Circuitry Progression of Cocaine-induced Cellular Adaptation

可卡因诱导的细胞适应的电路进展

• 批准号: 9982846
• 负责人: Yan Dong
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982846
• 关键词: Action Potentials; Anatomy; Back; Behavior; Behavioral; Brain region; Cocaine; Complex; Corpus striatum structure; Dopamine D1 Receptor; Dorsal; Drug Addiction; Drug Exposure; Drug usage; Ensure; Exhibits; Extinction (Psychology); Fire - disasters; Human; Knowledge; Lateral; Lead; Medial; Mediating; Membrane; Molecular; Monkeys; Mus; Neurons; Nucleus Accumbens; Output; Pharmaceutical Preparations; Procedures; Publishing; Rattus; Relapse; Reporter; Resistance; Rodent; Rodent Model; Role; Self Administration; Substantia nigra structure; Testing; Transgenic Organisms; Ventral Tegmental Area; Viral; Withdrawal; base; cocaine use; drug development; drug withdrawal; experience; experimental study; human model; prevent; recruit; response; success

Abstract Drug addiction has been conceptualized as the endpoint of cascades of transitions from initial voluntary and limited drug use to habitual and escalated drug use, and eventually to compulsive use. Results from brain region-specific studies lead to a prominent hypothesis that the initial cocaine use is primarily motivated by the nucleus accumbens (NAc)-based reinforcing effects, and transitions to more persistent or habitual drug use by recruiting the dorsal striatum (DS), resulting in escalated cocaine use and resistance to extinction. While the behavioral transition from limited to escalated cocaine use has been observed in both humans and rodent models, the key cocaine-induced cellular adaptations that progress from the NAc to DS to promote this behavioral transition remain underexplored. Targeting this knowledge gap, we focus on the intrinsic membrane excitability (IME) of NAc and DS medium spiny neurons (MSNs). IME determines the ability of neurons to fire action potentials in response to excitatory inputs, and thus directly determines the output of the neurons. Previous results demonstrate a critical IME adaptation—cocaine experience decreases IME of NAc MSNs, and this cocaine-induced IME adaptation in the NAc contributes to psychomotor effects of cocaine, cocaine withdrawal-associated general hypoactive state of the NAc, and cocaine seeking after drug withdrawal. The preliminary results show that during a short-term (5d) cocaine self-administration procedure, mice exhibited limited cocaine taking, and this cocaine procedure only induced the IME adaptation in NAc MSNs, but not DS MSNs. After prolonged (21d) cocaine self-administration, mice exhibited escalated cocaine taking, and the IME adaptation was observed in both NAc and medial/dorsal DS MSNs. Thus, cocaine-induced IME adaptation progresses from the NAc to DS after prolonged cocaine self-administration, correlated to escalated cocaine taking. Furthermore, experimentally preventing cocaine-induced IME adaptation in NAc MSNs prevented the progression of IME adaptation to DS MSNs during prolonged cocaine self-administration, suggesting a critical informational flow from the NAc to DS. This application will explore the anatomical basis mediating the NAc-to- DS progression of cocaine-induced IME adaptation and the behavioral consequence of this progression. The central hypothesis is that the NAc-to-DS progression of cocaine-induced IME adaptation after prolonged cocaine self-administration is mediated, in part, by the striatonigrostriatal ascending spiral, a circuit complex connecting the NAc and DS through reciprocal projections with the ventral tegmental area and substantia nigra, and this NAc-to-DS progression of cocaine-induced IME adaptation promotes the behavioral transition from limited to escalated cocaine use. The proposed experiments will characterize a critical form of cocaine- induced cellular adaptation that progresses from the NAc to DS after prolonged cocaine self-administration. The expected results may provide a circuit mechanism and concrete cellular substrates that mediate the progression of limited drug use toward escalated and eventually compulsive drug use.

抽象的 吸毒成瘾已被概念化为从初始自愿和 有限的药物用于习惯和升级的药物使用，最终用于强迫使用。大脑的结果 区域特异性研究导致了一个明显的假设，即最初的可卡因使用主要是由 基于基于核心的伏隔核（NAC）的增强作用，并过渡到更持久或习惯性的药物使用 募集背纹状体（DS），导致可卡因的使用和耐药性升级。而 在人类和啮齿动物中都观察到了从限制到升级可卡因的行为过渡 模型，关键可卡因诱导的细胞适应性，从NAC到DS发展以促进这一点 行为过渡仍然没有被逐渐解散。针对这个知识差距，我们专注于固有的膜 NAC和DS中棘神经元（MSN）的兴奋性（IME）。 IME确定神经元发射的能力 响应兴奋输入的动作电位，因此直接决定了神经元的输出。 先前的结果表明，重要的IME适应性 - 可卡因的经验下降了NAC MSN的IME，并且 NAC中可卡因诱导的IME适应性有助于可卡因，可卡因的心理效应 戒断相关的NAC的一般性低触发状态，并在戒毒后寻求可卡因。这 初步结果表明，在短期（5D）可卡因自我管理程序中，小鼠暴露 可卡因有限，可卡因程序仅诱导NAC MSN的IME适应，但不诱导DS MSN。长时间（21d）可卡因自我给药后，小鼠暴露了可卡因的升级，IME 在NAC和培养基DS MSN中都观察到适应性。那就是可卡因引起的IME适应 长时间可卡因自我管理后从NAC到DS，与可卡因升级有关 服用。此外，通过实验防止可卡因诱导的NAC MSN适应IME的适应 长期可卡因自我管理期间，IME适应DS MSN的进展，这表明很关键 NAC到DS的信息流。该应用程序将探讨介导NAC-to-to-的解剖基础 可卡因诱导的IME适应性的DS进展和该进展的行为后果。这 中心假设是可卡因诱导的IME适应的NAC-TO-DS进展。 可卡因自我给药是由纹状体式纹状体升螺旋介导的，这是电路复合物 通过互惠项目与腹侧段区域和底座连接NAC和DS Nigra，以及可卡因诱导的IME适应的NAC-TO-DS进展促进了行为转变 从限制到升级的可卡因使用。提出的实验将表征可卡因的关键形式 延长可卡因自我给药后，诱导的细胞适应从NAC到DS。 预期的结果可能会提供电路机制和混凝土细胞底物，以介导 有限使用的药物进展升级，最终是强迫性使用。