Neural Sensitivity to Stress During Drug Withdrawal

描述(申请人提供)：世界卫生组织将甲基苯丙胺列为仅次于大麻的第二大被滥用的非法药物，美国处方苯丙胺的滥用正在增加。毒瘾是一种慢性和复发性疾病，复发被认为部分是因为需要缓解焦虑和抑郁等消极的戒断症状。苯丙胺滥用与戒断综合征有关，包括戒毒期间焦虑状态增加。我们已经建立了一个在苯丙胺戒断过程中焦虑加剧的大鼠模型，并确定了几个关键的边缘大脑区域中5-羟色胺能神经传递的变化，这些区域对恐惧、焦虑和压力状态非常重要。目前这项提案的目标是阐明苯丙胺戒断导致5-羟色胺能神经传递改变的机制，并将其与戒断过程中焦虑状态和应激敏感性的升高直接联系起来。此外，这项建议将在苯丙胺戒断大鼠模型中测试传统和新的药物疗法，以确定大脑5-羟色胺能功能正常化是否逆转在苯丙胺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.