Departamento de Farmacologia, Universidade de São Paulo, São Paulo, Brazil; Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
Department of Psychiatry, University of Maryland, Baltimore, School of Medicine, Baltimore, USA; Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
Neuropharmacology. 2018 Aug;138:267-274. doi: 10.1016/j.neuropharm.2018.06.013. Epub 2018 Jun 21.
Environmental conditions, such as stress and environmental enrichment (EE), influence predisposition to alcohol use/abuse; however, the underlying mechanisms remain unknown. To assess the effect of environmental conditions on the initial rewarding effects of alcohol, we examined conditioned place-preference (CPP) to alcohol following exposure to EE in mice. Since social context is a major factor contributing to initial alcohol-drinking, we also assessed the impact of EE on the levels of the "social neuropeptide" oxytocin (OT) and its receptor, OTR. Finally, we assessed the effect of pharmacological manipulations of the oxytocinergic system on EE-induced alcohol CPP. While EE increased sociability and reduced anxiety-like behaviors, it caused a ∼3.5-fold increase in alcohol reward compared to controls. EE triggered profound neuroadaptations of the oxytocinergic system; it increased hypothalamic OT levels and decreased OTR binding in the prefrontal cortex and olfactory nuclei of the brain. Repeated administration of the OT analogue carbetocin (6.4 mg/kg/day) mimicked the behavioral effects of EE on ethanol CPP and induced similar brain region-specific alterations of OTR binding as those observed following EE. Conversely, repeated administration of the OTR antagonist L,369-899 (5 mg/kg/day) during EE exposure, but not during the acquisition of alcohol CPP, reversed the pronounced EE-induced ethanol rewarding effect. These results demonstrate for the first time, a stimulatory effect of environmental enrichment exposure on alcohol reward via an oxytocinergic-dependent mechanism, which may predispose to alcohol abuse. This study offers a unique prospective on the neurobiological understanding of the initial stages of alcohol use/misuse driven by complex environmental-social interplay.
环境条件，如压力和环境丰富（EE），会影响对酒精使用/滥用的易感性；然而，其潜在机制尚不清楚。为了评估环境条件对酒精初始奖赏效应的影响，我们在小鼠中检查了暴露于 EE 后对酒精的条件性位置偏好（CPP）。由于社交环境是导致初始饮酒的主要因素之一，我们还评估了 EE 对“社交神经肽”催产素（OT）及其受体 OTR 的水平的影响。最后，我们评估了催产素系统的药理学操作对 EE 诱导的酒精 CPP 的影响。虽然 EE 增加了社交能力并减少了焦虑样行为，但与对照组相比，它使酒精奖赏增加了约 3.5 倍。EE 引发了催产素能系统的深刻神经适应；它增加了下丘脑 OT 水平，并减少了前额叶皮层和大脑嗅球中的 OTR 结合。OT 类似物卡贝缩宫素（6.4mg/kg/天）的重复给药模拟了 EE 对乙醇 CPP 的行为影响，并诱导了与 EE 后观察到的相似的脑区特异性 OTR 结合改变。相反，在 EE 暴露期间而不是在获得酒精 CPP 期间重复给予 OTR 拮抗剂 L,369-899（5mg/kg/天），逆转了 EE 引起的乙醇奖赏作用的明显增强。这些结果首次证明，通过催产素能依赖的机制，环境丰富暴露对酒精奖赏具有刺激作用，这可能导致酒精滥用。这项研究为理解复杂环境-社会相互作用驱动的酒精使用/误用的初始阶段的神经生物学提供了独特的视角。
