Matchynski-Franks Jessica J, Susick Laura L, Schneider Brandy L, Perrine Shane A, Conti Alana C
Research Service, John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
PLoS One. 2016 May 17;11(5):e0155759. doi: 10.1371/journal.pone.0155759. eCollection 2016.
Impaired striatal neuroplasticity may underlie increased alcoholism documented in those with posttraumatic stress disorder (PTSD). Cannabinoid receptor-1 (CB1) is sensitive to the effects of ethanol (EtOH) and traumatic stress, and is a critical regulator of striatal plasticity. To investigate CB1 involvement in the PTSD-alcohol interaction, this study measured the effects of traumatic stress using a model of PTSD, mouse single-prolonged stress (mSPS), on EtOH-induced locomotor sensitization and striatal CB1 levels.
Mice were exposed to mSPS, which includes: 2-h restraint, 10-min group forced swim, 15-min exposure to rat bedding odor, and diethyl ether exposure until unconsciousness or control conditions. Seven days following mSPS exposure, the locomotor sensitizing effects of EtOH were assessed. CB1, post-synaptic density-95 (PSD95), and dopamine-2 receptor (D2) protein levels were then quantified in the dorsal striatum using standard immunoblotting techniques.
Mice exposed to mSPS-EtOH demonstrated impaired EtOH-induced locomotor sensitization compared to Control-EtOH mice, which was accompanied by reduced striatal CB1 levels. EtOH increased striatal PSD95 in control and mSPS-exposed mice. Additionally, mSPS-Saline exposure increased striatal PSD95 and decreased D2 protein expression, with mSPS-EtOH exposure alleviating these changes.
These data indicate that the mSPS model of PTSD blunts the behavioral sensitizing effects of EtOH, a response that suggests impaired striatal neuroplasticity. Additionally, this study demonstrates that mice exposed to mSPS and repeated EtOH exposure decreases CB1 in the striatum, providing a mechanism of interest for understanding the effects of EtOH following severe, multimodal stress exposure.
创伤后应激障碍（PTSD）患者中酒精成瘾增加可能与纹状体神经可塑性受损有关。大麻素受体-1（CB1）对乙醇（EtOH）和创伤应激的作用敏感，是纹状体可塑性的关键调节因子。为了研究CB1在PTSD与酒精相互作用中的作用，本研究使用PTSD模型，即小鼠单次长时间应激（mSPS），来测量创伤应激对EtOH诱导的运动敏化和纹状体CB1水平的影响。
将小鼠暴露于mSPS，包括：2小时束缚、10分钟群体强迫游泳、15分钟暴露于大鼠垫料气味以及乙醚暴露直至昏迷或处于对照条件。mSPS暴露7天后，评估EtOH的运动敏化作用。然后使用标准免疫印迹技术定量背侧纹状体中CB1、突触后密度蛋白95（PSD95）和多巴胺2受体（D2）的蛋白水平。
与对照-EtOH小鼠相比，暴露于mSPS-EtOH的小鼠表现出EtOH诱导的运动敏化受损，同时纹状体CB1水平降低。在对照小鼠和暴露于mSPS的小鼠中，EtOH均增加了纹状体PSD95。此外，mSPS-生理盐水暴露增加了纹状体PSD95并降低了D2蛋白表达，而mSPS-EtOH暴露减轻了这些变化。
这些数据表明，PTSD的mSPS模型减弱了EtOH的行为敏化作用，这种反应表明纹状体神经可塑性受损。此外，本研究表明，暴露于mSPS并反复接触EtOH的小鼠纹状体中CB1减少，这为理解严重多模式应激暴露后EtOH的作用提供了一个有意义的机制。
