Abstract

Imidazenil, a benzodiazepine recognition site ligand that acts as partial positive allosteric modulator of γ-aminobutyric acid (GABA) action at GABA_A receptors, inhibits in a dose-dependent manner (0.56–2.5 μmol/kg i.p. to rats) the cocaine-induced increase in dopamine (DA) content in the dialysates of the nucleus accumbens shell and striatum and also inhibits cocaine-induced locomotor activity. Diazepam, a full allosteric modulator of GABA action at GABA_A receptors, in a dose of 4.4 μmol/kg i.p. also attenuates the cocaine-induced increase in DA content in the dialysates of nucleus accumbens shell, and striatum and the cocaine-induced locomotor activity. However, imidazenil (2.5 μmol/kg i.p.) fails to reduce spontaneous locomotor activity, whereas diazepam (4.4 μmol/kg i.p.) elicits sedation and ataxia and clearly impairs spontaneous locomotor activity. When added in vitro, both imidazenil and diazepam potentiate the GABA-mediated reduction of the ventral tegmental area DA neuron firing rate. After protracted treatment (14 days/three times a day with an increasing-dose schedule), the inhibitory actions of imidazenil fail to develop tolerance, whereas the actions of diazepam exhibit high tolerance liability. We conclude that imidazenil is devoid of tolerance liability and that, via a GABA_A-mediated reduction in the extracellular DA in nucleus accumbens shell, it might reduce the psychomotor activity and reinforcing properties of cocaine.