Beta-noradrenergic Receptor Blockage of Cocaine Withdrawal-induced Anxiety

描述（由申请人提供）：可卡因依赖是一种严重的健康问题，具有重大的医疗和社会影响。由于复发率仍然很高，特别是在持续戒断症状的患者中，治疗进展甚微。戒断期间的焦虑可能会导致可卡因使用、戒断和复发的反复循环。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β - NE受体拮抗剂，在减轻戒断症状、提高患者的治疗保留率和减少可卡因使用方面显示出了希望，特别是对于报告严重戒断的个体。尽管焦虑和复发之间存在联系，但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，因为之前的研究只使用了非偶然的可卡因给药。本课题的目标是建立一种动物模型，用于研究有可卡因自我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潜在的药物治疗方法。将评估心得安在减轻戒断引起的焦虑以及预防或减少复发的动物模型中重新寻求可卡因的功效。此外，这些研究将使用c-fos免疫标记来揭示可卡因戒断背后潜在的神经元底物。据推测，在戒断期间心得安治疗将有利于减少焦虑，并且在测试期间与心得安联合使用，将减少药物寻求，在钝化压力诱导的恢复方面特别有效。此外，先前与焦虑相关的大脑区域，包括去甲肾上腺素能细胞群和中央和扩展杏仁核，可能与戒断性焦虑有关。总之，这项训练建议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减轻可卡因戒断焦虑的药物，以及在动物复发模型中显示有希望减少药物寻求的药物疗法。这种转化研究与公共卫生问题密切相关，特别是与可卡因滥用的普遍问题和缺乏有效治疗密切相关。

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.