Stress Sensitization of CRF-Induced Withdrawal Behaviors

为了进一步支持Ballenger和Post(1978)关于反复慢性酒精暴露会发生点燃过程的观点，我们实验室的工作表明，反复从慢性乙醇中戒断会导致戒断诱导的焦虑样行为敏感化[即社会互动减少和升高的正迷宫中的缺陷]。与多次戒酒一样，最近的数据也表明，在一次戒酒之前的重复应激会导致P-大鼠戒断诱导的焦虑样行为敏化。此外，多次戒酒期间的压力增加了P-鼠自愿饮用酒精的次数。初步数据表明，促肾上腺皮质激素释放因子(CRF)是大脑中的一种主要神经递质肽，CRF-1受体亚型与反复戒断和压力/戒断方案相关的焦虑样行为的敏感化，以及在反复戒酒过程中因压力而导致的饮酒增加。本系列研究的目的是明确CRF在反复戒断和应激诱导的戒断焦虑样行为敏化中所起作用的神经解剖学和神经生物学基础。基于CRF-1受体拮抗剂阻断反复戒断和重复应激/戒断方案引起的焦虑样行为的敏化，特定目标1将检验这样一种假设，即将CRF-1受体拮抗剂显微注射到杏仁核或其他具有CRF受体的选定脑部位，将阻断反复应激和多次戒断敏化焦虑样行为的持续后果。虽然重点将放在确定CRF-1受体拮抗剂阻止应激和反复戒断导致的焦虑样行为敏化的位置上，但将CRF-2拮抗剂微量注射到特定部位将确定该CRF受体亚型是否有助于这种敏化。特定目标2将测试这一假设，即与酒精剥夺效应相关的导致饮酒增加的多重压力和戒酒依赖于目标1中确定的与焦虑样行为敏化相关的大脑部位的CRF。最后，特定目标3将检验这一假设，即增加CRF释放，改变CRF受体数量，或对CRF的反应性增加，对于P-大鼠戒断诱导的焦虑样行为和特定目标1和2中确定的大脑部位自愿饮酒增加至关重要。因此，这一建议检验了总体假设，即多次戒断和使焦虑样行为敏化的应激/戒断方案以及自愿饮酒的增加依赖于偏爱酒精的大鼠特定脑部位CRF机制中适应性变化(S)的激活。由于长期接触酒精引起的压力和戒断症状都与持续的酒精滥用有关，这一基本努力有望提供数据，帮助确定在戒酒期间导致戒断症状和渴望的病理适应过程，并促进酗酒者在复发时失去控制。从这些知识中可能会出现新的治疗策略

In further support of Ballenger and Post (1978) that a kindling process occurs with repeated chronic ethanol exposures, work in our laboratory demonstrated that repeated withdrawals from chronic ethanol results in withdrawal-induced sensitization of anxiety-like behavior [i.e., a decrease in social interaction & deficit in the elevated plus-maze] in P-rats. Like multiple withdrawals, recent data also indicate that repeated stresses prior to a single withdrawal from chronic ethanol exposure results in sensitization of withdrawal-induced anxiety-like behavior in the P-rats. Additionally, stress during multiple withdrawals increases voluntary drinking of ethanol in P-rats. Preliminary data have implicated corticotropin releasing factor (CRF)--a major neurotransmitter peptide in brain-- and the CRF-1 receptor subtype in the sensitization of anxiety-like behavior associated with the repeated withdrawal and stresses/withdrawal protocols, as well as in the increased drinking induced by stress during repeated withdrawals. The purpose of the present series of investigations is to define the neuroanatomical and neurobiological basis of the CRF contribution to the sensitization of the withdrawal-induced anxiety-like behavior induced by repeated withdrawals and the stresses in P-rats. Based upon a CRF-1 receptor antagonist blocking sensitization of anxiety-like behavior induced by the repeated withdrawal as well as by the repeated stress/withdrawal protocols, Specific Aim 1 will test the hypothesis that a CRF-1 receptor antagonist microinjected into amygdala or other selected brain sites with CRF receptors will block the persistent consequence of repeated stress and multiple withdrawal sensitization of anxiety-like behavior. While focus will be on defining the site where a CRF- 1 receptor antagonist blocks sensitization of anxiety-like behavior by stress and repeated withdrawals, microinjection of a CRF-2 antagonist into specific sites will determine if this CRF receptor subtype can contribute to this sensitization. Specific Aim 2 will test the hypothesis that multiple stresses and withdrawals that induce increased drinking linked to the alcohol deprivation effect is dependent upon CRF at brain sites identified in Aim 1 that related to sensitization of anxiety-like behavior. Finally, Specific Aim 3 will test the hypothesis that increased CRF release, altered CRF receptor number, or an increased responsiveness to CRF is critical for the sensitization of withdrawal-induced anxiety-like behavior and the increased voluntary ethanol drinking at the brain sites identified in Specific Aims 1 & 2 in the P-rats. Thus, this proposal tests the overall hypothesis that multiple withdrawal and the stress/withdrawal protocols that sensitize anxiety-like behavior and the increased voluntary ethanol drinking are dependent upon activation of adaptive change(s) in CRF mechanisms within specific brain sites of ethanol preferring rats. Since both stress and withdrawal symptoms from chronic ethanol exposure have been implicated in sustaining alcohol abuse, this basic effort can be expected to provide data that will assist in defining the pathological adaptive processes that contribute to withdrawal symptoms and craving during abstinence and that facilitate loss of control upon relapse in the alcoholic. New treatment strategies could emerge from such knowledge