Homeostatic Regulation and Dysregulation in Cocaine Craving

可卡因渴望中的稳态调节和失调

• 批准号: 8573033
• 负责人: Yan Dong
• 金额: $ 30.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573033
• 关键词: Abstinence; Affect; Animals; Attenuated; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Brain; Calcium-Activated Potassium Channel; Cell physiology; Cocaine; Cocaine Dependence; Cocaine Users; Computer Analysis; Cues; Development; Electrophysiology (science); Exposure to; Functional RNA; Functional disorder; Gene Transfer; Goals; Homeostasis; Human; Incubated; Link; Mediating; Membrane; Methods; Modeling; Molecular; Motivation; N-Methyl-D-Aspartate Receptors; Neuronal Plasticity; Neurons; Nucleus Accumbens; Outcome; Output; Pharmaceutical Preparations; Physiological; Process; RNA Interference; Rattus; Recurrence; Regulation; Relapse; Research; Rodent; Role; Self Administration; Signal Transduction; Slice; Staging; Synapses; System; Testing; Up-Regulation; Viral; Withdrawal; Wolves; addiction; base; behavior test; cocaine exposure; cocaine use; craving; drug abstinence; drug craving; drug of abuse; experience; in vivo; interdisciplinary approach; multidisciplinary; neuroadaptation; phenome; prevent; public health relevance; response; tool; translational study; transmission process

DESCRIPTION (provided by applicant): Exposure to drugs of abuse causes dysfunction of nucleus accumbens (NAc) neurons, which are strongly linked to motivation and addiction. Despite the estimate that an enormous number of drug-induced effects represent homeostatic responses, drug-induced homeostatic regulation and dysregulation in the NAc have not been well characterized. This application will explore the contribution of homeostatic plasticity to cue induced cocaine craving. More specifically, it has been observed that cues associated with prior cocaine use are powerful triggers of relapse in abstinent cocaine users and of drug seeking in cocaine-experienced rodents. This cue-induced cocaine craving progressively intensifies (incubates) over the course of withdrawal from extended access cocaine self-administration. Growing evidence supports the relevance of incubation to drug craving in humans. A key feature of the incubation process is that, once initiated, it continues to exacerbate automatically during the withdrawal period, without apparent external stimulation. This suggests the involvement of homeostatic rather than Hebbian forms of neuronal plasticity. Using rats, we propose to determine the role of homeostatic plasticity in the NAc in the incubation of cocaine craving. Homeostatic plasticity is a physiological self-correcting mechanism through which neurons compensate for 'undesirable' cellular alterations, thus stabilizing their functional output Are there any forms of homeostatic regulation/dysregulation in NAc neurons that may be involved in incubation of craving? We previously demonstrated a form of homeostatic crosstalk between excitatory synaptic input and intrinsic membrane excitability in NAc neurons. This phenomenon, termed homeostatic synapse-membrane crosstalk (HSMC), enables NAc neurons to adjust their intrinsic membrane excitability to functionally offset alterations in excitatory synaptic strength. As a consequence, the optimal output of NAc neurons may be stably maintained. However, if misled by "false" homeostatic signals, HSMC may be erroneously engaged, triggering cascades of homeostatic dysregulation that progressively shift neuronal output further and further from the normal set-point. Our central hypothesis, based on extensive preliminary results, is that increased transmission via NR2B-containing NMDARs constitutes a "false" homeostatic signal that triggers HSMC and subsequent homeostatic dysregulation cascades, ultimately resulting in a persistent decrease in membrane excitability and an increase in synaptic strength. Together, these changes are hypothesized to magnify the response of NAc neurons to cocaine-associated cues and thereby contribute to incubation of cocaine craving. To test this hypothesis, this proposal will characterize key molecular substrates for HSMC-based dysregulation cascades and test the ability of HSMC-based approaches to attenuate incubation of cocaine craving. We will use a multidisciplinary approach combining in vivo molecular/pharmacological manipulations, biochemistry, slice electrophysiology, and behavioral tests. Our results will set the stage for translational studies aimed at developing a homeostasis-based pharmacological strategy to restore normal NAc function in cocaine users.

描述（由申请人提供）：暴露于滥用药物会导致伏隔核（NAC）神经元功能障碍，这与动机和成瘾密切相关。尽管估计有大量药物诱导的作用代表稳态反应，但NAC中药物诱导的稳态调节和失调尚未得到充分表征。该应用将探讨稳态可塑性对提示的贡献 诱发可卡因渴望。更具体地说，已经观察到，与先前使用的可卡因使用相关的提示是戒烟的可卡因使用者以及可卡因经验丰富的啮齿动物寻求药物的强大触发器。在从扩展访问可卡因自我管理的过程中，这种提示引起的可卡因渴望逐渐增强（孵化）。越来越多的证据支持在人类中孵化与毒品渴望的相关性。孵化过程的关键特征是，一旦开始，它将继续自动加重 在戒断期间，没有明显的外部刺激。这表明稳态而不是Hebbian形式的神经元可塑性参与。使用大鼠，我们建议确定稳态塑性在NAC中的作用在可卡因渴望中。稳态可塑性是一种生理自我校正机制，通过该机制，神经元补偿了“不良”的细胞改变，因此稳定其功能输出是否存在任何形式的NAC神经元中可能涉及抗忍受的NAC神经元中的稳态调节/失调？我们先前在NAC神经元中兴奋性突触输入和内在的膜兴奋性之间表现出了一种稳态串扰。这种现象称为稳态突触膜串扰（HSMC），使NAC神经元能够调整其内在的膜兴奋性，以抵消兴奋性突触强度的功能改变。结果，可以稳定地维持NAC神经元的最佳输出。但是，如果被“错误”的稳态信号误导，HSMC可能会错误地参与其中，从而触发了一系列稳态失调，这些调节逐渐从正常的设定点进一步移动神经元输出。我们的中心假设基于广泛的初步结果，是，通过含NR2B的NMDAR的传输增加构成了“虚假”的稳态信号，可触发HSMC并随后的稳态失调级联反应，最终导致膜兴奋性的持续降低，并增加了膜的兴奋性，并增加了膜的强度。 。共同考虑了这些变化，以放大NAC神经元对可卡因相关的提示的反应，从而有助于可卡因渴望的孵化。为了检验这一假设，该建议将表征基于HSMC的失调级联反应的关键分子底物，并测试基于HSMC的方法减轻可卡因渴望孵育的能力。我们将使用一种多学科方法，结合体内分子/药理学操纵，生物化学，切片电生理学和行为测试。我们的结果将为转化研究奠定阶段，旨在制定基于稳态的药理学策略，以恢复可卡因使用者中正常的NAC功能。