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

定义可卡因使用障碍中 GABA 调节多巴胺释放的性别差异

• 批准号: 10607079
• 负责人: Brooke A. Christensen
• 金额: $ 3.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607079
• 关键词: Ablation; Action Potentials; Address; Affect; Agonist; Behavior; Brain; Brain region; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cocaine; Cocaine use disorder; Coupled; Data; Development; Disease; Dopamine; Evidence based intervention; FDA approved; Feedback; Female; Foundations; GABA Receptor; GABA-A Receptor; GABA-B Receptor; Goals; Individual; Intervention; Knock-out; Lead; Learning; Link; Mediating; Mus; Nucleus Accumbens; Optics; Pharmaceutical Preparations; Pharmacology; Play; Population; Probability; Process; Property; Regulation; Rewards; Risk; Role; Sex Differences; Slice; System; Thinking; Time; Training; Vulnerable Populations; Woman; Work; addiction; antagonist; base; cocaine exposure; cocaine self-administration; dopamine system; dopaminergic neuron; efficacious treatment; experimental study; gamma-Aminobutyric Acid; male; men; neuromechanism; neurotransmission; prevent; receptor; receptor expression; sensor; sex; sexual dimorphism; virtual

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.

项目概要/摘要 尽管男性和女性都患有可卡因使用障碍 (CUD)，但女性尤其突出 弱势群体以及这种性别差异背后的神经机制仍然知之甚少。 CUD 其特征是可卡因诱导伏隔核 (NAc) 中多巴胺释放的改变。性别 多巴胺释放及其在 NAc 中的调节的差异也与不同性别的行为有关。 CUD。该提案的目标是定义 NAc 和 NAc 中多巴胺释放调节的性别差异。 确定可卡因自我给药后该过程如何失调。 GABA-A 和 GABA-B NAc 中的受体与可卡因的增强特性有关。此外，GABA 是一个关键的调节因子 通过 GABA 受体对 NAc 中多巴胺末端的直接作用来释放多巴胺。然而， 末端多巴胺释放的 GABA 能调节的长期可塑性尚不清楚，并且性别差异 这个过程实际上还没有被研究过。该提案的目标是定义 GABAergic 的性别差异 多巴胺释放的调节，确定可卡因自我给药是否会改变性别特异性的这种调节 时尚，并检查 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，我将在 NAc 中使用带有基因编码多巴胺传感器 (dLight1.2) 的离体光学记录 记录男性和女性诱发的多巴胺释放。我将利用药理学研究 GABA-A 和 B 受体调节多巴胺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 介导的对诱发多巴胺释放的抑制将是性别依赖性的，并且具有更大的抑制作用。 对男性的影响。在目标 2 中，我将研究可卡因自我调节后可卡因诱导的可塑性。 在小鼠中给药。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， 确定这些受体对于可卡因诱导的 NAc 中多巴胺释放的可塑性是否是必需的。采取 总之，本提案中的实验将是第一个定义 GABA 能调节的性别差异的实验。 NAc 中多巴胺的释放，确定可卡因自我给药如何改变这些过程，以及 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。这个提议 包括技术和理论培训，将提供基础专业知识和概念 需要思考来解决有关药物如何引起大脑和性别特异性变化的更大问题 支持 CUD 的发展和维持。此外，这些发现最终可以告知我们 了解奖励和学习过程背后的性别特异性机制，并导致更有效 针对男性和女性的治疗干预。