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Baclofen Inhibits Heroin Self-Administration Behavior and Mesolimbic Dopamine Release
Abstract
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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“In addition, lesion or inactivation of the mesolimbic DA system in the VTA [137,138] or in the NAc [139-143] decreases cocaine, amphetamine, heroin, and nicotine self-administration in rats.”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [138]
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“The importance of these observations in the possible treatment of drug abuse is reinforced by the finding that baclofen reduces craving for a host of addictive substances, including heroin, alcohol, and nicotine (Xi and Stein, 1999; Corrigall et al., 2000; Lobina et al., 2000).”
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Metadata
- Authors
- Xi, Z.-X., & Stein, E. A.
- Affiliations
- Medical College of Wisconsin (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1999-09
- Volume
- 290
- Issue
- 3
- Pages
- 1369-1374
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2164726829
- Cited by
- 177
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 6 · 2012: 7
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute on Drug Abuse (R01DA009465, DA 09465)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- baclofen, heroin self-administration, GABAB receptors, mesolimbic dopamine system, ventral tegmental area, nucleus accumbens, GABAergic interneurons, disinhibition, 2-hydroxysaclofen, GABAA receptor
- MeSH terms
- Animals, Baclofen, Behavior, Animal, Heroin, Dopamine, Electrodes, Limbic System, Male, Mesencephalon, Narcotic Antagonists, Narcotics, Nucleus Accumbens, Self Administration, Rats, Sprague-Dawley, Ventral Tegmental Area, GABA Agonists, Substance-Related Disorders, Rats
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