Vol. 287, Issue 1, 58-66, October 1998

Imidazenil, a Positive Allosteric GABA_A Receptor Modulator, Inhibits the Effects of Cocaine on Locomotor Activity and Extracellular Dopamine in the Nucleus Accumbens Shell Without Tolerance Liability¹

Marco Giorgetti^{2 3}, Javaid I. Javaid², John M. Davis², Erminio Costa^{2 3}, Alessandro Guidotti^{2 3}, Sarah B. Appel⁴ and Mark S. Brodie⁴

The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Imidazenil, a benzodiazepine recognition site ligand that acts as partial positive allosteric modulator of -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.