Prefrontal glutamate correlates of methamphetamine sensitization and preference.
Prefrontal glutamate correlates of methamphetamine sensitization and preference.
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DOI：
10.1111/ejn.13159
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
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作者：
Lominac KD;Quadir SG;Barrett HM;McKenna CL;Schwartz LM;Ruiz PN;Wroten MG;Campbell RR;Miller BW;Holloway JJ;Travis KO;Rajasekar G;Maliniak D;Thompson AB;Urman LE;Kippin TE;Phillips TJ;Szumlinski KK
甲基苯丙胺（MA）是一种广泛滥用、高度成瘾的精神兴奋剂，可诱发与前额叶皮层（PFC）功能减退相关的神经认知功能明显缺陷。我们的理解如何重复甲基苯丙胺影响兴奋性多巴胺能在PFC内的传输是有限的，是PFC谷氨酸和成瘾的脆弱性/弹性之间的关系的信息。体内微透析和免疫印迹研究表征了甲基苯丙胺的作用（10次注射2 mg/kg，IP）对C57 BL/6 J小鼠细胞外谷氨酸以及谷氨酸受体和转运蛋白表达的影响，通过对高与低MA饮用选择性繁殖的小鼠品系的研究，确定了MA偏好/摄入的遗传和特发性差异的谷氨酸能相关性（分别为MAHDR与MALDR）和近交系C57 BL/6 J小鼠表现出自发发散的位置调节表型。重复甲基苯丙胺致敏药物诱导的谷氨酸释放和降低C57 BL/6 J小鼠NMDA受体表达指数，但没有改变基础细胞外谷氨酸含量或总蛋白表达的荷马蛋白，或代谢型或AMPA谷氨酸受体。升高的基础谷氨酸，钝化甲基苯丙胺诱导的谷氨酸释放和ERK激活，以及减少的mGlu 2/3和Homer 2a/B的蛋白质表达都是选择高与低甲基苯丙胺饮用相关的生化特征，Homer 2a/B水平与C57 BL/6 J小鼠中甲基苯丙胺的动机价呈负相关。这些数据提供了新的证据表明，重复，低剂量，甲基苯丙胺是足以扰乱前和突触后方面的内侧PFC内的谷氨酸传输和谷氨酸异常在这个区域可能有助于遗传和特发性变异甲基苯丙胺成瘾的脆弱性/弹性。
Methamphetamine (MA) is a widely abused, highly addictive, psychostimulant that elicits pronounced deficits in neurocognitive function related to hypo-functioning of the prefrontal cortex (PFC). Our understanding of how repeated methamphetamine impacts excitatory glutamatergic transmission within the PFC is limited, as is information about the relation between PFC glutamate and addiction vulnerability/resiliency. In vivo microdialysis and immunoblotting studies characterized the effects of methamphetamine (10 injections of 2 mg/kg, IP) upon extracellular glutamate in C57BL/6J mice and upon glutamate receptor and transporter expression, within the medial PFC. Glutamatergic correlates of both genetic and idiopathic variance in MA preference/intake were determined through studies of high versus low MA-drinking selectively bred mouse lines (MAHDR versus MALDR, respectively) and inbred C57BL/6J mice exhibiting spontaneously divergent place-conditioning phenotypes. Repeated methamphetamine sensitized drug-induced glutamate release and lowered indices of NMDA receptor expression in C57BL/6J mice, but did not alter basal extracellular glutamate content or total protein expression of Homer proteins, or metabotropic or AMPA glutamate receptors. Elevated basal glutamate, blunted methamphetamine-induced glutamate release and ERK activation, as well as reduced protein expression of mGlu2/3 and Homer2a/b were all correlated biochemical traits of selection for high versus low methamphetamine drinking, and Homer2a/b levels were inversely correlated with the motivational valence of methamphetamine in C57BL/6J mice. These data provide novel evidence that repeated, low-dose, methamphetamine is sufficient to perturb pre- and post-synaptic aspects of glutamate transmission within the medial PFC and that glutamate anomalies within this region may contribute to both genetic and idiopathic variance in methamphetamine addiction vulnerability/resiliency.