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.

摘要 吸毒成瘾被概念化为从最初的自愿和自愿的过渡级联的终点， 有限的药物使用习惯和升级的药物使用，并最终强迫使用。脑结果 特定区域的研究导致一个突出的假设，即最初使用可卡因的动机主要是 基于神经核（NAc）的强化作用，并通过以下方式过渡到更持久或习惯性的药物使用： 招募背侧纹状体（DS），导致可卡因使用升级和抵抗灭绝。而 在人类和啮齿类动物中均观察到从有限可卡因使用到逐步增加可卡因使用的行为转变 模型，可卡因诱导的关键细胞适应，从NAc到DS的进展，以促进这一点 行为转变仍然未被探索。针对这一知识空白，我们将重点放在内在膜上 NAc和DS中等多棘神经元（MSN）的兴奋性（IME）。IME决定了神经元放电的能力 动作电位响应兴奋性输入，从而直接决定了神经元的输出。 以前的结果表明，一个关键的IME适应可卡因的经验减少IME的NAc MSN， 这种可卡因诱导的内啡肽适应有助于可卡因的精神作用， 戒断相关的NAc的一般活动减退状态，以及戒断后寻求可卡因。的 初步结果显示，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的IME适应，而不是DS MSN。在长时间（21天）可卡因自我给药后，小鼠表现出可卡因摄入量增加，并且IME 在NAc和内侧/背侧DS MSNs中均观察到适应。可卡因诱导的IME适应 长期可卡因自我给药后从NAc进展为DS，与可卡因剂量增加相关 拿。此外，通过实验阻止NAc MSN中可卡因诱导的IME适应，可以阻止 在长期可卡因自我给药期间，IME对DS MSN的适应进展，表明 从NAC到DS的信息流。本申请将探讨介导NAc-到- 可卡因诱导的IME适应的DS进展和这种进展的行为后果的 中心假设是，可卡因诱导的IME适应的NAC到DS的进展在长时间的 可卡因自我给药部分是由纹状体黑质纹状体上升螺旋介导的， 腹侧被盖区和腹侧实质通过相互投射连接NAc和DS 可卡因诱导的IME适应的NAC到DS进展促进了行为转变 从有限到逐步增加的可卡因使用。拟议中的实验将描述一种关键形式的可卡因- 诱导细胞适应，在长期可卡因自我给药后从NAc进展到DS。 预期的结果可能会提供一个电路机制和具体的细胞基质，介导 有限的药物使用向逐步升级和最终强迫性药物使用的进展。