The role of neurotensin in vulnerability for self-injurious behaviour: studies in a rodent model.
The role of neurotensin in vulnerability for self-injurious behaviour: studies in a rodent model.
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神经降压素在自伤行为脆弱性中的作用：啮齿动物模型的研究。
DOI：
10.1111/jir.12519
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Devine,DP
中科院分区：
文献类型：
--
作者：
Muehlmann,AM;Wolfman,SL;Devine,DP
背景：自残行为是一种使人衰弱的特征，通常在自闭症和其他神经发育障碍患者中表现出来，但这种适应不良行为的神经生物学基础尚不清楚。异常的多巴胺能和谷氨酸能神经传递已被牵连，特别是与基底节区和中皮质边缘回路有关。由于神经紧张素是这些神经回路中多巴胺和谷氨酸的重要调节剂，我们利用大鼠的佩莫林模型研究了它在自伤易感性中的潜在作用。方法连续5天，每天给Long - Evans大鼠注射一次精神兴奋剂pemoline或花生油载体。在实验的每一天，通过测量每只大鼠的损伤面积来量化自伤。在第六天采集每个大脑，并解剖纹状体和腹侧被盖。神经紧张素样免疫反应性通过放射免疫测定法从一些大鼠的解剖脑区定量。用Western blot法检测剩余的pemoline处理或对照处理大鼠纹状体的膜和细胞内神经紧张素受体nts1。在另一项实验中，雄性Long - Evans大鼠每天注射载体或帕莫林，在整个帕莫林治疗方案中，每天两次共给药nts1神经紧张素受体激动剂PD149163或nts1受体拮抗剂SR48692（或各自的载体溶液）。测量受伤组织的面积，并通过每天的视频记录时间样本来量化自伤性口腔接触的持续时间。结果喷油林组纹状体神经紧张素免疫反应性明显高于喷油林组。此外，pemoline处理的大鼠纹状体中膜结合和细胞内的nts1受体水平均显著高于对照。当nts1受体激动剂PD149163在培莫林治疗方案中同时使用时，它延长了自伤大鼠的每日口腔接触时间，并增加了自伤大鼠的损伤程度。相反，nts1受体拮抗剂SR48692的联合使用减少了自伤性口腔接触的每日持续时间，并降低了损伤的严重程度。结论纹状体神经紧张素免疫反应性升高，加上nts1激动剂和拮抗剂的作用，提示纹状体神经紧张素传递可能是派莫林模型中自我伤害行为的重要调节剂。总的来说，行为学和生物化学研究结果的结合表明，神经紧张素信号传导可能是自我伤害行为药物治疗干预的重要目标。
BackgroundSelf‐injurious behaviour is a debilitating characteristic that is commonly expressed in people with autism and other neurodevelopmental disorders, but the neurobiological basis of this maladaptive behaviour is not understood. Abnormal dopaminergic and glutamatergic neurotransmission has been implicated, especially in relation to basal ganglia and mesocorticolimbic circuits. As neurotensin is an important modulator of dopamine and glutamate in these circuits, we investigated its potential role in vulnerability for self‐injury, using the pemoline model in rats.MethodsMale Long‐Evans rats were injected once daily with the psychostimulant pemoline or peanut oil vehicle on each of five consecutive days. Self‐injury was quantified by measuring the area of injuries for each rat on each day of the experiment. Each brain was harvested on the sixth day, and the striatum and ventral tegmentum were dissected. Neurotensin‐like immunoreactivity was quantified by radioimmunoassay from the dissected brain regions of some of the rats. Membrane and intracellular neurotensin receptor NTS1were assayed from the striata of the remaining pemoline‐treated or vehicle‐treated rats by Western blot. In an additional experiment, male Long‐Evans rats were treated with daily injections of vehicle or pemoline, and the NTS1neurotensin receptor agonist PD149163 or the NTS1receptor antagonist SR48692 (or respective vehicle solutions) was co‐administered twice daily throughout the pemoline treatment regimen. The areas of injured tissue were measured, and the duration of self‐injurious oral contact was quantified by video‐recorded time samples throughout each day.ResultsStriatal neurotensin immunoreactivity was found to be significantly higher in pemoline‐treated than in vehicle‐treated rats. Moreover, both membrane‐bound and intracellular levels of NTS1receptor were significantly higher in the striata of pemoline‐treated rats than in the striata of the vehicle‐treated controls. When the NTS1receptor agonist PD149163 was co‐administered during the pemoline treatment regimen, it prolonged the daily durations of self‐injurious oral contact and increased the severity of the injuries in the self‐injurious rats. Conversely, co‐administration of the NTS1receptor antagonist SR48692 diminished the daily durations of self‐injurious oral contact and decreased the severity of the injuries.ConclusionsThe elevation of striatal neurotensin immunoreactivity during pemoline treatment, coupled with the effects of the NTS1agonist and antagonist, suggests that neurotensin transmission in the striatum may be an important modulator of self‐injurious behaviour in the pemoline model. Overall, the convergence of the behavioural and biochemical findings suggests that neurotensin signalling could be an important target for pharmacotherapeutic interventions for self‐injurious behaviour.