Involvement of alpha2 subunit-containing GABAA receptors in circuits underlying drug abuse

可卡因和海洛因等滥用药物会促进特定神经细胞的工作，这些细胞使用化学信使多巴胺与其他神经细胞进行交流。一些研究人员将多巴胺细胞描述为形成大脑奖赏回路的一部分。与多巴胺细胞交流的最重要的神经细胞之一使用一种不同的化学信使——氨基丁酸。酒精和苯二氮卓类药物对GABA系统有影响。与多巴胺的研究相比，对GABA系统在奖励中的作用的研究相对较少。该项目将使用经过基因改造的小鼠，这样GABA信号的特定方面就会受到损害。具体来说，它将研究那些使用GABA受体的GABA系统的重要性，这些GABA受体含有所谓的α 2蛋白，因为这些受体存在于大脑中与学习遇到奖励的环境有关的区域。初步研究表明，经过基因工程改造的老鼠不能制造α 2蛋白，当它们反复接受可卡因时，不会表现出正常老鼠所表现出的行为适应，这表明它们可能没有能力学习某些类型的奖励（激励学习）。该项目将证实这些初步观察结果，并在更严格、但技术上更困难的药物滥用动物模型中测试这一想法。如果含有- 2的GABA受体在了解药物奖励方面发挥了重要作用，那么就有可能开发出使这些受体失效的药物，作为药物滥用的治疗方法。

Abused drugs such as cocaine and heroin act to facilitate the workings of particular nerve cells that use the chemical messenger, dopamine to communicate with other nerve cells. Dopamine cells have been described by some researchers as forming part of the reward circuitry of the brain. One of the most important kinds of nerve cell with which dopamine cells communicate uses a different chemical messenger, GABA. Drugs such as alcohol and benzodiazepines have their effects on GABA systems. Compared to studies of dopamine, relatively little research has been invested into the function of the GABA system in reward. This project will use mice that have been genetically altered so that particular aspects of GABA signalling are compromised. Specifically, it will investigate the importance of those GABA systems that use GABA receptors that contain the so-called alpha 2 protein, since these kinds of receptor are found in the brain areas involved in learning about the circumstances in which rewards are encountered. Preliminary research suggests that mice genetically engineered so that they cannot make the alpha 2 protein do not show the behavioural adaptations that normal mice display when they repeatedly receive cocaine, which suggests they may not be capable of some kinds of learning about rewards (incentive learning). The project will confirm these preliminary observations, and test the idea in more rigorous, but technically more difficult animal models of drug abuse. If alpha 2-containing GABA receptors can be shown to play an important role in learning about drug rewards, then it may be possible to develop drugs that disable these receptors as a treatment for drug abuse.