PT  - JOURNAL ARTICLE
AU  - Zheng-Xiong Xi
AU  - Elliot A. Stein
TI  - Increased Mesolimbic GABA Concentration Blocks Heroin Self-Administration in the Rat
DP  - 2000 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 613--619
VI  - 294
IP  - 2
4099  - http://jpet.aspetjournals.org/content/294/2/613.short
4100  - http://jpet.aspetjournals.org/content/294/2/613.full
SO  - J Pharmacol Exp Ther2000 Aug 01; 294
AB  - Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic γ-aminobutyric acid (GABA) release that subsequently disinhibits ventral tegmental area (VTA) dopamine neurons. In support of this hypothesis, this study demonstrates that when administered directly into the lateral ventricle, the VTA, or the ventral pallidum, but not the nucleus accumbens, γ-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20–50 μg) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as assessed by an increase in heroin SA at low doses of GVG and an initial increase followed 1 to 2 h later by a blockade of heroin SA at higher GVG doses. This effect lasted 3 to 5 days. In drug-naı̈ve rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by systemic or intra-VTA pretreatment with the GABABantagonist 2-hydroxysaclofen, but not the GABAA antagonist bicuculline. Similarly, coadministration of heroin with aminooxy-acetic acid (1–4 mg/kg) or ethanolamine-O-sulfate (50–100 mg/kg), two reversible GABA transaminase inhibitors, dose dependently reduced heroin reinforcement. Coadministration of (±)-nipecotic acid (0.1–5 mg/kg) with heroin, or intra-VTA or -ventral pallidum pretreatment with (±)-nipecotic acid (10 μg) or NO-711 (2 μg), two GABA uptake inhibitors, significantly increased heroin SA behavior, an effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline. Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABAB receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment. The American Society for Pharmacology and Experimental Therapeutics