Increased mesolimbic GABA concentration blocks heroin self-administration in the rat.
Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic gamma-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, gamma-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 microg) 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-naïve 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 GABA(B) antagonist 2-hydroxysaclofen, but not the GABA(A) 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 microg) or NO-711 (2 microg), 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 GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment.
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Department of Cellular Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee 53226, USA.
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D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage*; D007276:Injections, Intraventricular; D020547:Lateral Ventricles / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008845:Microinjections; D009294:Narcotics / Q000008:administration & dosage*; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013687:Telencephalon / Q000187:drug effects / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D020888:Vigabatrin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009294:Narcotics; D014179:Neurotransmitter Uptake Inhibitors; D005680:gamma-Aminobutyric Acid; D003932:Heroin; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D001418:Baclofen; C057491:2-hydroxysaclofen; D001640:Bicuculline