ALPHA-1 ADRENERGIC SYSTEM IN ACTIVITY AND DEPRESSION

描述（由申请人提供）：本提案是对先前拨款 MH45265 的修订，其目的是阐明抑郁症中缺乏的积极动机行为的神经生物学。该项目的目标是更准确地确定这些行为在这种疾病期间是如何受到干扰的。这项资助的先前研究表明，大脑肾上腺素 (EPI) 和中枢 α-1 肾上腺素受体在之前的抑郁症研究中被忽视，但它们在动物的积极动机行为中发挥着关键作用，并且会被已知会诱发抑郁行为的压力源所改变。具体来说，这些研究提出了这样的假设：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的行为。这些假设将在本提案中通过神经药理学、行为、免疫组织化学和神经化学实验的结合进行测试，这些实验将评估大脑EPI作为该系统的内源性兴奋剂的作用，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、条件性方法和避免正负强化物以及努力的操作行为。该研究可能会将 EPI/alpha-1 系统确定为抗抑郁和抗应激药物的新的重要靶点

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