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发病的机制。目前的研究验证了癫痫伴随下丘脑-垂体-肾上腺皮质（HPA）轴慢性间期失调的假设，这反过来又破坏了中缝-海马血清素能通路，并通过后者的机制导致抑郁症的发展。我们将采用雄性Wistar大鼠在匹罗卡品诱导的癫痫持续状态（SE）后发展的慢性癫痫模型。该项目的第一部分是为了证明癫痫是伴随着HPA轴的间断性失调。这将通过使用放射免疫测定法测量基础和地塞米松/促肾上腺皮质激素释放激素（DEX/CRH）诱导的慢性癫痫期（SE后8-12周）血浆皮质酮（CORT）水平的升高来实现。CORT水平升高将与癫痫的行为和电参数（自发发作的频率）以及放电后试验中测定的海马兴奋性的间期增加具有统计学相关性。第二部分的目的是证明HPA轴的失调会损害中脑-海马的血清素能通路，特别是通过中脑5-HT1A自受体的上调。在se后的动物中，我们将血浆CORT水平的升高与体内快速循环伏安法（FCV）测量的中脑海马血清素能传递的减少以及放射自显影法测量的中脑5-HT1A自身受体的功能状态相关联。此外，我们将研究癫痫相关的海马5-羟色胺释放减少和中缝背水平糖皮质激素受体的上调是否可以通过长期药物阻断来逆转。我们还将研究药物阻断raphe 5- HT1A自身受体是否能恢复raphe-海马血清素能通路的功能。该项目的第三部分解决的问题是，下丘脑轴的失调和随后的rape -海马血清素能传递的损害是否转化为抑郁症的发展。在se后的动物中，我们将统计地将血浆CORT水平与抑郁行为当量的严重程度相关联——绝望，如在强迫游泳测试中检测，以及快感缺乏，用糖精消耗味觉偏好测试分析。我们还将研究长期阻断中缝糖皮质激素受体和5-HT1A自身受体是否会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机制的理解，并开发癫痫和抑郁症合并症的有效治疗方法。

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.