Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine
Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine
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DOI：
10.1093/brain/awn117
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发表时间：
2008-08-01
期刊：
影响因子：
14.5
通讯作者：
Sankar, Raman
中科院分区：
文献类型：
--
作者：
Mazarati, Andrey;Siddarth, Prabha;Sankar, Raman
抑郁症是癫痫患者最常见的合并症之一。然而，癫痫患者抑郁的机制尚不清楚。建立这种合并症的动物模型对于了解这种疾病的机制和有效治疗的临床前开发至关重要。目前的研究检查了一种常用的颞叶癫痫（TLE）动物模型是否具有与抑郁症有关的行为和生化改变的特征。雄性Wistar大鼠给予LiCl和匹罗卡品治疗癫痫持续状态（SE）。自发性发作和脑兴奋性增强证实了慢性癫痫状态的发展。se后动物在强迫游泳测试（FST）条件下的静止时间增加，表明其处于绝望状态；在糖精溶液消耗测试中，味觉偏好丧失，表明其具有快感缺乏的症状等效性。生化研究表明，在raphe- hippocampus的5-羟色胺能通路中，5-羟色胺能传递受损：通过高效液相色谱法测量海马中5-羟色胺（5-HT）浓度和周转减少，通过快速循环伏安法测量海马对raphe刺激的反应中5-HT释放减少。氟西汀（FLX， 20 mg/kg/天，连用10天）可显著缩短FST条件下的静止时间，抑制海马5-羟色胺的转换。在se后大鼠中，FLX治疗导致海马5-羟色胺转化率进一步降低；然而，在FST中的性能没有得到改善。同时，FLX逆转硒诱导的脑兴奋性增加。综上所述，我们的研究提供了初步证据，证明TLE的se后模型可能作为癫痫和抑郁共病的模型。抑郁症的行为等同物对抗抑郁药物具有抗性，这一发现表明，癫痫抑郁症可能具有不同的潜在机制，而不仅仅是血清素能通路的改变。
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.