Brown Chelsea N, Fultz Elissa K, Ferdousian Sami, Rogers Sarina, Lustig Elijah, Page Ariana, Shahin John R, Flaherty Daniel M, Von Jonquieres Georg, Bryant Camron D, Kippin Tod E, Szumlinski Karen K
Department of Psychological and Brain Sciences, University of California, Santa Barbara, Santa Barbara, CA, United States.
Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Front Psychiatry. 2020 Feb 5;11:11. doi: 10.3389/fpsyt.2020.00011. eCollection 2020.
Problems associated with the abuse of amphetamine-type stimulants, including methamphetamine (MA), pose serious health and socioeconomic issues world-wide. While it is well-established that MA's psychopharmacological effects involve interactions with monoamine neurotransmission, accumulating evidence from animal models implicates dysregulated glutamate in MA addiction vulnerability and use disorder. Recently, we discovered an association between genetic vulnerability to MA-taking and increased expression of the glutamate receptor scaffolding protein Homer2 within both the shell and core subregions of the nucleus accumbens (NAC) and demonstrated a necessary role for Homer2 within the shell subregion in MA reward and reinforcement in mice. This report extends our earlier work by interrogating the functional relevance of Homer2 within the NAC core for the conditioned rewarding and reinforcing properties of MA. C57BL/6J mice with a virus-mediated knockdown of Homer2b expression within the NAC core were first tested for the development and expression of a MA-induced conditioned place-preference/CPP (four pairings of 2 mg/kg MA) and then were trained to self-administer oral MA under operant-conditioning procedures (5-80 mg/L). Homer2b knockdown in the NAC core augmented a MA-CPP and shifted the dose-response function for MA-reinforced responding, above control levels. To determine whether Homer2b within NAC subregions played an active role in regulating MA reward and reinforcement, we characterized the MA phenotype of constitutive knockout (KO) mice and then assayed the effects of virus-mediated overexpression of Homer2b within the NAC shell and core of wild-type and KO mice. In line with the results of NAC core knockdown, deletion potentiated MA-induced CPP, MA-reinforced responding and intake, as well as both cue- and MA-primed reinstatement of MA-seeking following extinction. However, there was no effect of Homer2b overexpression within the NAC core or the shell on the KO phenotype. These data provide new evidence indicating a globally suppressive role for Homer2 in MA-seeking and MA-taking but argue against specific NAC subregions as the neural loci through which Homer2 actively regulates MA addiction-related behaviors.
与滥用苯丙胺类兴奋剂（包括甲基苯丙胺，MA）相关的问题在全球范围内引发了严重的健康和社会经济问题。虽然人们已经充分认识到MA的精神药理作用涉及与单胺神经传递的相互作用，但来自动物模型的越来越多的证据表明，谷氨酸调节异常与MA成瘾易感性和使用障碍有关。最近，我们发现对MA摄入的遗传易感性与伏隔核（NAC）壳区和核心亚区中谷氨酸受体支架蛋白Homer2的表达增加之间存在关联，并证明了壳区中的Homer2在小鼠MA奖赏和强化中起必要作用。本报告通过探究NAC核心区内Homer2对MA条件性奖赏和强化特性的功能相关性，扩展了我们早期的研究工作。首先对通过病毒介导在NAC核心区内敲低Homer2b表达的C57BL/6J小鼠进行MA诱导的条件性位置偏爱/CPP（2mg/kg MA，共配对四次）的发展和表达测试，然后在操作性条件反射程序（5 - 80mg/L）下训练它们自行口服MA。NAC核心区内Homer2b的敲低增强了MA - CPP，并使MA强化反应的剂量反应函数高于对照水平。为了确定NAC亚区内的Homer2b是否在调节MA奖赏和强化中发挥积极作用，我们对组成型敲除（KO）小鼠的MA表型进行了表征，然后检测了病毒介导的Homer2b在野生型和KO小鼠的NAC壳区和核心区内过表达的影响。与NAC核心区敲低的结果一致，基因缺失增强了MA诱导的CPP、MA强化反应和摄入量，以及消退后线索引发和MA引发的MA觅求恢复。然而，NAC核心区或壳区内Homer2b的过表达对KO表型没有影响。这些数据提供了新的证据，表明Homer2在MA觅求和MA摄入方面具有全局抑制作用，但反对将特定的NAC亚区作为Homer2积极调节MA成瘾相关行为的神经位点。
