MONOAMINE RECEPTORS: EFFECTS OF DEPRESSION & TREATMENT

一个推论的假设，脱敏的β- 肾上腺素能结合或反应性代表了最后一个共同的 产生抗抑郁作用的途径是 抑郁症的发病机制涉及β-肾上腺素能 受体复合物 我们已经发现了一个）减少的反应， 淋巴细胞β-肾上腺素能受体复合物 内源性抑郁症住院患者。 次敏感β- 反应与更严重的，复发性的 DST上的抑郁和非抑制; B）用 三环类抗抑郁药导致β- 肾上腺素能受体复合物 建议延长这些 研究者： (1)进一步定义临床、神经内分泌和生化 淋巴细胞β-肾上腺素能反应性减弱的相关因素 抑郁症患者; (2)阐明β受体异常的机制 在受体水平上对抑郁症患者的作用 结合研究，以评估受体功能，（ii）测定N 和Ni偶联蛋白质和（iii）在体外和体内的测量 突触非依赖性淋巴细胞β- 受体; (3)间接评估突触后β 1 -肾上腺素能受体 通过测量心率变化， 儿茶酚胺水平; (4)调节受体的因素的研究，包括（i） 血浆NE和EPI，而仰卧位和姿势挑战后 测试以及24小时尿排泄水平的CA和（ii） 治疗前后血浆和尿皮质醇水平 地塞米松; (5)在住院期间纵向研究患者， 以及六个月的门诊以确定治疗效果 （去甲替林）。 测试将在6个月后进行， 在无药物的正常胸腺患者中完成治疗， 控制，以允许区分国家和- 性状依赖性以及药物诱导的生物学差异。 初步数据表明淋巴细胞β- 三环类抗抑郁药对抑郁症患者肾上腺素能反应性的影响 治疗部分依赖于DexA的正常化， 对地塞米松的抗药性 重新敏感化的基础将是 研究和与心脏β-肾上腺素能反应的关系， NT药物水平，临床改善，HYPAC状态，血浆CAs 水平将被确定。 这些研究将提供新的 对单极的潜在神经生物学亚型的见解 内源性抑郁症，β-肾上腺素能受体在 抑郁症的病理生理学，以及 三环类抗抑郁药

A corollary of the hypothesis that desensitization of beta- adrenergic binding or responsiveness represents a final common pathway for generating an antidepressant effect is that the pathogenesis of depressive disorders involves the beta-adrenergic receptor complex. We have found a) diminished responsiveness of the lymphocyte beta-adrenergic receptor complex in drug-free inpatients with endogenous depression. Subsensitive beta- responses were associated with a more severe, recurrent form of depression and nonsuppression on the DST; b) treatment with tricyclic antidepressants resulted in resensitization of beta- adrenergic receptor complexes. It is proposed to extend these studies by: (1) further defining clinical, neuroendocrine and biochemical correlates of blunted lymphocyte beta-adrenergic responsiveness in depressed patients; (2) clarifying the mechanism of abnormalities in beta-receptor function in depressed patients at the receptor level by (i) agonist binding studies to assess receptor function, (ii) assays of the Ns and Ni coupling proteins and (iii) measurement of in vitro and in vivo downregulability of synapse independent lymphocyte beta- receptors; (3) indirectly assessing postsynaptic beta 1 - adrenergic receptors by measurement of heart rate change after an increase in catecholamine levels; (4) studies of factors that regulate the receptor including (i) plasma NE and EPI while supine and after a postural challenge test as well as 24 hour urinary excretion levels of CAs and (ii) plasma and urinary cortisol levels before and after dexamethasone; (5) studying patients longitudinally both during the inpatient phase and six months as an outpatient to determine treatment effects (nortriptyline). Testing will be carried out after 6 months of treatment is completed in drug-free euthymic patients and controls to permit a distinction to be made between state-and- trait dependent as well as drug-induced biological differences. Preliminary data suggest resensitization of lymphocyte beta- adrenergic responsiveness in depressed patients after tricyclic treatment is partly dependent on normalization of dexa- methasone resistance. The basis for resensitization will be studied and relationships to cardiac beta-adrenergic responsivity, NT drug level, clinical improvement, HYPAC status, plasma CAs levels will be determined. These studies should provide new insights into potential neurobiological subtypes of unipolar endogenous depression, the role of beta-adrenergic receptors in the pathophysiology of depression, and the mechanism of action of tricyclic antidepressants.