GABA _B receptor-positive modulators: Enhancement of GABA _B receptor agonist effects in vivo

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 γ-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 ^ω-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.