Department of Pharmacy and Pharmaceutical Tech. and Parasit., University of València, Spain.
Department of Anesthesiology, Washington University Pain Center, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jun 8;100:109875. doi: 10.1016/j.pnpbp.2020.109875. Epub 2020 Jan 22.
The neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-d-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRNA levels of GluN1 and GluN2A subunits in designated brain areas. The expression of CPP or CPA was characterized following intra-VTA ethanol administration and we showed that either reinforcing (CPP) or aversive (CPA) properties are dependent on the dose administered (ranging here from 35 to 300 nmol). Furthermore, the critical contribution of local MORs in the acquisition of CPP was revealed by a selective antagonist, namely β-Funaltrexamine. Finally, modifications of the expression of NMDA receptor subunits in the Nucleus Accumbens (NAc) and Hippocampus after ethanol-induced CPP were analyzed at the proteomic and transcriptomic levels by western blot and In Situ Hybridation RNAscope techniques, respectively. Results showed that the mRNA levels of GluN2A but not GluN1 in NAc are higher after ethanol CPP. These novel results pave the way for further characterisation of the mechanisms by which ethanol motivational properties are associated with learned environmental cues.
虽然酒精动机特性的神经生物学机制尚未完全阐明，但μ-阿片受体（MORs）已被证明是表现出酒精强化特性的核心要素。与药物相关的环境刺激可以引发酒精复发并促进酒精消费，其中 N-甲基-D-天冬氨酸（NMDA）受体起着关键作用。在这里，我们首次试图证明，当局部给予腹侧被盖区（VTA）时，乙醇会引起条件性位置偏好或厌恶（CPP 或 CPA），并且 MORs 发挥相关作用。我们进一步分析了指定脑区中 GluN1 和 GluN2A 亚基表达和 mRNA 水平的变化。在 VTA 内给予乙醇后，对 CPP 或 CPA 的表达进行了特征分析，结果表明，无论是强化（CPP）还是厌恶（CPA）特性都取决于所给予的剂量（这里从 35 到 300nmol）。此外，通过选择性拮抗剂β-Funaltrexamine 揭示了局部 MORs 在 CPP 获得中的关键作用。最后，通过 Western blot 和原位杂交 RNAscope 技术分别在蛋白质组学和转录组学水平上分析了乙醇诱导 CPP 后核仁 Accumbens（NAc）和海马中 NMDA 受体亚基表达的变化。结果表明，NAc 中 GluN2A 的 mRNA 水平而不是 GluN1 在乙醇 CPP 后升高。这些新结果为进一步研究乙醇动机特性与习得环境线索相关的机制铺平了道路。
