Mechanisms of comorbidity between epilepsy and depression

癫痫和抑郁症的共病机制

• 批准号: 8460873
• 负责人: ANDREY M MAZARATI
• 金额: $ 34.47万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460873
• 关键词: Address; Anhedonia; Animals; Antidepressive Agents; Antiepileptic Agents; Area; Autoradiography; Autoreceptors; Behavior; Behavioral; Behavioral Symptoms; Biochemical; Cell Count; Chronic; Comorbidity; Consumption; Corticosterone; Corticotropin-Releasing Hormone; Data; Development; Dexamethasone; Dorsal; Dose; Endocrine; Epilepsy; Event; Exhibits; Experimental Models; Fatigue; Frequencies; Glucocorticoid Receptor; Goals; Hippocampus (Brain); Hormones; Impairment; Injection of therapeutic agent; Knowledge; Measures; Mental Depression; Mifepristone; Modeling; Neurons; Pathway interactions; Patients; Pilocarpine; Pituitary Gland; Plasma; Quality of life; Radioimmunoassay; Rattus; Saccharin; Seizures; Serotonin; Serotonin Receptor 5-HT1A; Severities; Staging; Status Epilepticus; Swimming; Taste Perception; Testing; Time; Translating; Up-Regulation; Validation; Wistar Rats; depressive symptoms; design; dorsal raphe nucleus; effective therapy; functional restoration; in vivo; male; nerve supply; preference; public health relevance; response; topiramate; transmission process

DESCRIPTION (provided by applicant): The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The current study tests the hypothesis that epilepsy is accompanied by chronic interictal dysregulation of the hypothalamo-pituitary-adrenocortical (HPA) axis, which in turn compromises raphe- hippocampal serotonergic pathway, and via the latter mechanism leads to the development of depression. We will employ a model of chronic epilepsy that develops in male Wistar rats following pilocarpine - induced status epilepticus (SE). The first part of the project is designed to prove that epilepsy is accompanied by the interictal dysregulation of the HPA axis. This will be achieved by measuring, using radioimmunoassay, both basal and dexamethasone/corticotropine releasing hormone (DEX/CRH)- induced increase of plasma corticosterone (CORT) levels during chronic stage of epilepsy (8-12 weeks after SE). Increased CORT level will be statistically correlated with behavioral and electrographic parameters of epilepsy (frequency of spontaneous seizures) and interictal increase of hippocampal excitability determined in the afterdischarge test). The purpose of the second part is to prove that the dysregulation of the HPA axis compromises raphe- hippocampal serotonergic pathway, specifically through the upregulation of raphe 5-HT1A autoreceptors. In post-SE animals, we will correlate the increase in plasma CORT levels with the decrease of raphe- hippocampal serotonergic transmission, as measured by fast cyclic voltammetry (FCV) in vivo, and with the functional state of raphe 5-HT1A autoreceptors, as measured by autoradiography. Further, we will examine, whether epilepsy-associated decrease of serotonin release in the hippocampus and the upregulation or raphe 5-HT1A autoreceptors can be reversed by the protracted pharmacological blockade of glucocorticoid receptors on the level of dorsal raphe. We will also examine whether pharmacological blockade of raphe 5- HT1A autoreceptors restores the functioning of raphe-hippocampal serotonergic pathway. The third part of the project addresses the question whether the dysregulation of the HPA axis and subsequent impairment of raphe-hippocampal serotonergic transmission translates into the development of depression. In post-SE animals, we will statistically correlate plasma CORT levels with the severity of behavioral equivalents of depression - despair, as examined in the forced swim test, and anhedonia, analyzed using saccharin consumption taste preference test. We will also investigate whether protracted blockade of raphe glucocorticoid receptors and of 5-HT1A autoreceptors alleviate depressive behavior in epileptic animals. Data obtained in the proposed studies will likely advance our understanding of the mechanisms, and the development of effective therapies of co-morbidity between epilepsy and depression.

描述（由申请人提供）：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。当前的研究检验了癫痫的假说，伴随着下丘脑 - 垂体 - 肾上腺皮质（HPA）轴的慢性间歇性失调，进而损害了海马血清体能力途径，并通过后一种机制导致抑郁症的发育。我们将采用一种慢性癫痫模型，该模型在毛果皮诱导的癫痫持续状态（SE）后在雄性Wistar大鼠中发展。该项目的第一部分旨在证明癫痫病伴随着HPA轴的间隙失调。这将通过使用放射免疫分子（基底和地塞米松/皮质果仁果释放激素（DEX/CRH） - 在癫痫病的慢性阶段诱导的血浆皮质酮（CORT）水平的增加（SE后8-12周）。 CORT水平的提高将在统计上与癫痫的行为和电图参数（自发性癫痫发作的频率）和在后放电测试中确定的海马兴奋性的息息相关的增加相关。第二部分的目的是证明HPA轴的失调会损害Raphe-Happocampal血清素能途径，特别是通过Raphe 5-HT1A自身受体的上调。在SE后动物中，我们将通过快速循环伏安法（FCV）在体内和Raphe 5-HT1A自动疗法的功能状态进行测量，将血浆皮质水平的增加与Raphe-Happocampal血清素能传播的降低相关联。此外，我们将研究海马中癫痫相关的5-羟色胺释放的降低，以及在背raphe水平上的型糖皮质激素受体的药理学阻滞剂的质地药理学阻断型的上调或Raphe 5-HT1A自身受体可以逆转。我们还将检查Raphe 5-HT1A自身受体的药理阻滞是否恢复了Raphe-Hampocampal血清素能途径的功能。该项目的第三部分解决了以下问题。HPA轴的失调以及随后的Raphe-Hampocampal血清素能传播的损害是否转化为抑郁症的发展。在SE后动物中，我们将在统计学上将血浆CORT水平与抑郁症的行为等效物的严重程度相关联 - 在强制游泳测试和Anhedonia中使用糖精蛋白消耗味味偏好测试进行了分析。我们还将调查对Raphe糖皮质激素受体和5-HT1A自身受体的持久封锁是否减轻了癫痫动物的抑郁行为。在拟议的研究中获得的数据可能会提高我们对机制的理解，以及癫痫和抑郁症之间合并症的有效疗法的发展。