重复给予拉莫三嗪治疗对大鼠抑郁症状模型的抗抑郁及促动机作用
Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms.
作者信息
Scheggi Simona, Pelliccia Teresa, Cuomo Alessandro, De Montis Maria Graziella, Gambarana Carla
机构信息
Department of Molecular and Developmental Medicine, University of Siena, Italy.
出版信息
Heliyon. 2018 Oct 12;4(10):e00849. doi: 10.1016/j.heliyon.2018.e00849. eCollection 2018 Oct.
BACKGROUND
The antiepileptic lamotrigine is approved for maintenance treatment of bipolar disorder and augmentation therapy in treatment-resistant depression. Previous preclinical investigations showed lamotrigine antidepressant-like effects without addressing its possible activity on motivational aspects of anhedonia, a symptom clinically associated with poor treatment response and with blunted mesolimbic dopaminergic responsiveness to salient stimuli in preclinical models. Thus, in rats expressing a depressive-like phenotype we studied whether repeated lamotrigine administration restored behavioral responses to aversive and positive stimuli and the dopaminergic response to sucrose in the nucleus accumbens shell (NAcS), all disrupted by stress exposure.
METHODS
Depressive-like phenotype was induced in non-food-deprived adult male Sprague-Dawley rats by exposure to a chronic protocol of alternating unavoidable tail-shocks or restraint periods. We examined whether lamotrigine administration (7.5 mg/kg twice a day, i.p.) for 14-21 days restored a) the competence to escape aversive stimuli; b) the motivation to operate in sucrose self-administration protocols; c) the dopaminergic response to sucrose consumption, evaluated measuring phosphorylation levels of cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS, by immunoblotting.
RESULTS
Lamotrigine administration restored the response to aversive stimuli and the motivation to operate for sucrose. Moreover, it reinstated NAcS DARPP-32 phosphorylation changes in response to sucrose consumption.
LIMITATIONS
The pro-motivational effects of lamotrigine that we report may not completely transpose to clinical use, since anhedonia is a multidimensional construct and the motivational aspects, although relevant, are not the only components.
CONCLUSIONS
This study shows antidepressant-like and pro-motivational effects of repeated lamotrigine administration in a rat model of depressive symptoms.
背景
抗癫痫药物拉莫三嗪被批准用于双相情感障碍的维持治疗以及难治性抑郁症的增效治疗。先前的临床前研究显示拉莫三嗪具有抗抑郁样作用，但未涉及它对快感缺失动机方面的可能活性，快感缺失是一种临床上与治疗反应不佳相关的症状，并且在临床前模型中与中脑边缘多巴胺能对显著刺激的反应迟钝有关。因此，在表现出抑郁样表型的大鼠中，我们研究了重复给予拉莫三嗪是否能恢复对应激暴露所破坏的厌恶性和阳性刺激的行为反应以及伏隔核壳（NAcS）中对蔗糖的多巴胺能反应。
方法
通过暴露于交替不可避免的尾部电击或束缚期的慢性方案，在未禁食的成年雄性Sprague-Dawley大鼠中诱导出抑郁样表型。我们检查了给予拉莫三嗪（7.5毫克/千克，每天两次，腹腔注射）14至21天是否能恢复：a）逃避厌恶性刺激的能力；b）在蔗糖自我给药方案中操作的动机；c）通过免疫印迹法测量NAcS中cAMP调节的磷蛋白32,000 Mr（DARPP-32）的磷酸化水平来评估对蔗糖消耗的多巴胺能反应。
结果
给予拉莫三嗪恢复了对应激刺激的反应以及为蔗糖而操作的动机。此外，它恢复了NAcS中DARPP-32磷酸化对蔗糖消耗的反应变化。
局限性
我们报告的拉莫三嗪的促动机作用可能无法完全转化为临床应用，因为快感缺失是一个多维度的概念，动机方面虽然相关，但不是唯一的组成部分。
结论
本研究显示了在抑郁症状大鼠模型中重复给予拉莫三嗪具有抗抑郁样和促动机作用。
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