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

项目摘要/摘要 虽然男性和女性都患有可卡因使用障碍(CUD)，但女性代表着一个特别的 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 其特征是可卡因引起伏核(NAC)多巴胺释放的改变。性 NAC中多巴胺释放及其调节的差异也与性别特异性行为有关 丘德。这项提案的目标是确定NAC和NAC中多巴胺释放调节的性别差异 确定这一过程在可卡因自我给药后是如何失调的。GABA-A和GABA-B NAC中的受体与可卡因的增强特性有关。此外，GABA是一个关键的调节器 通过GABA受体在NAC的多巴胺终末的直接作用而释放多巴胺。然而， GABA能调节终末多巴胺释放的长期可塑性尚不清楚，性别差异在 这一过程几乎没有人研究过。这项提案的目标是定义GABA基因的性别差异 多巴胺释放的调节，确定可卡因自我给药是否改变了性别特异性的这种调节 时尚，并研究GABA-A和GABA-B受体在可卡因诱导的NAC可塑性中的因果作用。 在目标1中，我将使用NAC中的体外光学记录和遗传编码的多巴胺传感器(dLight1.2) 记录男性和女性诱发的多巴胺释放。利用药理学，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介导的对诱发的多巴胺释放的抑制将是性别依赖性的， 对男性的影响。在目标2中，我将研究可卡因诱导的可卡因自我调节的可塑性。 小鼠给药。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 确定这些受体是否对可卡因诱导的NAc中多巴胺释放的可塑性是必需的。已被占用 总之，这项计划中的实验将是第一次定义GABA能调节的性别差异 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，以及 探讨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，即药物诱导的大脑变化和性别特异性变化 支持联合国可持续发展委员会的发展和持续。此外，这些发现最终可以告诉我们 理解奖励和学习过程背后的性别特有机制，并导致更有效 针对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.