Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.
Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.
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DOI：
10.1016/j.biopsych.2016.10.005
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发表时间：
2017-06-01
影响因子：
10.6
通讯作者：
Kippin TE
中科院分区：
文献类型：
--
作者：
Szumlinski KK;Lominac KD;Campbell RR;Cohen M;Fultz EK;Brown CN;Miller BW;Quadir SG;Martin D;Thompson AB;von Jonquieres G;Klugmann M;Phillips TJ;Kippin TE
甲基苯丙胺（MA）滥用的高流行率和严重性要求对其病因有更深入的神经生物学了解。在这里，我们在甲基苯丙胺高/低饮酒（MAH/LDR）小鼠以及在MA偏好/服用不同的同基因C57 BL/6 J小鼠中进行免疫印迹和体内微透析程序，以检查MA滥用脆弱性的谷氨酸基础。还在C57 BL/6 J小鼠中采用神经药理学和Homer 2敲低方法来确认谷氨酸/Homer 2表达在MA偏好/厌恶中的作用。我们确定了一个hyper-amatergic状态内的核内的神经节细胞（NAC）作为一个生化性状对应的遗传和特发性的脆弱性高MA偏好和服用。我们还证实，亚慢性，亚毒性MA的经验eliminates一个hyper-amatergic国家内的NAC在旷日持久的撤退，其特征是升高mGlu 1/5受体功能和Homer 2受体支架蛋白的表达。通过升高小鼠NAC壳内的内源性谷氨酸来重现高MA偏好表型，并且我们通过降低该亚区内的内源性谷氨酸和/或Homer 2表达来逆转MA偏好/服用。我们的数据指出，NAC内的特发性、遗传性或药物诱导的高多巴胺能状态是MA成瘾脆弱性的介导者。
The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology. Here, we conducted immunoblotting and in vivo microdialysis procedures in Methamphetamine High/Low Drinking (MAH/LDR) mice, as well as in isogenic C57BL/6J mice that varied in their MA-preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knock-down approaches were also employed in C57BL/6J mice to confirm the role for nucleus accumbens glutamate/Homer2 expression in MA preference/aversion. We identified a hyper-glutamatergic state within the nucleus accumbens (NAC) as a biochemical trait corresponding with both genetic and idiopathic vulnerability for high MA-preference and -taking. We also confirmed that subchronic, subtoxic MA experience elicits a hyper-glutamatergic state within the NAC during protracted withdrawal, characterized by elevated mGlu1/5 receptor function and Homer2 receptor-scaffolding protein expression. A high MA-preferring phenotype was recapitulated by elevating endogenous glutamate within the NAC shell of mice and we reversed MA-preference/taking by lowering endogenous glutamate and/or Homer2 expression within this subregion. Our data point to an idiopathic, genetic or drug-induced hyper-glutamatergic state within the NAC as a mediator of MA addiction vulnerability.