Defining sex differences in GABA regulation of dopamine release in cocaine use disorder

项目总结/摘要 虽然男性和女性都患有可卡因使用障碍（CUD），但女性特别多。 脆弱人群和这种性别差异背后的神经机制仍然知之甚少。CUD 其特征在于可卡因诱导的中脑核（NAc）中多巴胺释放的改变。性 多巴胺释放的差异及其在NAc中的调节也与性别特异性行为有关， CUD。这项建议的目的是确定NAc中多巴胺释放调节的性别差异， 确定可卡因自我给药后这一过程如何失调。GABA-A和GABA-B NAc中的受体与可卡因的增强特性有关。此外，GABA是一种关键的调节剂， 通过GABA受体直接作用于NAc中的多巴胺末端来释放多巴胺。然而，在这方面， GABA能调节末端多巴胺释放的长期可塑性尚不清楚， 这一过程实际上还没有被研究过。该提案的目标是确定GABA能的性别差异， 调节多巴胺的释放，确定可卡因自我管理是否改变了这种调节在性别特异性 时尚，并检查因果关系的作用，GABA-A和GABA-B受体可卡因诱导的可塑性在NAc。 在目标1中，我将使用带有遗传编码多巴胺传感器（dLight1.2）的NAc体外光学记录。 来记录雄性和雌性的多巴胺释放。使用药理学，我将研究GABA-A和 B受体调节多巴胺的释放，并确定是否存在性别差异。根据我的初步数据， 我假设GABA-A介导的多巴胺释放抑制是性别依赖性的， 对男性的影响在目标2中，我将研究可卡因诱导的可塑性，在可卡因自我调节后， 在小鼠中施用。在目标3中，我将敲除多巴胺能神经元中的GABA-A和GABA-B受体， 确定这些受体是否是可卡因诱导的NAc多巴胺释放可塑性所必需的。采取 总之，这项建议中的实验将是第一个确定GABA能调节的性别差异的实验。 NAc中的多巴胺释放，确定可卡因自我给药如何改变这些过程， 研究GABA受体在可卡因诱导的NAc多巴胺释放可塑性中的作用。这项建议 包括技术和理论培训，将提供基本的专业知识和概念 思考需要解决更大的问题，即药物引起的大脑和性别特异性变化 支持CUD的发展和维持。此外，这些发现最终可以为我们提供信息， 了解奖励和学习过程的性别特异性机制，并导致更有效的 男性和女性的治疗干预。

Project Summary/Abstract Although males and females both suffer from cocaine use disorder (CUD), females represent a particularly vulnerable population and the neural mechanisms underlying this sex difference remain poorly understood. CUD is characterized by cocaine-induced alterations in dopamine release in the nucleus accumbens (NAc). Sex differences in dopamine release and its regulation in the NAc has also been linked to sex-specific behaviors in CUD. The goal of this proposal is to define sex differences in dopamine release regulation in the NAc and determine how this process is dysregulated following cocaine self-administration. GABA-A and GABA-B receptors in the NAc have been linked to the reinforcing properties of cocaine. Further, GABA is a key regulator of dopamine release through direct actions of GABA receptors on dopamine terminals in the NAc. However, long-term plasticity in GABAergic regulation of terminal dopamine release is unknown, and sex-differences in this process have been virtually unstudied. The goal of this proposal is to define sex differences in GABAergic regulation of dopamine release, determine if cocaine self-administration alters this regulation in a sex-specific fashion, and examine the causal role of GABA-A and GABA-B receptors in cocaine-induced plasticity in the NAc. In Aim 1, I will use ex vivo optical recordings in the NAc with a genetically encoded dopamine sensor (dLight1.2) to record evoked dopamine release in males and females. Using pharmacology, I will investigate GABA-A and B receptor regulation of dopamine release and determine if sex differences exist. Based on my preliminary data, I hypothesize that GABA-A-mediated inhibition of evoked dopamine release will be sex-dependent, with greater effects in males. In Aim 2, I will investigate cocaine-induced plasticity in this regulation following cocaine self- administration in mice. In Aim 3, I will knock out GABA-A and GABA-B receptors in dopaminergic neurons and determine if these receptors are necessary for cocaine-induced plasticity in dopamine release in the NAc. Taken together, the experiments in this proposal will be the first to define sex-differences in GABAergic regulation of dopamine release in the NAc, determine how these processes are altered by cocaine self-administration, and investigate the roles of GABA receptors in cocaine-induced plasticity in NAc dopamine release. This proposal encompasses technical and theoretical training that will provide the foundational expertise and conceptual thinking needed to address larger questions regarding how drug-induced and sex-specific changes in the brain support the development and sustainment of CUD. Additionally, these findings can ultimately inform our understanding of sex-specific mechanisms underlying reward and learning process and lead to more efficacious treatment interventions for males and females.