Xi Z X, Stein E A
Department of Cellular Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Pharmacol Exp Ther. 1999 Sep;290(3):1369-74.
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.
一种用于解释海洛因诱导的正性强化机制的新假说认为，阿片类药物抑制中脑皮质边缘多巴胺（DA）系统内的γ-氨基丁酸（GABA）能中间神经元，从而解除对DA神经元的抑制。为支持这一假说，我们报告称，当GABA（B）受体激动剂巴氯芬与海洛因共同给药时，未接触过药物的大鼠海洛因自我给药（SA）行为的形成以及经海洛因训练的大鼠SA行为的维持均受到抑制。向腹侧被盖区（VTA）而非伏隔核微量注射巴氯芬，会降低海洛因强化作用，这可通过SA行为的代偿性增加来表明。此外，单独给予巴氯芬或与海洛因一起给予时，巴氯芬会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-羟基巴氯芬可部分阻断这种作用，提示存在一种额外的、可能由GABA（A）受体介导的去抑制作用。综上所述，这些实验首次证明，海洛因强化的SA行为和伏隔核DA释放主要由VTA中的GABA（B）受体介导，并表明巴氯芬可能是治疗阿片类药物滥用的有效药物。
