Negative allosteric modulation of GABA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice.

Rationale: There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. Objectives: We tested the hypothesis that the GABA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Results: Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. Conclusions: These results demonstrate that negative modulation of GABA receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies. [ABSTRACT FROM AUTHOR]