Mechanisms of comorbidity between epilepsy and depression

癫痫和抑郁症的共病机制

• 批准号: 9213087
• 负责人: ANDREY M MAZARATI
• 金额: $ 2.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213087
• 关键词: Adrenergic Agents; Animal Model; Animals; Antidepressive Agents; Area; Autoradiography; Autoreceptors; Behavior; Chronic; Combined Modality Therapy; Comorbidity; Development; Electron Microscopy; Epilepsy; Experimental Models; Fluoxetine; Functional disorder; Glucocorticoid Receptor; Hippocampus (Brain); Hyperactive behavior; Immunofluorescence Immunologic; Impairment; Knowledge; Link; Measures; Mental Depression; Mifepristone; Neocortex; Neurons; Norepinephrine; Output; Pathway interactions; Patients; Pilocarpine; Pituitary Gland; Population; Prosencephalon; Quality of life; Radioimmunoassay; Rattus; Regulation; Resistance; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Severities; Status Epilepticus; Swimming; Techniques; Testing; Therapeutic Effect; Time; Tyrosine 3-Monooxygenase; Up-Regulation; Wistar Rats; antidepressant effect; base; behavioral impairment; depressive behavior; depressive symptoms; design; effective therapy; evidence base; improved; in vivo; inhibitor/antagonist; locus ceruleus structure; neocortical; noradrenergic; public health relevance; raphe nuclei; reboxetine; receptor; reuptake; stem; transmission process; treatment effect; venlafaxine

DESCRIPTION (provided by applicant): The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The present proposal tests the hypothesis that epilepsy-associated depression may stem from specific dysfunction of central noradrenergic transmission. The study focuses on the ascending noradrenergic pathway and on the plasticity of ¿2A adrenoreceptors that regulate norepinephrine (NE) release in this pathway. The study employs an animal model whereby chronic epilepsy and concurrent depression-like impairments develop in Wistar rats following pilocarpine-induced status epilepticus. The first part of the study describes perturbations in central noradrenergic transmission in relation to the severity of depressive behavioral impairments, the latter being measured and classified using the forced swim test. The strength and the integrity of noradrenergic transmission in the locus coeruleus-forebrain (i.e. the hippocampus and the neocortex) noradrenergic projections will be measured by means of the in vivo fast cyclic voltammetry, as well as the tyrosine hydroxylase immunofluorescence. The number and the function of ¿2A adrenoreceptors that regulate NE release (i.e. somatodendritic autoreceptors in locus coeruleus and axonal autoreceptors in the forebrain), as well those that regulate serotonin release in the forebrain (i.e. heteroreceptors) will be characterized using autoradiography and electron microscopy. The second part of the study examines whether restoring noradrenergic transmission in the ascending pathway exerts therapeutic effects in animals with epilepsy-associated depression. A selective norepinephrine reuptake inhibitor reboxetine will be delivered over two weeks. A selective ¿2A adrenoreceptor blocker RX-821002 will be administered locally into the locus coeruleus, the hippocampus, the neocortex, and in raphe nucleus, in order to target specific population of ¿2A adrenoreceptors. The effects of treatments on depressive behavior, norepinephrine and serotonin release in the forebrain, tyrosine hydroxylase expression, as well as the number, function and subcellular localization of ¿2A adrenoreceptors will be examined using respective techniques listed above. In the third part of the study possible upstream mechanisms leading to central noradrenergic dysfunction will be examined. The dysregulation of the hypothalamo-pituitary-adrenocortical axis will be studied using radioimmunoassay and correlated with the extent of noradrenergic impairments; further the effects of a glucocorticoid receptor blocker mifepristone delivered locally into the locus coeruleus, on central noradrenergic deficits and depressive behavior will be examined. The proposed studies will contribute to our understanding of mechanisms of the comorbidity between epilepsy and depression, to the development of evidence-based therapies of this condition, and to improving of the quality of life in those epilepsy patients who suffer from concurrent depression.

描述（由适用提供）：该项目的长期目标是了解癫痫和抑郁症之间合并症的机制。本提案检验了以下假设：癫痫相关的抑郁症可能源于中央甲肾上腺素能传播的特定功能障碍。该研究的重点是上升的去甲肾上腺素能途径和2A肾上腺受体的可塑性，这些肾上腺素受体，这些肾上腺素（NE）在此途径中释放。该研究员工是一种动物模型，在该模型中，在Pilocarpine诱导的癫痫持续状态后，Wistar大鼠的慢性癫痫和同时抑郁症状损害会出现。该研究的第一部分描述了中央甲肾上腺素能传播的扰动，与抑郁行为障碍的严重程度有关，后者使用强制游泳测试进行了测量和分类。将通过体内快速循环伏安法（以及酪氨酸羟化酶免疫荧光酶）来测量Nor义脑前脑（即海马和新皮层）中的甲肾上腺素传播的强度和完整性。调节NE释放的肾上腺受体的数量和功能（即，前脑中的圆锥体自身受体和轴突自动对象中的体体自身受体），以及使用自身层面和电子摄影的前脑（即杂型疗法）调节5-羟色胺释放的人（即杂型疗法）的表征。研究的第二部分检查是否恢复上升途径中的非肾上腺素能传播是否在与癫痫相关抑郁症的动物中执行治疗作用。选择性去甲肾上腺素再摄取抑制剂将在两周内交付。选择性»2A肾上腺受体阻滞剂RX-821002将在局部施用到局部凝乳，海马，新皮层和Raphe Nucorus中，以靶向2A肾上腺受体的特定种群。治疗对前脑中抑郁行为，去甲肾上腺素和5-羟色胺释放的影响，酪氨酸羟化酶表达以及使用上面列出的相关技术检查2A肾上腺受体的数量，功能和亚细胞定位。在这项研究的第三部分中，将检查导致中央甲肾上腺功能障碍的上游机制。下丘脑 - 垂体 - 肾上腺皮质轴的失调将使用放射免疫测定法进行研究，并与去甲肾上腺素能损伤的程度相关。进一步，将检查糖皮质激素受体阻滞剂米非酮的影响，并将检查中央甲肾上腺素能定义和抑郁行为。拟议的研究将有助于我们理解癫痫和抑郁症之间合并症的机制，对这种疾病的循证疗法的发展，并改善患有并发抑郁症的癫痫患者的生活质量。