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的共病机制。目前的研究验证了以下假设：癫痫伴随着下丘脑-垂体-肾上腺皮质（HPA）轴的慢性发作间期失调，这反过来又损害中缝-海马多巴胺能通路，并通过后者机制导致抑郁症的发展。我们将采用一种慢性癫痫模型，该模型在毛果芸香碱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伴随着发作间期HPA轴的失调。这将通过使用放射免疫测定法测量癫痫慢性期（SE后8-12周）期间基础和地塞米松/促肾上腺皮质激素释放激素（DEX/CRH）诱导的血浆皮质酮（CORT）水平升高来实现。增加的CORT水平将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发作间期增加在统计学上相关。第二部分的目的是证明HPA轴的失调影响中缝-海马神经元能通路，特别是通过中缝5-HT 1A自身受体的上调。在SE后动物中，我们将血浆CORT水平的增加与中缝-海马多巴胺能传递的减少（通过体内快速循环伏安法（FCV）测量）以及中缝5-HT 1A自身受体的功能状态（通过放射自显影测量）相关联。此外，我们将研究，是否癫痫相关的减少5-羟色胺释放的海马和上调中缝5-HT 1A自身受体可以逆转的糖皮质激素受体的水平上的中缝背核的长期药理学阻滞。我们还将研究中缝5-HT 1A自身受体的药物阻断是否恢复中缝-海马多巴胺能通路的功能。该项目的第三部分解决的问题是否HPA轴的失调和随后的中缝-海马神经传导障碍转化为抑郁症的发展。在SE后动物中，我们将使血浆CORT水平与抑郁症-绝望的行为等同物的严重程度统计学相关，如在强迫游泳测试中所检查的，以及快感缺乏，使用糖精消耗味觉偏好测试分析。我们也将调查是否延长封锁中缝糖皮质激素受体和5-HT 1A自身受体减轻癫痫动物的抑郁行为。在拟议的研究中获得的数据可能会促进我们对癫痫和抑郁症之间的共病机制的理解，以及开发有效的治疗方法。