Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1752, USA.
Neuropsychopharmacology. 2011 May;36(6):1305-16. doi: 10.1038/npp.2011.18. Epub 2011 Feb 23.
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
抑郁症是颞叶癫痫的常见合并症，对患者的生活质量有很大的负面影响。我们之前的研究表明，匹鲁卡品诱导的大鼠癫痫持续状态（SE），同时伴有慢性癫痫，会导致抑郁损伤，而后者可能源于下丘脑-垂体-肾上腺皮质（HPA）轴的失调和/或中缝核-海马 5-羟色胺能传递的减少。我们研究了 5-羟色胺 1A（5-HT1A）受体的突触前和突触后参与癫痫相关抑郁的可能性。根据它们在强迫游泳测试（FST）中的表现，SE 后的动物被分为中度和重度抑郁损伤的动物。在中度受损的大鼠中，HPA 轴的活性（使用血浆皮质酮放射免疫测定法检测）高于未处理的动物，但中缝核的突触前 5-HT1A 受体的功能能力（使用放射自显影在中缝核检测）保持不变。在严重抑郁的动物中，与未处理和中度抑郁的动物相比，HPA 轴的活性和突触前 5-HT1A 受体的功能都增加了。HPA 轴与中缝核的药理学分离对严重受损的大鼠具有抗抑郁作用，但对未处理和中度抑郁的动物的行为没有影响。此外，SE 后大鼠海马中的突触后 5-HT1A 受体功能减弱。突触后 5-HT1A 受体的药理学激活改善了癫痫动物的抑郁缺陷。我们认为，在慢性癫痫的情况下，过度活跃的 HPA 轴激活突触前 5-HT1A 受体，从而有利于自动抑制，改变了 5-羟色胺释放的调节。突触后 5-HT1A 受体的下调可能进一步加剧与癫痫相关的抑郁的严重程度。
