GABA_B Receptor-Positive Modulators: Enhancement of GABA_B Receptor Agonist Effects In Vivo

Abstract

In vivo effects of GABA B receptor-positive modulators suggest that they have therapeutic potential for treating central nervous system disorders such as anxiety, depression, and drug abuse. Although these effects generally are thought to be mediated by positive modulation of GABA B receptors, such modulation has been examined primarily in vitro. The present study was aimed at further examining the in vivo positive modulatory properties of the GABA B receptor-positive modulators, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl) phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF). Both compounds enhanced loss of righting induced by baclofen in mice. However, CGP7930 was less effective and rac-BHFF was less potent for enhancing loss of righting induced by ␥-hydroxybutyrate (GHB), which, like baclofen, has GABA B receptor agonist properties. In contrast with baclofen-and GHB-induced loss of righting, the hypothermic effects of baclofen and GHB were not enhanced by rac-BHFF but were enhanced by CGP7930 only at doses that produced hypothermia when given alone. CGP7930-induced hypothermia was not attenuated by the GABA B receptor antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348), at doses that blocked baclofen-induced hypothermia, and was not increased by the nitric-oxide synthase inhibitor N -nitro-L-arginine methyl ester, at doses that increased the hypothermic effects of baclofen and GHB. The results provide evidence that CGP7930 and rac-BHFF act in vivo as positive modulators at GABA B receptors mediating loss of righting, but not at GABA B receptors mediating hypothermia. Conceivably, CGP7930, but not rac-BHFF, acts as an allosteric agonist at these latter receptors. Taken together, the results provide further evidence of pharmacologically distinct GABA B receptor subtypes, possibly allowing for a more selective therapeutic interference with the GABA B system.

Effects of the GABAB Receptor-Positive Modulators CGP7930 and rac-BHFF in Baclofen- and γ-Hydroxybutyrate-Discriminating Pigeons

“…These findings are further evidence of the effectiveness of rac-BHFF and CGP7930 as GABA B receptor-positive modulators in vivo. Previously, they were found to enhance baclofen-induced loss of righting, but not baclofen-induced hypothermia (Koek et al, 2010). The present results indicate that their effectiveness as positive modulators is not limited to loss of righting produced by high doses of baclofen, which probably involves cerebellar GABA B receptors that are especially sensitive to positive modulation (Hensler et al, 2012).…”

“…These studies showed that rac-BHFF was approximately 3-fold more potent than CGP7930 in enhancing baclofen-induced loss of righting in mice. However, baclofen-induced hypothermia, which occurs at lower doses than loss of righting, was not altered by rac-BHFF and was enhanced by CGP7930 only at doses that produced hypothermia when given alone (Koek et al, 2010). Thus, rac-BHFF and CGP7930 act in vivo as positive modulators at GABA B receptors that mediate loss of righting, but not at those mediating hypothermia.…”

“…This suggests the possibility that CGP7930 preferentially enhances the in vivo effects of baclofen compared with GHB. Indeed, CGP7930 was more effective in enhancing loss of righting induced by baclofen than loss of righting induced by GHB (Koek et al, 2010). To examine the generality of this differential enhancement, the present study compared the ability of CGP7930 and rac-BHFF to enhance the discriminative stimulus effects of baclofen with their ability to enhance the discriminative stimulus effects of GHB.…”

“…CGP7939 and rac-BHFF increase loss of righting in mice induced by a subthreshold dose of the GABA B receptor agonist baclofen without producing loss of righting when given alone (Carai et al, 2004;Malherbe et al, 2008), which shows that they could have positive modulating properties at GABA B receptors in vivo. Recently, these properties were characterized in more detail by using shifts of dose-response curves for GABA B receptor agonists to compare the relative potency and effectiveness of the positive modulators (Koek et al, 2010). These studies showed that rac-BHFF was approximately 3-fold more potent than CGP7930 in enhancing baclofen-induced loss of righting in mice.…”

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

“…The sedative and hypothermic effects of the prototypical GABA B receptor agonist baclofen have limited its use in behavioral pharmacological studies (Bowery et al, 2002). Thus, PAMs have recently been proposed as therapeutically superior drugs with respect to undesired side effects Koek et al, 2010). In fact, GS-39783 (novel GABA B receptor PAM) was shown to increase in vitro the GABA B receptor agonist affinity and potency, as well as the capacity of GABA to reduce cAMP production (Urwyler et al, 2005).…”