Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release.
An emerging hypothesis to explain the mechanism of heroin-induced positive reinforcement states that opiates inhibit gamma-aminobutyric acid (GABA)-ergic interneurons within the mesocorticolimbic dopamine (DA) system to disinhibit DA neurons. In support of this hypothesis, we report that the development of heroin self-administration (SA) behavior in drug-naive rats and the maintenance of SA behavior in heroin-trained rats were both suppressed when the GABA(B) receptor agonist baclofen was coadministered with heroin. Microinjections of baclofen into the ventral tegmental area (VTA), but not the nucleus accumbens, decreased heroin reinforcement as indicated by a compensatory increase in SA behavior. Additionally, baclofen administered alone or along with heroin dose-dependently reduced heroin-induced DA release. This effect was blocked partially by intra-VTA infusion of the GABA(B) antagonist 2-hydroxysaclofen, suggesting an additional, perhaps GABA(A) receptor-mediated, disinhibitory effect. Taken together, these experiments, for the first time, demonstrate that heroin-reinforced SA behavior and nucleus accumbens DA release are mediated predominantly by GABA(B) receptors in the VTA and suggest that baclofen may be an effective agent in the treatment of opiate abuse.
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Department of Cellular Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D004566:Electrodes; D018755:GABA Agonists / Q000494:pharmacology*; D003932:Heroin / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000209:etiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D018755:GABA Agonists; D009292:Narcotic Antagonists; D009294:Narcotics; D003932:Heroin; D001418:Baclofen; D004298:Dopamine