GABA B receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area

Abstract

2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) is a recently reported positive allosteric modulator of γ-aminobutyric acid (GABA) B receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen-induced depression of dopamine (DA) neuron activity via the activation of GABA B receptors in the ventral tegmental area in rat midbrain slices. The selective GABA B receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration-dependent manner (EC 50 = 0.27 μM, n = 11). CGP7930 (30 μM) significantly (P < 0.05) shifted the baclofen concentration-response curve to the left (EC 50 = 0.15 μM, n = 5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 μM, (2S)-3-[[(1S)-1-(3,4- dichloropheny)ethyl]amino-2-hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABA B receptor antagonist. In similar experiments, N-[3,3-diphenylpropyl]-α-methylbenzylamine (fendiline) (30 or 50 μM), a compound shown to potentiate GABA B receptor-mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen. It is therefore concluded that the recently reported GABA B receptor modulators, CGP7930 and fendiline, can enhance GABA B receptor-mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABA B potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system. © 2005 Nature Publishing Group. All rights reserved.