Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release.
Baclofen inhibits heroin self-administration behavior and mesolimbic dopamine release.
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发表时间：
1999-09
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通讯作者：
Z. Xi;E. Stein
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作者：
Z. Xi;E. Stein
一个新兴的假说来解释海洛因诱导的正强化的机制，即阿片类药物抑制中皮质边缘多巴胺（DA）系统内的γ-氨基丁酸（GABA）能中间神经元，以解除对DA神经元的抑制。为了支持这一假设，我们报告说，海洛因自我管理（SA）行为的药物幼稚大鼠的发展和海洛因训练大鼠的SA行为的维持都受到抑制时，GABA（B）受体激动剂巴氯芬与海洛因共同管理。微量注射巴氯芬到腹侧被盖区（VTA），但不是核的腹侧被盖区，减少海洛因加固所示的补偿性增加SA行为。此外，巴氯芬单独给药或与海洛因一起沿着剂量依赖性地减少海洛因诱导的DA释放。VTA内注入GABA（B）拮抗剂2-羟基苯氯芬可部分阻断这种作用，提示可能存在GABA（A）受体介导的额外去抑制作用。综上所述，这些实验，第一次，表明海洛因增强的SA行为和多巴胺的释放主要是由GABA（B）受体介导的腹侧被盖区，并建议巴氯芬可能是一种有效的药物在阿片类药物滥用的治疗。
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.