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之间的共病机制。目前的建议测试的假设，癫痫相关的抑郁症可能源于特定的中枢去甲肾上腺素能传递功能障碍。这项研究的重点是上行去甲肾上腺素能通路和调节去甲肾上腺素（NE）释放的<$2A肾上腺素受体的可塑性。该研究采用了一种动物模型，其中慢性癫痫和并发抑郁样损害的发展在Wistar大鼠毛果芸香碱诱导的癫痫持续状态。研究的第一部分描述了中枢去甲肾上腺素能传递的扰动与抑郁性行为障碍的严重程度有关，后者使用强迫游泳试验进行测量和分类。蓝斑-前脑（即海马和新皮质）去甲肾上腺素能投射中去甲肾上腺素能传递的强度和完整性将通过体内快速循环伏安法以及酪氨酸羟化酶免疫荧光来测量。调节NE释放的<$2A肾上腺素受体（即蓝斑中的体树突自受体和前脑中的轴突自受体）以及调节前脑中5-羟色胺释放的肾上腺素受体（即异源受体）的数量和功能将使用放射自显影术和电子显微镜进行表征。本研究的第二部分检查是否恢复上行通路中的去甲肾上腺素能传递对癫痫相关抑郁症动物产生治疗作用。选择性去甲肾上腺素再摄取抑制剂reboxeratin将在两周内提供。选择性的2A肾上腺素受体阻滞剂RX-821002将局部给予蓝斑、海马、新皮质和中缝核，以靶向特定的2A肾上腺素受体群体。将使用上文列出的相应技术检查治疗对抑郁行为、前脑中去甲肾上腺素和5-羟色胺释放、酪氨酸羟化酶表达以及<$2A肾上腺素受体的数量、功能和亚细胞定位的影响。在研究的第三部分中，将检查导致中枢去甲肾上腺素能功能障碍的可能上游机制。将使用放射免疫测定法研究下丘脑-垂体-肾上腺皮质轴的失调，并将其与去甲肾上腺素能损伤的程度相关联;将进一步检查局部递送至蓝斑的糖皮质激素受体阻断剂米非司酮对中枢去甲肾上腺素能缺陷和抑郁行为的影响。这些研究将有助于我们了解癫痫和抑郁症之间的共病机制，发展这种疾病的循证治疗，并改善那些患有并发抑郁症的癫痫患者的生活质量。

DESCRIPTION (provided by applicant): The long-term objective of the project is to understand mechanisms of co-morbidity between epilepsy and depression. The 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.