Stress Sensitization of CRF-Induced Withdrawal Behaviors

为了进一步支持Ballenger和Post（1978），即点燃过程发生在反复的慢性乙醇暴露中，我们实验室的工作表明，反复从慢性乙醇中戒断导致戒断诱导的焦虑样行为敏感化[即，在P-大鼠中的社会互动减少和高架十字迷宫中的缺陷]。与多次戒断一样，最近的数据也表明，在从慢性乙醇暴露中单次戒断之前的重复应激导致P大鼠戒断诱导的焦虑样行为的致敏。此外，压力在多次撤退增加自愿饮用乙醇的P-大鼠。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受体亚型在与反复戒断和压力/戒断方案相关的焦虑样行为的敏化中，以及在反复戒断期间由压力引起的饮酒增加中。本系列研究的目的是确定CRF对P大鼠反复戒断和应激诱导的戒断诱导焦虑样行为致敏作用的神经解剖学和神经生物学基础。基于CRF-1受体拮抗剂阻断由反复戒断以及反复应激/戒断方案诱导的焦虑样行为的致敏性，具体目标1将检验以下假设：将CRF-1受体拮抗剂显微注射到杏仁核或具有CRF受体的其他选定脑部位将阻断反复应激的持续后果和焦虑样行为的多次戒断致敏性。虽然重点将是定义的网站，CRF- 1受体拮抗剂阻断敏感性焦虑样行为的压力和反复撤药，微量注射CRF-2拮抗剂到特定的网站将确定是否这种CRF受体亚型可以有助于这种敏感性。具体目标2将检验以下假设：诱导与酒精剥夺效应相关的饮酒增加的多重压力和戒断依赖于目标1中确定的与焦虑样行为敏感化相关的脑部位的CRF。最后，具体目标3将检验以下假设：增加的CRF释放、改变的CRF受体数量或对CRF的反应性增加对于戒断诱导的焦虑样行为的致敏性和P大鼠中具体目标1和2中确定的脑部位处自愿饮酒的增加至关重要。因此，该提议测试了以下总体假设：使焦虑样行为敏感的多次戒断和应激/戒断方案以及自愿饮酒的增加依赖于乙醇偏好大鼠特定脑部位内CRF机制中的适应性变化的激活。由于长期乙醇暴露的压力和戒断症状都与持续的酒精滥用有关，这种基本的努力有望提供数据，帮助定义导致戒断症状和戒断期间渴望的病理适应过程，以及促进酒精复发后失去控制的病理适应过程。新的治疗策略可以从这些知识中产生

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