甲基苯丙胺成瘾易感性：谷氨酸、有害因素与不良后果
Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.
作者信息
Szumlinski Karen K, Lominac Kevin D, Campbell Rianne R, Cohen Matan, Fultz Elissa K, Brown Chelsea N, Miller Bailey W, Quadir Sema G, Martin Douglas, Thompson Andrew B, von Jonquieres Georg, Klugmann Matthias, Phillips Tamara J, Kippin Tod E
机构信息
Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California; Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California.
Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, California.
出版信息
Biol Psychiatry. 2017 Jun 1;81(11):959-970. doi: 10.1016/j.biopsych.2016.10.005. Epub 2016 Oct 13.
BACKGROUND
The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.
METHODS
We conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking 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 knockdown approaches were also used in C57BL/6J mice to confirm the role for nucleus accumbens (NAC) glutamate/Homer2 expression in MA preference/aversion.
RESULTS
We identified a hyperglutamatergic state within the 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 hyperglutamatergic state within the NAC during protracted withdrawal, characterized by elevated metabotropic glutamate 1/5 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.
CONCLUSIONS
Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.
背景
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理解。
方法
我们在MA高/低饮用量小鼠以及在MA偏好/摄取量不同的同基因C57BL/6J小鼠中进行了免疫印迹和体内微透析实验，以研究MA滥用易感性的谷氨酸基础。还在C57BL/6J小鼠中使用了神经药理学和Homer2基因敲低方法，以确认伏隔核（NAC）谷氨酸/Homer2表达在MA偏好/厌恶中的作用。
结果
我们确定NAC内的高谷氨酸能状态是一种生化特征，与高MA偏好和摄取的遗传及特发性易感性相对应。我们还证实，亚慢性亚毒性MA经历在长期戒断期间会引发NAC内的高谷氨酸能状态，其特征是代谢型谷氨酸1/5受体功能增强和Homer2受体支架蛋白表达增加。通过提高小鼠NAC壳内的内源性谷氨酸可重现高MA偏好表型，而通过降低该亚区域内的内源性谷氨酸和/或Homer2表达，我们逆转了MA偏好/摄取。
结论
我们的数据表明，NAC内特发性、遗传性或药物诱导的高谷氨酸能状态是MA成瘾易感性的介导因素。
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