Neural Sensitivity to Stress During Drug Withdrawal

描述（由申请人提供）：世界卫生组织将甲基苯丙胺确定为大麻之后第二大滥用非法药物，美国处方安非他明的滥用正在增加。药物成瘾是一种慢性和复发性疾病，复发被认为部分是由于需要减轻消极的戒断症状，如焦虑和抑郁。安非他明滥用与戒断综合征有关，戒断综合征包括戒毒期间焦虑状态增加。我们已经开发了一种大鼠模型，在苯丙胺戒断过程中焦虑加剧，并确定了几个关键的边缘脑区域内的多巴胺能神经传递的变化，这些区域对恐惧，焦虑和压力状态很重要。目前的建议的目标是阐明安非他明戒断导致改变的多巴胺能神经传递的机制，并直接将这些与戒断过程中的焦虑状态和应激敏感性升高联系起来。此外，该提案将在安非他明戒断的大鼠模型中测试传统和新型药物疗法，以确定大脑中的多巴胺能功能正常化是否逆转在安非他明戒断期间观察到的高度焦虑状态。

DESCRIPTION (provided by applicant): The World Health Organization identifies methamphetamine as the second most widely abused illicit drug after marijuana, and abuse of prescription amphetamines in the US is increasing. Drug addiction is a chronic and relapsing disorder, and relapse is thought to arise, in part, from the need to alleviate negative withdrawal symptoms such as anxiety and depression. Amphetamine abuse is associated with a withdrawal syndrome that includes increased anxiety states during drug abstinence. We have developed a rat model of heightened anxiety during amphetamine withdrawal and have identified changes in serotonergic neurotransmission within several key limbic brain areas that are important for fear, anxiety and stress states. The goal of the current proposal is to elucidate the mechanisms by which amphetamine withdrawal results in altered serotonergic neurotransmission, and directly relate these to heightened anxiety states and stress sensitivity during withdrawal. Furthermore this proposal will test traditional and novel pharmacotherapies in this rat model of amphetamine withdrawal, to determine whether normalizing serotonergic function in the brain reverses heightened anxiety states that are observed during abstinence from amphetamine.