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

1 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. 2 The selective GABA B receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration‐dependent manner (EC 50 =0.27  μ M , n =11). CGP7930 (30  μ M ) significantly ( P <0.05) shifted the baclofen concentration–response curve to the left (EC 50 =0.15  μ M , n =5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1  μ M (2 S )‐3‐[[(1 S )‐1‐(3,4‐dichloropheny)ethyl]amino‐2‐hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABA B receptor antagonist. 3 In similar experiments, N ‐[3,3‐diphenylpropyl]‐ α ‐methylbenzylamine (fendiline) (30 or 50  μ M ), a compound shown to potentiate GABA B receptor‐mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen. 4 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.British Journal of Pharmacology (2005) 144 , 926–932. doi: 10.1038/sj.bjp.0706100