Stress Sensitization of CRF-Induced Withdrawal Behaviors

为了进一步支持Ballenger和Post（1978）关于反复的慢性乙醇暴露会发生点燃过程的观点，我们实验室的工作表明，反复退出慢性乙醇会导致p大鼠戒断诱导的焦虑样行为敏化[即，社交互动减少和增加+迷宫的缺陷]。与多次戒断一样，最近的数据也表明，在慢性乙醇暴露的单次戒断之前，反复的压力会导致p大鼠戒断诱导的焦虑样行为的敏化。此外，多次停药期间的压力增加了p大鼠的自愿饮酒。初步数据表明促肾上腺皮质激素释放因子（CRF）——大脑中的一种主要神经递质肽——和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化，以及反复戒断期间压力引起的饮酒增加有关。本系列研究的目的是确定CRF对反复戒断和应激诱导的戒断诱导的焦虑样行为致敏的神经解剖学和神经生物学基础。基于CRF-1受体拮抗剂阻断由反复戒断和重复应激/戒断方案引起的焦虑样行为的致敏，特异性目标1将验证以下假设：将CRF-1受体拮抗剂微注射到杏仁核或其他具有CRF受体的特定脑部位，将阻断重复应激和多次戒断对焦虑样行为的持续后果。虽然重点将放在确定CRF- 1受体拮抗剂阻断应激和反复戒断引起的焦虑样行为致敏的部位，但向特定部位微量注射CRF-2拮抗剂将确定该CRF受体亚型是否有助于致敏。特定目标2将检验多重压力和戒断导致饮酒增加与酒精剥夺效应相关的假设，这取决于目标1中确定的与焦虑样行为敏感化相关的大脑部位的CRF。最后，特异性目的3将验证以下假设：在特异性目的1和2中确定的p大鼠中，CRF释放增加、CRF受体数量改变或对CRF反应性增加对于戒断诱导的焦虑样行为的敏化和自愿饮酒增加至关重要。因此，这一提议验证了多重戒断和压力/戒断方案对焦虑样行为和自愿饮酒增加的敏感性的总体假设，这些假设依赖于乙醇偏好大鼠特定脑内CRF机制中适应性变化的激活。由于慢性酒精暴露的压力和戒断症状都与持续的酒精滥用有关，这项基本工作有望提供数据，以帮助定义导致戒断症状和戒断期间渴望的病理适应过程，并促进再次酗酒时失去控制。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