Synaptic Plasticity in the Ventral Tegmental Area and Cocaine Addiction

描述(由申请者提供)：情境学习在引发药物渴望和复发方面发挥着重要作用，这是药物成瘾的两个核心特征。人们认为，奖赏回路中突触可塑性的改变是药物相关学习的基础。因此，阻断药物诱导的突触可塑性改变将为治疗药物成瘾提供新的治疗策略。中脑的腹侧被盖区(VTA)是奖赏回路的关键组成部分，该回路调节包括可卡因在内的许多滥用药物的成瘾特性。我们最近的工作表明，在VTA多巴胺神经元中，谷氨酸能兴奋性传递的长时程增强(LTP)受到3-氨基丁酸(GABA)抑制的严格控制，体内反复暴露可卡因通过减少GABA能抑制而促进LTP的诱导。了解其潜在的机制有助于找到阻止这种减少的GABA能抑制的方法。我们假设，体内反复暴露可卡因诱导了VTA多巴胺神经元抑制传递(I-LTD)的长期抑郁样调制，这是可卡因导致GABA能抑制减少、LTP诱导和成瘾行为形成的基础。通过将电生理记录与行为测试相结合，我们将通过三个具体目标来验证这一假设。目的确定I-LTD诱导中脑片多巴胺神经元的条件和机制；AIMS II和IMS III将确定在体内应用这种I-LTD诱导的抑制剂是否阻断可卡因诱导的GABA能抑制的减少、LTP诱导和成瘾行为的易化。提高大脑中GABA水平的药物已被用于临床试验，作为治疗可卡因依赖的潜在药物治疗，这表明操作GABA能抑制在原则上是治疗可卡因成瘾的合理治疗策略。然而，整个大脑中GABA能抑制的普遍增加会产生副作用。选择性阻断可卡因诱导的GABA能抑制的减少，这是该提案的一个目标，可以帮助开发比整体加强GABA能抑制更有效的抗成瘾治疗。公共卫生意义本项目调查可卡因成瘾的机制，并寻求开发治疗可卡因成瘾的新的治疗策略。

DESCRIPTION (provided by applicant): Contextual learning plays an important role in triggering drug craving and relapse, two core features of drug addiction. It is thought that alteration in synaptic plasticity in the reward circuit underlies drug-associated learning. As such, blocking drug-induced alteration of synaptic plasticity will provide a novel therapeutic strategy for treating drug addiction. The ventral tegmental area (VTA) of the midbrain is a key component of the reward circuit that mediates the addictive properties of many drugs of abuse, including cocaine. Our recent work has shown that in VTA dopamine neurons long-term potentiation (LTP) of glutamatergic excitatory transmission is tightly controlled by 3-aminobutyric acid (GABAergic) inhibition and repeated cocaine exposure in vivo facilitates LTP induction by reducing GABAergic inhibition. Understanding its underlying mechanisms is instrumental in finding ways to block this reduced GABAergic inhibition. We hypothesize that repeated cocaine exposure in vivo induces a long-term depression-like modulation of inhibitory transmission (I-LTD) of VTA dopamine neurons, which underlies cocaine-induced reduction of GABAergic inhibition, facilitation of LTP induction and development of addictive behavior. By combining electrophysiological recordings with behavioral tests, we will test this hypothesis via three Specific Aims. Aim I will identify conditions and mechanisms for I- LTD induction in dopamine neurons of midbrain slices; Aims II and III will determine whether in vivo application of inhibitors of this I-LTD induction blocks the cocaine-induced reduction of GABAergic inhibition, facilitation of LTP induction and addictive behavior. Drugs that increase GABA level in the brain have been used in clinical trials as a potential pharmacotherapy for cocaine dependence, suggesting that manipulation of GABAergic inhibition is in principle a sound therapeutic strategy for treating cocaine addiction. However, universal increase in GABAergic inhibition throughout the brain produces side effects. Selective blockade of cocaine-induced reduction of GABAergic inhibition, an objective of this proposal, could help develop anti-addiction treatments that would be more efficacious than global enhancement of GABAergic inhibition. PUBLIC HEALTH RELEVANCE This project investigates the mechanisms for cocaine addiction and seeks to develop novel therapeutic strategy for treating cocaine addiction.