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Research ArticleNEUROPHARMACOLOGY

Increased Mesolimbic GABA Concentration Blocks Heroin Self-Administration in the Rat

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics August 2000, 294 (2) 613-619;
Zheng-Xiong Xi
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Elliot A. Stein
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Abstract

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.

Footnotes

  • Send reprint requests to: Elliot A. Stein, Ph.D., 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 and the Schering Plough Research Foundation.

  • Abbreviations:
    DA
    dopamine
    GABA
    γ-aminobutyric acid
    GABAT
    GABA transaminase
    GVG
    γ-vinyl-GABA
    2-OH-saclofen
    2-hydroxysaclofen
    SA
    self-administration
    CPP
    conditioned place preference
    VP
    ventral pallidum
    VTA
    ventral tegmental area
    NAcc
    nucleus accumbens
    AOAA
    aminooxy-acetic acid
    EOS
    ethanolamine-O-sulfate
    NipA
    (±)-nipecotic acid
    i.c.
    intracranial
    • Received January 28, 2000.
    • Accepted April 4, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 2
1 Aug 2000
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Research ArticleNEUROPHARMACOLOGY

Increased Mesolimbic GABA Concentration Blocks Heroin Self-Administration in the Rat

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 613-619;

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Research ArticleNEUROPHARMACOLOGY

Increased Mesolimbic GABA Concentration Blocks Heroin Self-Administration in the Rat

Zheng-Xiong Xi and Elliot A. Stein
Journal of Pharmacology and Experimental Therapeutics August 1, 2000, 294 (2) 613-619;
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