Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.
Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.
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DOI：
10.1038/mp.2015.151
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发表时间：
2016-08
影响因子：
11
通讯作者：
Kalivas PW
中科院分区：
文献类型：
--
作者：
Garcia-Keller C;Kupchik YM;Gipson CD;Brown RM;Spencer S;Bollati F;Esparza MA;Roberts-Wolfe DJ;Heinsbroek JA;Bobadilla AC;Cancela LM;Kalivas PW
应激障碍和物质使用障碍（SUD）之间存在大量的共病，在动物模型中，急性应激增强了可卡因的运动刺激作用。在这里，我们奋进了解共病的应激障碍和药物使用的神经基础，确定是否由急性应激引起的可卡因自我管理的特征性的神经适应。大鼠暴露于急性（2小时）制动应力和3周后的核延髓核心进行了检查谷氨酸转运，谷氨酸介导的突触电流，树突棘形态的变化。我们还确定了急性应激是否增强了可卡因自我给药的获得。急性应激产生持久的谷氨酸转运减少，并加强兴奋性突触中型多刺神经元。急性压力也增加了可卡因自我管理的收购。重要的是，通过用头孢曲松恢复谷氨酸转运，急性应激增加可卡因自我给药的获得的能力被消除。类似地，头孢曲松治疗防止可卡因诱导的运动活动的应激诱导的增强。然而，头孢曲松没有逆转应激诱导的突触增强，表明应激暴露的这种作用并没有支持可卡因自我给药的增加。通过使谷氨酸转运正常化来逆转急性应激诱导的自我管理可卡因的脆弱性，为减少应激障碍中的共病SUD提供了一种新的治疗可能性。
There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining if the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate mediated synaptic currents, and dendritic spine morphology. We also determined if acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport, and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.