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仅次于大麻的第二大滥用非法药物，并且在美国滥用处方安非他明的情况正在增加。药物成瘾是一种慢性和反复发作的疾病，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。滥用安非他明与戒断综合症有关，包括戒断期间焦虑状态的增加。我们已经开发了一个大鼠模型，在安非他明戒断期间焦虑加剧，并确定了在几个关键的大脑边缘区域中血清素能神经传递的变化，这些区域对恐惧、焦虑和压力状态很重要。当前提案的目标是阐明安非他明戒断导致血清素能神经传递改变的机制，并直接将其与戒断期间焦虑状态和压力敏感性的升高联系起来。此外，本研究将在安非他明戒断大鼠模型中测试传统和新型药物疗法，以确定大脑中血清素功能的正常化是否能逆转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.