Dysregulation of Brain Stress Systems and of Relapse

描述（由申请人提供）：申请人以前提供的数据表明，长期暴露于滥用药物会导致大脑中肽能应激调节系统功能的长期紊乱。这方面的证据在下丘脑外促肾上腺皮质激素释放因子（CRF）系统的情况下是最强的。最近，另一种与应激调节功能有关的神经肽系统——痛觉啡肽/孤啡肽FQ （N/OFQ）系统被证明在长期暴露于药物滥用后会出现严重失调。慢性药物使用后这些肽系统的病理状态可能在应激反应异常和暴露于应激事件的长期易感性复发中起关键作用。因此，拟议的研究将检验这样一种假设，即长期高剂量可卡因暴露会导致对压力的敏感性异常增强，这种状态持续很长一段时间的戒断，是易复发的主要因素。这一假设与以下预期直接相关，即这些行为变化是慢性可卡因对下丘脑外CRF和脑N/OFQ肽系统功能破坏的结果，这些系统可以追溯到特定脑部位的突触前、突触后或基因表达水平。为了验证这些假设，将在12周的时间内，在行为和神经生物学水平上，分三次测量可卡因后压力敏感性的变化。特异性目的1将通过几项改变应激敏感性的试验，研究与只有有限自我给药经历的大鼠或可卡因初始大鼠相比，有逐渐增加的可卡因自我给药史的大鼠对急性应激的敏感性是否增强。这些包括对急性应激引起的复发易感性和可卡因相关环境刺激引起的恢复应激加剧的直接测量，以及在两种焦虑行为模型（升高+迷宫和防御掩埋试验）中由应激引起的焦虑样行为加剧所反映的“适应负荷”测量。具体目标2和4（分别关注下丘脑外CRF和N/OFQ系统）将确定对应激挑战的行为超敏反应与CRF和N/OFQ应激调节系统功能的特定异常之间是否存在关系。SPECIFIC AIMS 3和5中的实验将采用特定部位的药物显微注射，以证实特异性CRF和N/OFQ功能的特异性异常是导致特异性Aim 1中确定的应激反应加剧和复发易感的原因。除了提供药物诱导的应激调节系统改变与其未来成瘾行为相关性之间关系的基本神经生物学信息外，这些研究预计对旨在改善慢性可卡因诱导的脑应激系统失调和减少与暴露于压力事件相关的复发风险的治疗药物开发具有重要意义。

DESCRIPTION (provided by applicant): Previous data generated by the applicants suggest that chronic exposure to drugs of abuse leads to long-lasting perurbations in the functioning of peptidergic stress-regulatory systems in the brain. Evidence in this regard is strongest in the case of extrahypothalamic corticotrophin-releasing factor (CRF) systems. More recently, a second neuropeptide system implicated in stress-regulatory functions, the nociceptin/orphanin FQ (N/OFQ) system, was shown to be stronlgy dysregulated following chronic exposure to drugs of abuse. The pathological status of these peptide systems following chronic drug use may play a critical role in abnormal responsiveness to stress and long-lasting vulnerability to relapse associated with exposure to stressful events. The proposed studies will, therefore, test the hypothesis that chronic, high-dose cocaine exposure leads to abnormally enhanced sensitivity to stress, that this state persists over prolonged periods of abstinence and represents a major factor for vulnerability to relapse. This hypothesis is directly linked to the expectation that these behavioral changes are the result of disruptions produced by chronic cocaine in the functioning of extrahypothalamic CRF and brain N/OFQ peptide systems that can be traced to the presynaptic, postsynaptic, or gene expression level within specific brain sites. To test these hypotheses, alterations in stress sensitivity will be measured at three post-cocaine intervals over a 12-week period at the behavioral and neurobiological level. SPECIFIC AIM 1 will examine whether rats with a history of escalated cocaine self-administration show enhanced sensitivity to acute stress compared to rats with only limited-access self-administration experience or cocaine-naive rats using several tests of altered stress-sensitivity. These include direct measures of susceptibility to relapse induced by acute stress and the exacerbation by stress of reinstatement produced by cocaine-related environmental stimuli, as well as measures of "allostatic load" reflected by stress-induced exacerbation of anxiety-like behavior in two behavioral models of anxiety, the elevated plus maze and defensive burying test. SPECIFIC AIMS 2 and 4 (focusing respectively on extrahypothalamic CRF and the N/OFQ system) will then determine whether relationships exist between behavioral hypersensitivity to stress challenges and specific abnormalities in the functioning of the CRF and N/OFQ stress-regulatory systems. Experiments in SPECIFIC AIMS 3 and 5 will employ site-specific microinjection of pharmacological agents to confirm that specific abnormalities in CRF and N/OFQ functioning are responsible for exacerbated stress responses and vulnerability to relapse identified in Specific Aim 1. In addition to providing essential neurobiological information on the relationship between drug-induced alterations of stress-regulatory systems and their relevance for future addictive behavior, these studies are expected to have important implications for treatment drug development aimed at ameliorating chronic cocaine-induced dysregulation of brain stress systems and reducing relapse risk associated with exposure to stressful events.