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 吸毒成瘾被概念化为从最初的自愿到最终的一系列转变的终点。 将药物使用限制为习惯性药物使用和升级药物使用，并最终发展为强迫性使用。来自大脑的结果 针对特定地区的研究得出了一个突出的假设，即最初使用可卡因的主要动机是 基于伏隔核（NAc）的强化作用，并过渡到更持久或习惯性的药物使用 募集背侧纹状体（DS），导致可卡因使用量增加和对灭绝的抵抗。虽然 在人类和啮齿动物中都观察到从有限使用可卡因到逐步使用可卡因的行为转变 模型中，可卡因诱导的关键细胞适应从 NAc 进展到 DS 以促进这一点 行为转变仍有待探索。针对这一知识差距，我们重点关注内在膜 NAc 和 DS 中型多棘神经元 (MSN) 的兴奋性 (IME)。 IME 决定神经元放电的能力 动作电位响应兴奋性输入，从而直接决定神经元的输出。 先前的结果表明，可卡因体验降低了 NAc MSN 的 IME 适应能力，并且 这种可卡因诱导的 NAc 中的 IME 适应有助于可卡因的精神运动效应，可卡因 戒断相关的 NAc 普遍低活性状态，以及药物戒断后寻求可卡因。这 初步结果表明，在短期（5天）可卡因自我给药过程中，小鼠表现出 有限的可卡因摄入，并且这种可卡因程序仅诱导 NAc MSN 中的 IME 适应，而不诱导 DS MSN。长期（21天）自我给予可卡因后，小鼠表现出可卡因服用量增加，IME 在 NAc 和内侧/背侧 DS MSN 中都观察到了适应性。因此，可卡因诱导的 IME 适应 长期自我施用可卡因后从 NAc 进展为 DS，与可卡因升级相关 服用。此外，通过实验阻止 NAc MSN 中可卡因诱导的 IME 适应，防止了 在长期可卡因自我给药期间，IME 对 DS MSN 的适应进展，表明关键 从 NAc 到 DS 的信息流。该应用程序将探索介导 NAc 到 - 的解剖学基础 可卡因诱导的 IME 适应的 DS 进展以及该进展的行为后果。这 中心假设是可卡因诱导的 IME 适应在长时间后从 NAc 到 DS 的进展 可卡因的自我给药部分是由纹状体黑质纹状体上升螺旋（一种循环复合体）介导的 通过与腹侧被盖区和实质的相互投影连接 NAc 和 DS 黑质，可卡因诱导的 IME 适应的 NAc 到 DS 进程促进了行为转变 从限制可卡因使用到逐步升级。拟议的实验将表征可卡因的一种关键形式—— 长期自我施用可卡因后，诱导细胞适应从 NAc 进展到 DS。 预期的结果可能会提供介导这一过程的电路机制和具体的细胞基质。 有限的药物使用逐渐升级，最终发展为强迫性药物使用。