ALPHA-1 ADRENERGIC SYSTEM IN ACTIVITY AND DEPRESSION

描述(由申请人提供)：目前的建议是对之前的资助MH45265的修订，该资助的目的是阐明抑郁疾病中缺乏积极动机的行为的神经生物学。该项目的目标是更准确地确定这些行为在这种紊乱期间是如何被破坏的。以前关于这项拨款的工作表明，脑肾上腺素(EPI)和中枢α-1肾上腺素受体在动物的积极动机行为中发挥关键作用，并被已知的诱导抑郁行为的应激源改变。这两个受体在先前关于抑郁症的研究中都被忽视。具体地说，这些研究提出了这样的假设，即大脑EPI是行为激活α-1受体的内源性神经递质，这个“EPI/α-1系统”专门参与积极动机的行为，而不是消极动机的行为。这些假说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组合进行验证，这些实验将评估脑EPI作为该系统的内源性刺激剂的作用，以及该系统在各种积极动机活动中的作用，包括对下丘脑外侧核的自我刺激、条件化方法和避免正负向增强剂，以及努力操作行为。这项研究可能会将EPI/α-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