DEPRESSION--LOCUS COERULEUS AFFECTS DOPAMINE VIA GALANIN

描述（改编自申请人摘要）：此处提出的研究 研究了脑内去甲肾上腺素能神经元 大脑影响多巴胺能神经元产生行为变化， 萧条 这些研究涉及一个重要问题， 抑郁症的神经生物学;也就是说，虽然许多证据表明，大脑 去甲肾上腺素（NE）在肾上腺素缺乏症的发病机制和治疗中均起重要作用。 抑郁症，基础研究暗示多巴胺（DA）与抑郁症有关 反应（运动活动变化，享乐反应）比NE多得多。 这项拟议中的研究来源于并将继续使用一种动物， (rat)抑郁症的模型，再现了临床 通过将动物暴露在无法控制的压力条件下而导致抑郁症 （被称为“压力诱发的行为抑郁症”）。 行为抑郁症 这个模型可以追溯到蓝斑的增强的“爆发”放电 (LC)神经元 根据最近的电生理学研究， LC神经元的快速放电会释放甘丙肽（GAL）， 腹侧被盖（VTA）中的LC-NE终末，其抑制LC-NE终末的活性。 投射到前脑的DA细胞。 由于腹侧被盖区DA神经元介导运动 活动和奖励过程，它们的抑制会导致 抑郁症（即，精神发育迟滞和快感缺乏）。 在测试这一假设时，先前的工作表明， GAL转化为VTA模仿行为抑郁症。 本文提出的研究将 确定（1）相反，VTA中GAL受体的阻断是否可以逆转 行为抑郁，和（2）细胞外DA的相应变化 （通过微透析测量）在前脑中也发生。 其次，使用newly 开发出了动物模型，显示出（a）长期的行为抑郁， 和（B）响应抗抑郁药的敏感性和选择性 治疗，研究建议（1）测量单胺（DA，NE，5-HT） 长时程抑郁模型中前脑的变化，（2）确定 是否治疗长期的行为抑郁症发生， 阻断VTA中的GAL受体，和（3）测量抗抑郁药的作用 治疗（药物和电休克）（i）电生理 LC神经元的活性（因为GAL以高速率释放， （ii）VTA和其他LC投影区域中的GAL（通过 测量细胞外液和组织中的GAL）和LC中的GAL mRNA，以及 (iii)细胞外DA（和其他单胺）在前脑区域。 通过关注GAL，潜在的参与发病机制的新递质 抑郁症，一个新的目标，治疗干预这种疾病 可能会出现。

DESCRIPTION (adapted from applicant's abstract): The research proposed here investigates a possible mechanism by which noradrenergic neurons in the brain influence dopaminergic neurons to produce behavioral changes seen in depression. These studies address an important issue related to the neurobiology of depression; namely, that while much evidence shows brain norepinephrine (NE) is important in both the pathogenesis and therapy of depression, basic research implicates dopamine (DA) in depression-related responses (motor activity changes, hedonic responses) much more so than NE. The proposed research derives from, and will continue to use, an animal (rat) model of depression that reproduces characteristics of clinical depression by exposing animals to uncontrollable stressful conditions (called "stress-induced behavioral depression"). Behavioral depression in this model has been traced to heightened "burst" firing of locus coeruleus (LC) neurons. The proposed hypothesis, based on recent electrophysiological data, is that the rapid firing of LC neurons releases galanin (GAL) from LC-NE terminals in the ventral tegmentum (VTA), which inhibits activity of DA cells that project to forebrain. Because VTA DA neurons mediate motor activity and reward processes, their inhibition causes changes seen in depression (i.e., psychomotor retardation and anhedonia). In testing this hypothesis, previous work has shown that microinjection of GAL into VTA mimics behavioral depression. Studies proposed here will determine if (1), conversely, blockade of GAL receptors in VTA can reverse behavioral depression, and (2) commensurate changes in extracellular DA (measured by microdialysis) in forebrain also occur. Next, using newly developed animal models that show (a) long-lasting behavioral depression, and (b) sensitivity and selectivity for responding to antidepressant treatments, studies are proposed to (1) measure monoamine (DA, NE, 5-HT) changes in forebrain in the model of long-lasting depression, (2) determine whether therapy for the long-lasting behavioral depression occurs if one blocks GAL receptors in VTA, and (3) measure effects of antidepressant treatments (drugs and electroconvulsive shock) on (i) electrophysiological activity of LC neurons (since GAL is released at high rates of depolarization), (ii) GAL in VTA and other LC projection regions (by measuring GAL in extracellular fluid and tissue) and GAL mRNA in LC, and (iii) extracellular DA (and other monoamines) in forebrain regions. By focusing on GAL, potential new transmitter involved in the pathogenesis of depression, a novel target for therapeutic intervention in this disorder may emerge.