Homeostatic Regulation and Dysregulation in Cocaine Craving

描述(申请人提供)：接触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。尽管据估计，大量的药物诱导的效应是稳态反应，但药物诱导的稳态调节和NAC的调节失调还没有得到很好的表征。这项应用将探索动态平衡可塑性对CUE的贡献 诱导了可卡因的渴望。更具体地说，已经观察到，与以前使用可卡因有关的线索是戒除可卡因使用者复发和有可卡因经验的啮齿动物寻求毒品的有力触发因素。这种线索诱导的可卡因渴求在戒断长期接触可卡因自我给药的过程中逐渐加剧(孵化)。越来越多的证据支持孵化与人类毒瘾的相关性。孵化过程的一个关键特征是，一旦启动，它会继续自动恶化 在戒断期间，没有明显的外部刺激。这表明，神经元的可塑性与稳态有关，而不是Hebbian形式。利用大鼠，我们建议确定NAC的稳态可塑性在可卡因渴求的孵化中所起的作用。动态平衡可塑性是一种生理上的自我纠正机制，神经元通过它来补偿“不受欢迎的”细胞变化，从而稳定其功能输出。NAC神经元中是否存在某种形式的动态平衡调节/失调，可能与渴求的孕育有关？我们以前在NAC神经元中证明了兴奋性突触输入和固有的膜兴奋性之间存在一种形式的稳态串扰。这种现象被称为稳态突触-膜串扰(HSMC)，使NAC神经元能够调节其固有的膜兴奋性，从功能上抵消兴奋性突触强度的变化。因此，可以稳定地维持NAC神经元的最佳输出。然而，如果被“错误的”稳态信号误导，HSMC可能会被错误地参与，触发一连串的稳态失调，逐渐使神经元的输出越来越远离正常的设定点。基于广泛的初步结果，我们的中心假设是，通过含有NR2B的NMDARs传递的增加构成了一个“错误的”稳态信号，触发HSMC和随后的稳态失调级联反应，最终导致膜兴奋性的持续下降和突触强度的增加。综上所述，这些变化被认为是为了放大NAC神经元对可卡因相关线索的反应，从而有助于孵化可卡因欲望。为了验证这一假设，这项提议将表征基于HSMC的失调级联反应的关键分子底物，并测试基于HSMC的方法抑制对可卡因的渴望的能力。我们将使用一种多学科的方法，结合体内分子/药物操作、生物化学、切片电生理学和行为测试。我们的结果将为旨在开发基于动态平衡的药理学策略以恢复可卡因使用者正常NAC功能的转译研究奠定基础。

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.