The GABAB receptor antagonist CGP36742 improves learned helplessness in rats
Introduction
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABA interacts with three receptor subtypes designated GABAA, GABAB and GABAC Matsumoto, 1989, Bowery, 1993, Johnston, 1997. There are two GABA receptor hypotheses of the antidepressant action: an increase in GABAA receptor-mediated neurotransmission or a decrease in GABAB receptor-mediated neurotransmission may contribute to action of antidepressants. Pilc and Lloyd (1984) and Lloyd (1990) found that chronic treatment with antidepressants up-regulated GABAB receptor binding in the rat frontal cortex. These results raise the possibility that chronic antidepressants treatment may decrease GABAB receptor-mediated neurotransmission resulting in an increase in postsynaptic GABAB receptor binding. On the other hand, Suzdak and Gianutsos (1985) reported that chronic treatment with antidepressants decreased GABAA receptor binding in the mouse cortex and hippocampus, suggesting that chronic treatment with antidepressants may increase GABAA receptor-mediated neurotransmission, thereby decreasing postsynaptic GABAA receptor binding.
We previously examined the involvement of GABAergic systems in antidepressant action in the forced swim test and the learned helplessness paradigm in rats Nakagawa et al., 1996a, Nakagawa et al., 1996b. We found that baclofen (GABAB receptor agonist) attenuated the action of antidepressants, suggesting that the increased GABAB receptor-mediated neurotransmission may attenuate antidepressant action Nakagawa et al., 1996a, Nakagawa et al., 1996b. On the other hand, bicuculline (GABAA receptor antagonist) failed to antagonize the effect of antidepressants (Nakagawa et al., 1996a). Muscimol (GABAA receptor agonist) did not improve learned helplessness (Nakagawa et al., 1996b). Therefore, our previous findings support the above-mentioned GABAB receptor hypothesis of depression rather than GABAA receptor hypothesis of depression and have an implication that GABAB receptor antagonists may have an antidepressant action.
CGP36742 (3-aminopropyl-n-butyl-phosphinic acid) has an affinity for the GABAB receptor with an IC50 of 32 μM (Bittiger et al., 1996) and antagonizes the baclofen action in vitro and in vivo Carletti et al., 1993, Olpe et al., 1993, Bittiger et al., 1996, Knight and Bowery, 1996, Nakagawa and Takashima, 1997. Pratt and Bowery (1993) found that chronic CGP36742 treatment decreased β-adrenoceptor binding in rat brain, which manifest in the desipramine-treated rats. It has been widely accepted that chronic antidepressants treatment decreases β-adrenoceptors in the brain (Banerjee and Kung, 1977). Bittiger et al. (1996) reported that CGP36742 decreased the duration of immobility in the rat forced swim test.
It has become increasingly clear that 5-hydroxytryptamine (5-HT)3 receptors may be involved in antidepressant action (Greenshaw, 1993). It was reported that responses mediated by 5-HT3 receptor activation were inhibited by antidepressants in vitro Fan, 1994, Lucchelli et al., 1995. 5-HT3 receptor antagonists were effective in the forced swim test and the learned helplessness paradigm in rats Martin et al., 1992, Nakagawa et al., 1998. In our previous study (Nakagawa et al., 1998), we showed that 1-(m-chlorophenyl)-biguanide (mCPBG), a 5-HT3 receptor agonist attenuated antidepressant action in the rat forced swim test. These observations suggest that the suppression of 5-HT3 receptor activity may contribute to antidepressant action. Since presynaptic 5-HT3 receptors regulate Ca2+-dependent neurotransmitter release Barnes et al., 1989, Blandina et al., 1989, it would be expected that antidepressants may decrease neurotransmitter release via 5-HT3 receptors.
In this study, therefore, effects of CGP36742 in the learned helplessness paradigm were examined in comparison with those of imipramine and endo-8-methyl-8-azabicyclo[3,2,1]oct-3-ol indol-3-yl-carboxylate hydrochloride, 5-HT3 receptor antagonist (ICS205-930). We also assessed whether mCPBG as well as baclofen attenuated the effects of CGP36742, imipramine and ICS205-930 to characterize the sites of action for these drugs.
Section snippets
Animals
Male Wistar rats (Charles River, Japan) weighing 130–180 g, at the beginning of the experiment, were used. They were housed in groups of five in an air- and light-controlled room (temperature; 24±2°C, light phase; 0800–2000 h). Food and water were given ad libitum. Experiments were all carried out in accordance with the Guide for the Care and Use of Laboratory Animals of Japanese Pharmacological Society.
Apparatus
A shock pre-treatment chamber (28×21×25 cm3) and a two-way shuttle box (56×21×25 cm3; Toyo
Antidepressant effect of CGP36742, imipramine and ICS205-930 in the learned helplessness paradigm
The escape test was carried out 24 h after the final drug treatment in order to avoid a false-positive effect induced by increased motor activity. CGP36742, imipramine and ICS205-930 had no significant effects on the intertrial crossings in the escape test (Table 1). ANOVA indicated no significant group differences [for CGP36742: F(4, 45)=0.65, P>0.05; for imipramine: F(4, 45)=0.57, P>0.05; for ICS205-930: F(4, 45)=0.61, P>0.05].
As shown in Fig. 1, the exposure to inescapable shocks induced the
Discussion
CGP36742 has an affinity for the GABAB receptor with an IC50 of 32 μM (Bittiger et al., 1996) and antagonizes the baclofen action in vitro and in vivo Carletti et al., 1993, Olpe et al., 1993, Bittiger et al., 1996, Knight and Bowery, 1996, Nakagawa and Takashima, 1997. In the present study, we showed that a 14-day treatment with CGP36742 dose-dependently improved the increased escape failures induced by the inescapable shocks as imipramine did (Fig. 1). As shown in Fig. 3, the escape
Acknowledgements
We are grateful to Drs. Helmut Bittiger and Wolfgang Froestl (Novartis, Basel) for kindly supplying CGP36742.
References (40)
- et al.
The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices
Neuropharmacology
(1996) - et al.
5-HT3 receptor antagonists reverse helpless behaviour in rats
Eur. J. Pharmacol.
(1992) GABA receptors: are cellular differences reflected in function?
Brain Res. Rev.
(1989)- et al.
Effects of p-chloroamphetamine on release of [3H]γ-aminobutyric acid from slices of rat caudate–putamen
Eur. J. Pharmacol.
(1991) - et al.
The GABAB receptor antagonist CGP36742 attenuates the baclofen- and scopolamine-induced deficit in Morris water maze task in rats
Brain Res.
(1997) - et al.
Involvement of GABAB receptor systems in action of antidepressants: baclofen but not bicuculline attenuates the effects of antidepressants on the forced swim test in rats
Brain Res.
(1996) - et al.
Involvement of GABAB receptor systems in action of antidepressants: II. Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats
Brain Res.
(1996) - et al.
Involvement of GABAB receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats
Brain Res.
(1996) - et al.
The 5-HT3 receptor agonist attenuates the action of antidepressants in the forced swim test in rats
Brain Res.
(1998) - et al.
The actions of orally active GABAB receptor antagonists on GABAergic transmission in vivo and in vitro
Eur. J. Pharmacol.
(1993)