Synaptic Plasticity in the Ventral Tegmental Area and Cocaine Addiction

描述（由申请人提供）：情境学习在引发药物成瘾的两个核心特征——药物渴望和复发中起着重要作用。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，阻断药物引起的突触可塑性改变将为治疗药物成瘾提供一种新的治疗策略。中脑的腹侧被盖区（VTA）是奖赏回路的关键组成部分，该回路介导包括可卡因在内的许多药物滥用的成瘾性。我们最近的研究表明，在VTA多巴胺神经元中，谷氨酸能兴奋传递的长期增强（LTP）受到3-氨基丁酸（GABAergic）抑制的严格控制，体内反复暴露于可卡因可通过减少GABAergic抑制促进LTP的诱导。了解其潜在机制有助于找到阻断这种减少的gaba能抑制的方法。我们假设，体内重复的可卡因暴露诱导VTA多巴胺神经元抑制传递（I-LTD）的长期抑郁样调节，这是可卡因诱导的gaba能抑制减少、LTP诱导促进和成瘾行为发展的基础。通过结合电生理记录和行为测试，我们将通过三个具体目标来验证这一假设。目的探讨I- LTD诱导中脑多巴胺神经元的条件和机制；目的II和III将确定在体内应用这种I-LTD诱导抑制剂是否会阻断可卡因诱导的gaba能抑制的减少、LTP诱导的促进和成瘾行为。增加大脑中GABA水平的药物已被用于临床试验，作为一种潜在的药物治疗可卡因依赖，这表明操纵GABA能抑制原则上是治疗可卡因成瘾的一种良好的治疗策略。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GABAergic抑制的减少，这是本提案的目标，可以帮助开发抗成瘾治疗，这将比全面增强GABAergic抑制更有效。本项目调查了可卡因成瘾的机制，并寻求开发新的治疗策略来治疗可卡因成瘾。

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.