ALPHA-1 ADRENERGIC SYSTEM IN ACTIVITY AND DEPRESSION

描述（由申请人提供）：目前的提案是对先前拨款MH45265的修订，其目的是阐明抑郁症缺乏积极动机行为的神经生物学。该项目的目标是更精确地确定这些行为在这种疾病中是如何被破坏的。此前的研究表明，大脑肾上腺素（EPI）和中枢α -1肾上腺素受体（central alpha-1 adrenoceptors）在动物的积极动机行为中起着关键作用，并被已知的诱发抑郁行为的压力源改变。这两种受体在之前的抑郁症研究中被忽视。具体来说，这些研究提出了大脑EPI是行为激活α -1受体的内源性神经递质，并且这种“EPI/ α -1系统”专门参与积极而非消极动机行为的假设。这些假设将在本提案中通过神经药理学、行为学、免疫组织化学和神经化学实验的结合来验证，这些实验将评估大脑EPI作为该系统的内源性刺激物的作用，以及该系统在各种积极动机活动中的作用，包括外侧下丘脑的自我刺激、条件接近和回避正强化物和负强化物，以及努力的操作行为。这项研究可能会确定EPI/ α -1系统作为抗抑郁和抗压力药物的一个新的重要靶点

DESCRIPTION (provided by applicant): The present proposal is a revision of a previous grant, MH45265, whose aim was to elucidate the neurobiology of positively motivated behaviors that are deficient in depressive illness. The goal of the project is to identify more precisely how these behaviors are disrupted during this disorder. Previous work on this grant has shown that brain epinephrine (EPI) and central alpha-1 adrenoceptors, both of which have been neglected in prior research on depression, play key roles in positively motivated behaviors in animals and are altered by stressors that are known to induce depressive behavior. Specifically these studies have suggested the hypotheses that brain EPI is the endogenous neurotransmitter for behaviorally activating alpha-1 receptors and that this "EPI/alpha-1 system" is specifically involved in positively- rather than negatively-motivated behaviors. These hypotheses will be tested in the present proposal by a combination of neuropharmacological, behavioral, immunohistochemical and neurochemical experiments that will assess the role of brain EPI as the endogenous stimulant of this system and the role of the system in various positively-motivated activities including self-stimulation of the lateral hypothalamus, conditioned approach and avoidance of positive and negative reinforcers, and effortful operant behavior. The research will likely identify the EPI/alpha-1 system as a new and important target for antidepressant and antistress medications