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Research ArticleArticle

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics September 1999, 290 (3) 1369-1374;
Zheng-Xiong Xi
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Elliot A. Stein
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Abstract

An emerging hypothesis to explain the mechanism of heroin-induced positive reinforcement states that opiates inhibit γ-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 GABABantagonist 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.

Footnotes

  • Send reprint requests to: Dr. Elliot A. Stein, Medical College of Wisconsin, Department of Psychiatry, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: estein{at}mcw.edu

  • ↵1 This investigation was supported in part by National Institute on Drug Abuse Grant DA09465 to E.A.S.

  • Abbreviations:
    DA
    dopamine
    FCV
    fast cyclic voltammetry
    SA
    self-administration
    VTA
    ventral tegmental area
    NAcc
    nucleus accumbens
    AA
    ascorbic acid
    DOPAC
    dihydroxyphenylacetic acid
    6-OHDA
    6-hydroxydopamine
    • Received March 8, 1999.
    • Accepted May 14, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 3
1 Sep 1999
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Research ArticleArticle

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1369-1374;

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Research ArticleArticle

Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics September 1, 1999, 290 (3) 1369-1374;
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