1000-
i
i
i
500-
I
(6) (6) (6) (6) (6) (6) (6) (6) (6) (6)
0 "~ N-

".F +
+ +
-I- +

+ + + +

Fig. 2. The effects of baclofen (Bac; 4 or 16mg/kg, i.p.), y-hydroxybutyricacid (GHBA;

200 or 800mg/kg, i.p.) and CGP 35348 (CGP; 400mg/kg, i.p., given 5rain before saline,
baclofen or GHBA) on the dopamine concentrations in forebrain. Saline, baclofen or
GHBA was given 60rain before sacrifice. Shown data are means _+SEM for the numbers
of animals given within brackets. Statistical significancebetween groups were calculated
utilising Mann-Whitney's U-test.; + p < 0.05, **p < 0.01 vs. NaC1 + NaC1treated group,
***p < 0.01 vs. NaC1 + NaC1 treated group

Concomitant with the reduced locomotor activity seen after baclofen or

G H B A administration we also observed the well-known increase in forebrain
D A concentration induced by these drugs (Gessa et al., 1966; And6n and
Wachtel, 1977). The D A increasing effects of these drugs are considered to be
secondary to their inhibitory action on the firing rate (Roth et al., 1973) and
their ability to affect the firing pattern (Engberg and Nissbrandt, 1993;
Engberg et al., 1993) of midbrain D A neurons. Thus, the inhibition of firing
induces a decrease of D A release (Imperato and Di Chiara, 1984; Santiago
and Westerink, 1991) which in turn induces an increase of D A synthesis due
to decreased stimulation of D A autoreceptors. The present finding that CGP
35348 antagonised the increase in D A is therefore in line with our previous
results showing that the effects of G H B A on the firing properties of D A
neurons are mediated by GABAB-receptor stimulation (Engberg and
Nissbrandt, 1993; Engberg et al., 1993). The present results are also in line
with previous findings showing that the increases in D A synthesis rate induced
by GBL and baclofen are antagonised by CGP 35348 (Waldmeier, 1991).
A large body of previous experiments has shown that D A release in the
forebrain is of importance for the control of locomotor activity (see Beninger,
1983; Bloom et al., 1989). Althought it may be hypothesised that the
1260 H. Nissbrandt and G. Engberg

hypoactivity seen after administration of baclofen or G H B A is a consequence

of a reduced release of D A in the forebrain, the quality of the behaviour
induced by these drugs differs dramatically from the cataleptic behaviour
induced by drugs that blocks dopaminergic neurotransmission. Furthermore,
as compared to the increase in forebrain D A concentration the decrease in
locomotor activity was seen following comparatively smaller doses of
baclofen and GHBA. Therefore, it is more likely that the behavioural depres-
sion, manifested as a decreased locomotor activity, and the decrease in D A
release induced by G H B A and baclofen not are causally related but instead
are due to stimulation of different GABAB receptor populations in the brain
and/or different subtypes of GABAB receptors (Bonnano and Raiteri, 1993;
see Misgeld et al., 1995).
Baclofen is regarded as a selective GABAB receptor agonist with low
affinity for G A B A a receptors (see Bowery, 1993; Misgeld et al., 1995) and
there is also poor evidence for that G H B A directly or indirectly stimulates
neurotransmission at GABAA receptors (Benavides et al., 1982; Serra et al.,
1991; Diana et al., 1993; for discussion see Snead and Liu, 1993). Therefore it
is interesting that the behavioural depression induced by G H B A or baclofen in
many aspects is similar to that induced by sedative-hypnotic drugs, such as
barbiturates and benzodiazepines, that primarily interact with the GABAA
receptor. Furthermore, like barbiturates and bensodiazepines, G H B A shows
a cross-tolerance against ethanol (Colombo et al., 1995a), is self-administered
by rats (Colombo et al., 1995b), decreases alcohol withdrawal symptoms (see
Introduction) and has a liability to be abused by humans (Food and Drug
Administration, 1991). The similarity in behavioural response following
GABAA and GABAB receptor stimulation, is not consistent with the view that
GABAB receptors preferentially are located presynaptically on GABAergic
terminals and there function as autoreceptors inhibiting G A B A release.
Rather, as supported by the present results, a large proportion of GABAB
receptors has to be localized postsynaptically and, like GABAA receptors,
induce postsynaptic hyperpolarisation when stimulated (see Misgeld et al.,
1995). In addition, stimulation of presynaptically located GABAB receptors
decreases the release of excitatory amino acids and consequently the
depolarising actions of these transmitters (see Misgeld et al., 1995).
GABAB-receptors are believed to exert a general inhibitory action in
the brain, thereby, in many aspects, counterbalancing the excitatory action of
excitatory amino acids, e.g. glutamate (see Banarjee and Snead, 1995;
Engberg et al., 1993; see Misgeld et al., 1995). In recent years much
interest has been focused on a putative deficiency of glutamate in the patho-
genesis of schizophrenia (Kim et al., 1980; Carlsson, 1988; Deutsch et al.,
1989). A problem with this hypothesis is that, at present, there are few clini-
cally suitable pharmacological probes available to clinically test this idea.
However, if the hypothesis is correct, a GABAB-receptor antagonist, e.g.
CGP 35348 which in the present study is shown to antagonise behavioural
actions of baclofen and GHBA, may be of therapeutic value in the treatment
of psychotic disorders by indirectly promoting the central actions of
glutamate.
 y-Hydroxybutyrate effects mediated by GABAB receptors 1261

In s u m m a r y , the results o b t a i n e d in the p r e s e n t study indicate that the

behaviourally depressive effect and the D A increasing effect of G H B A and
baclofen are m e d i a t e d by activation of GABAB-receptors.

Acknowledgements
This study was supported by the Swedish Medical Research Council (no 7484),
"A_hl6nstiftelsen", "Magnus Bergvalls stiftelse", "Gun och Bertil Stohnes stiftelse",
"Lundbeckfonden", and "Loo och Hans Ostermans fond f6r medicinsk forskning". The
expert technical assistance of Mrs. A.-M. Dahlberg is gratefully acknowledged.

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Authors' address: H. Nissbrandt, MD, PhD, Department of Pharmacology, Institute

of Physiology and Pharmacology, G6teborg University, Medicinaregatan 7, S-413 90
G6teborg, Sweden
Received June 26, 1996