Homeostatic Regulation and Dysregulation in Cocaine Craving

描述（由申请人提供）：暴露于滥用药物会导致丘脑核（NAc）神经元功能障碍，这与动机和成瘾密切相关。尽管估计大量的药物诱导的作用代表稳态反应，但药物诱导的NAc稳态调节和失调尚未得到很好的表征。本研究将探讨内稳态可塑性对提示的作用 诱发对可卡因的渴望更具体地说，已经观察到，与先前可卡因使用相关的线索是戒断可卡因使用者复发和可卡因经验丰富的啮齿动物寻求药物的强大触发因素。这种线索诱导的可卡因渴望在从长期接触可卡因自我给药的戒断过程中逐渐加剧（潜伏）。越来越多的证据支持潜伏期与人类药物渴求的相关性。潜伏过程的一个关键特征是，一旦启动，它会自动继续恶化 停药期间，无明显外部刺激。这表明神经元可塑性的稳态形式而不是赫布形式的参与。使用大鼠，我们建议确定的作用，稳态可塑性的NAC在可卡因渴望的孵化。稳态可塑性是一种生理学上的自我校正机制，通过这种机制，神经元可以补偿“不希望的”细胞变化，从而稳定它们的功能输出。我们以前证明了一种形式的稳态串扰兴奋性突触输入和内在的膜兴奋性NAC神经元。这种现象，称为稳态突触膜串扰（HSMC），使NAc神经元，以调整其内在的膜兴奋性，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“假”稳态信号误导，HSMC可能会错误地参与，触发稳态失调的级联，逐渐将神经元输出从正常设定点进一步转移。基于广泛的初步结果，我们的中心假设是，通过含NR 2B的NMDAR的传输增加构成了一个“假”稳态信号，触发HSMC和随后的稳态失调级联，最终导致膜兴奋性持续降低和突触强度增加。总之，这些变化被假设为放大NAc神经元对可卡因相关线索的反应，从而有助于可卡因渴望的孵化。为了验证这一假设，该提案将表征基于HSMC的失调级联的关键分子底物，并测试基于HSMC的方法减弱可卡因渴望的孵化的能力。我们将使用多学科的方法结合体内分子/药理学操作，生物化学，切片电生理学和行为测试。我们的研究结果将为旨在开发基于稳态的药理学策略以恢复可卡因使用者正常NAc功能的转化研究奠定基础。

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.