Beta-noradrenergic Receptor Blockage of Cocaine Withdrawal-induced Anxiety

描述(申请人提供)：可卡因依赖是一个严重的健康问题，具有重大的医学和社会影响。治疗方面进展甚微，因为复发率仍然很高，特别是在有持续戒断症状的患者中。戒断过程中的焦虑可能会导致可卡因的反复使用、戒除和复发。焦虑状态涉及大脑的去甲肾上腺素能系统，研究表明去甲肾上腺素(NE)功能障碍与可卡因戒断焦虑有关。心得安是一种βNE受体拮抗剂，它在减少戒断症状、促进患者更好的治疗保留率和减少可卡因使用方面表现出了希望，特别是对于报告严重戒断的患者。尽管焦虑和复发之间存在联系，但还没有研究在最相关的临床前动物模型中仔细描述可卡因戒断引起的焦虑，因为以前的研究只使用非或有可卡因注射。本研究的目的是建立一种动物模型，用于研究有可卡因自身给药史的大鼠的可卡因戒断焦虑，并利用该模型研究心得安作为一种潜在的药物治疗方法。将评估心得安在缓解戒断诱导的焦虑以及防止或减少复发动物模型中寻求可卡因的恢复方面的效果。此外，这些研究将使用c-fos免疫标记来揭示可卡因戒断的潜在神经元底物。假设戒断期间的心得安治疗将有益于减少焦虑，与测试期间使用的心得安联合使用将减少药物寻求，在钝化应激诱导的恢复方面尤其有效。此外，大脑以前与焦虑相关的区域，包括去甲肾上腺素能细胞群和中央杏仁核和延伸的杏仁核，很可能与戒断诱导的焦虑有关。综上所述，这项训练计划将有助于揭示可卡因戒断焦虑的行为、生理和神经机制。这些数据将有助于筛选可能缓解可卡因戒断焦虑的药物，以及在减少复发动物模型中寻找药物的药物疗法。这项转化研究与公共卫生问题高度相关，特别是关于普遍存在的可卡因滥用问题和缺乏有效治疗的问题。

DESCRIPTION (provided by applicant): Cocaine dependence is a severe health problem with significant medical and societal impact. Little progress has been made in treatment, as relapse rates remain high, particularly among patients with persisting withdrawal symptoms. Anxiety during withdrawal may significantly contribute to the repetitive cycle of cocaine use, abstinence, and relapse. Anxiogenic states involve noradrenergic systems of the brain, and studies implicate norepinephrine (NE) dysfunction in cocaine withdrawal anxiety. Propranolol, a beta NE receptor antagonist, has shown promise in reducing withdrawal symptoms and promoting better treatment retention rates and less cocaine use in patients, particularly for individuals reporting severe withdrawal. Despite the connection between anxiety and relapse, no studies have carefully characterized cocaine withdrawal-induced anxiety in the most relevant preclinical animal models, in that prior studies have only used noncontingent cocaine administration. The goal of the current proposal is to develop an animal model for studying cocaine withdrawal anxiety in rats with a history of cocaine self-administration, and to use this model to study propranolol as a potential pharmacotherapy. Propranolol will be evaluated for its efficacy in alleviating withdrawal-induced anxiety, as well as preventing or reducing reinstatement of cocaine-seeking in an animal model of relapse. Furthermore, these studies will use c-fos immunolabeling to reveal potential neuronal substrates underlying cocaine withdrawal. It is hypothesized that propranolol treatment during withdrawal will be beneficial in reducing anxiety, and in combination with propranolol administered during testing, will reduce drug-seeking, with particular efficacy in blunting stress-induced reinstatement. In addition, regions of the brain previously associated with anxiety, including noradrenergic cell groups and the central and extended amygdala, are likely to be linked to withdrawal-induced anxiety. In summary, this training proposal will help reveal the behavioral, physiological, and neuronal mechanisms of cocaine withdrawal anxiety. Such data will be useful in the screening of agents which may alleviate cocaine withdrawal anxiety, as well as pharmacotherapies that show promise in decreasing drug-seeking in animal models of relapse. This translational research is highly relevant to public health issues, particularly with regard to the widespread problem of cocaine abuse and the lack of effective treatment.