Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.
Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.
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DOI：
10.3389/fnsys.2014.00070
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发表时间：
2014
影响因子：
3
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
--
作者：
Lominac KD;McKenna CL;Schwartz LM;Ruiz PN;Wroten MG;Miller BW;Holloway JJ;Travis KO;Rajasekar G;Maliniak D;Thompson AB;Urman LE;Phillips TJ;Szumlinski KK
甲基苯丙胺（MA）是一种高度成瘾性的精神兴奋剂，在世界范围内，终生滥用率为5-10%。然而，缺乏研究存在关于MA成瘾的脆弱性/弹性和神经生物学介质的过渡到成瘾，可能会发生在反复低剂量MA暴露，早期药物使用的特点。由于兴奋引起的神经可塑性多巴胺神经元支配的神经核（NAC）和前额叶皮层（PFC）的理论是中央成瘾相关的行为异常，我们使用了多学科的研究方法在小鼠中检查亚毒性MA剂量，动机MA和mesocorticolimbic单胺之间的相互作用。C57 BL/6 J（B6）小鼠的生化研究显示，在从10次（每日一次）2 mg/kg MA注射中撤出期间，细胞外多巴胺、DAT和/或D2受体发生短期（1天）和长期（21天）变化。在选择性饲养的高与低MA饮酒小鼠（分别为MAHDR与MALDR小鼠）中进行的后续生化研究为中皮质边缘多巴胺异常提供了新的支持，作为遗传易感性与高MA摄入量的相关性。最后，在MA处理的B6小鼠中NAC多巴胺的神经药理学靶向证明了MA诱导的位置调节的双向调节。这些结果扩展了现有的MA神经毒性文献，证明即使亚慢性暴露于相对较低的MA剂量也足以引起中皮质边缘多巴胺相对持久的变化，并且药物诱导的或特发性的中皮质边缘多巴胺异常可能是MA成瘾的脆弱性/弹性的基础。
Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5–10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.