Mechanisms of comorbidity 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共同发病的机制。目前的研究验证了癫痫伴随慢性发作间歇期下丘脑-垂体-肾上腺皮质(HPA)轴的调节失调，进而损害中缝-海马5-羟色胺能通路，并通过后者导致抑郁的假说。我们将采用一种慢性癫痫模型，该模型在雄性Wistar大鼠中发生在匹罗卡品诱导的癫痫持续状态(SE)之后。该项目的第一部分旨在证明癫痫伴随着发作期HPA轴的失调。这将通过用放射免疫分析法检测癫痫慢性期(SE后8-12周)基础和地塞米松/促肾上腺皮质激素释放激素(DEX/CRH)引起的血浆皮质酮(CORT)水平升高来实现。皮质醇水平的升高将与癫痫的行为和电信号参数(自发性癫痫发作的频率和在后放电试验中确定的海马区兴奋性的间歇性增加)在统计学上相关。第二部分的目的是证明HPA轴的失调损害了中缝-海马5-羟色胺能通路，特别是通过中缝5-HT1A自体受体的上调。在SE后的动物中，我们将通过体内快速循环伏安法(FCV)测量血浆皮质醇水平的升高与中缝-海马5-羟色胺能传递的减少以及放射自显影测量的中缝5-HT1A自身受体的功能状态之间的关系。进一步，我们将研究癫痫相关的5-羟色胺在海马区的释放减少和5-HT1A自体受体的上调是否可以被长期药物阻断在中缝背侧水平上的糖皮质激素受体所逆转。我们还将研究药物阻断中缝5-HT1A自身受体是否恢复中缝-海马5-羟色胺能通路的功能。该项目的第三部分解决了HPA轴的失调以及随后的中缝-海马5-羟色胺能传递障碍是否会转化为抑郁症的发展的问题。在SE后的动物中，我们将在统计学上将血浆皮质醇水平与抑郁-绝望行为等价物的严重程度相关联，如在强迫游泳测试中所检测的那样，以及通过糖精消费品味偏好测试分析的快感缺失的严重程度。我们还将研究长期阻断中缝糖皮质激素受体和5-HT1A自身受体是否能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机制的理解，以及开发有效的治疗癫痫和抑郁症共病的方法。 公共卫生相关性：抑郁症经常出现在癫痫患者中，并导致患者的生活质量下降；同时，癫痫相关抑郁的机制尚不清楚，这种疾病缺乏有效的治疗方法。这项拟议的项目使用了一个癫痫的实验模型来研究导致癫痫患者抑郁发展的可能机制。这一领域知识的进步可能有助于开发有效的治疗方法，并改善患有癫痫和抑郁症的患者的生活质量。

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. PUBLIC HEALTH RELEVANCE: Depression is frequently observed in, and contributes to a lowered quality of life in patients with epilepsy; at the same time, mechanisms that underlie epilepsy-associated depression are poorly understood, and effective therapies of this condition are lacking. The proposed project uses an experimental model of epilepsy to examine a possible mechanism that leads to the development of depression in epilepsy patients. Advancement of knowledge in this area will likely contribute to the development of effective therapy and the improvement of quality of life in those patients who suffer from both epilepsy and depression.