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Vol. 290, Issue 3, 1369-1374, September 1999

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release1

Zheng-Xiong Xi and Elliot A. Stein

Departments of Cellular Biology, Neurobiology, and Anatomy (Z.-X.X., E.A.S.), Psychiatry and Behavioral Medicine (E.A.S.), Pharmacology (E.A.S.), and The Biophysics Research Institute (E.A.S.), Medical College of Wisconsin, Milwaukee, Wisconsin

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 GABAB 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 GABAB antagonist 2-hydroxysaclofen, suggesting an additional, perhaps GABAA 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 GABAB receptors in the VTA and suggest that baclofen may be an effective agent in the treatment of opiate abuse.

0022-3565/99/2903-1369$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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