Dysregulation of Brain Stress Systems and of Relapse

描述(由申请人提供)：申请人之前提供的数据表明，长期接触滥用药物会导致大脑中肽能压力调节系统的功能长期反复发作。这方面的证据在下丘脑外促肾上腺皮质激素释放因子(CRF)系统的情况下最为明显。最近，与压力调节功能有关的第二个神经肽系统，即伤害素/孤儿FQ(N/OFQ)系统，被证明在长期接触滥用药物后严重失调。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与应激事件相关的长期复发易感性中发挥关键作用。因此，拟议的研究将检验这样一种假设，即长期、高剂量的可卡因暴露会导致对压力的异常增强的敏感性，这种状态在长期戒断期间持续存在，是易复发的主要因素。这一假说直接与预期有关，即这些行为变化是慢性可卡因对下丘脑外CRF和脑N/OFQ多肽系统功能破坏的结果，这些系统可以追溯到突触前、突触后或特定大脑部位的基因表达水平。为了验证这些假说，我们将在12周的时间里，在行为和神经生物学水平上，以三次可卡因后间隔时间测量应激敏感性的变化。SPICAL AIM 1将通过几项压力敏感性改变的测试，检查与仅有有限自我给药经历的大鼠或未接触可卡因的大鼠相比，自我给药升级的大鼠对急性应激是否表现出更高的敏感性。其中包括对急性应激引起的复发易感性的直接测量，以及对可卡因相关环境刺激产生的恢复的应激加剧的直接测量，以及在两种焦虑行为模型--高架+迷宫和防御性埋葬测试中，由应激诱导的焦虑样行为加剧所反映的“恒定负荷”的测量。然后，特定的目标2和4(分别集中在下丘脑外CRF和N/OFQ系统)将确定对应激挑战的行为过敏与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。在特定目标3和5的实验中，将使用特定部位的微量注射药物来确认CRF和N/OFQ功能的特定异常是导致特定目标1中确定的应激反应加剧和易复发的原因。除了提供关于药物诱导的应激调节系统变化及其与未来成瘾行为的相关性的基本神经生物学信息外，这些研究有望对旨在改善慢性可卡因引起的大脑应激系统调节失调的治疗药物开发和降低与暴露于应激事件相关的复发风险具有重要意义。

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.