NEUROPHARMACOLOGY RESEARCH PROJECT

描述(申请人提供)：慢性酒精引起的神经适应性改变 与长期戒断症状有关，并在禁欲期间有复发风险。该实验室和TSRI酒精研究中心其他小组在先前资助期间进行的研究表明，下丘脑外促肾上腺皮质激素释放因子(CRF)系统调节失调，可能是长期使用乙醇导致的神经适应性后果，对急性和长期戒断期间的情感变化和寻求酒精行为起重要作用。本研究旨在对酒精戒断不同阶段下丘脑外CRF系统的功能异常进行系统的多学科研究，并建立这些变化的行为学意义。该实验计划首先表征与酒精相关的行为的性质和时间过程，以及在12周的戒断期内应激对其进行修改。随后的研究将确定这些实验中发现的行为变化是否与Pre的特定异常一致 或突触后CRF在杏仁中央核(CEA)和终纹床核(BNST)起作用。最后，通过定点给予CRF-R1和CRF-R2受体拮抗剂以及通过靶向病毒载体方法控制CRF受体的表达，将证实这些CRF系统中的功能异常与伴随长期酒精戒断而发生的行为变化的相关性。这些实验将遵循这样一种假设，即有依赖史的大鼠的酒精自我给药、寻求酒精的行为、类焦虑行为以及应激对这些行为的增强将比非依赖大鼠更大。此外，预计(A)非依赖和依赖后大鼠之间的行为差异将与CEA和/或BNST内CRF功能的差异有关，以及(B)在长时间戒断过程中酒精相关行为的时间依赖性变化与CEA和/或BNST内CRF功能的特定变化之间存在一定的预测关系。最后一个预测是，依赖后大鼠焦虑、寻求酒精和摄入的加剧对操纵CEA或BNST中CRF神经传递的改变很敏感。通过增加对急性和长期戒断的神经生物学基础的了解， 这些研究有望对制定药物治疗策略以防止戒酒行为和戒酒不同阶段的复发具有直接意义。

DESCRIPTION (provided by applicant): Neuroadaptive changes induced by chronic ethanol have been implicated in symptoms of protracted withdrawal, and relapse risk during abstinence. Studies during the previous funding by this lab and other groups at the TSRI Alcohol Research Center suggest that dysregulation of extrahypothalamic corticotropin-releasing factor (CRF) systems that mediate behavioral and emotional responses to stress may be a neuroadaptive consequence of chronic ethanol use that contributes importantly to affective changes and ethanol-seeking behavior during acute and protracted withdrawal. The present proposal is designed to extend these studies to a systematic multidisciplinary investigation of functional abnormalities in extra hypothalamic CRF systems at different stages of ethanol withdrawal, and to establish the behavioral significance of these changes. The experimental plan is to first characterize the nature and time course of ethanol-related behaviors and their modification by stress over a 12-week withdrawal period. Subsequent studies will determine whether behavioral changes identified in these experiments coincide with specific abnormalities in pre or postsynaptic CRF function in the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). Finally, the relevance of functional abnormalities in these CRF systems for behavioral changes that accompany protracted ethanol withdrawal will be confirmed using site-specific administration of CRF-R1 and CRF-R2 receptor antagonists and manipulation of CRF receptor expression by targeted viral vector approaches. The experiments will be guided by the hypothesis that ethanol self-administration, ethanol-seeking behavior, anxiety-like behavior, as well as the augmentation of these behaviors by stress will be greater in rats with a history of dependence than in nondependent rats. Moreover, it is expected (a) that behavioral differences between non-dependent and post-dependent rats will be related to differences in CRF function within the CeA and/or BNST, and (b) that some predictive relationship exists between time-dependent changes in ethanol-related behaviors over course of protracted withdrawal and specific alterations in CRF function in the CeA and/or BNST. A final prediction is that the exacerbation of anxiety, ethanol-seeking and intake in postdependent rats is sensitive to modification by manipulation of CRF neurotransmission in the CeA or BNST. By increasing understanding of the neurobiological basis of acute and protracted withdrawal, these studies are expected to have direct implications for the development of pharmacotherapeutic treatment strategies for the prevention of ethanol-seeking behavior and relapse at different stages of withdrawal and abstinence.