Besheer Joyce, Fisher Kristen R, Jaramillo Anel A, Frisbee Suzanne, Cannady Reginald
1] Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Curriculum in Neurobiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [3] Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Neuropsychopharmacology. 2014 Sep;39(10):2376-86. doi: 10.1038/npp.2014.85. Epub 2014 Apr 9.
Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.
与经历应激性生活事件和慢性生活压力源相关的饮酒量增加，可能与对酒精的内感受性/主观效应的敏感性改变有关。事实上，通过药物辨别方法，大鼠在暴露于应激激素皮质酮（CORT）后，对酒精的辨别刺激（内感受性）效应的敏感性降低。这种暴露会使血浆CORT水平升高（例如，个体在应激发作期间可能经历的情况）。我们假设，对酒精敏感性降低可能部分与伏隔核中代谢型谷氨酸受体5（mGluR5）的变化有关，因为已知该脑区的这些受体可调节酒精的辨别刺激效应。在伏隔核中，我们发现CORT暴露（7天）后，对中等剂量酒精（1 g/kg）的反应中，mGluR5表达降低（免疫组织化学和蛋白质免疫印迹法），神经激活减少（通过c-Fos免疫组织化学测量）。这些由CORT诱导的适应性变化与酒精辨别刺激效应相关的功能作用得到了证实，因为mGluR5正变构调节剂3-氰基-N-（1,3-二苯基-1H-吡唑-5-基）苯甲酰胺（CDPPB）的全身给药以及mGluR5激动剂（R,S）-2-氨基-2-（2-氯-5-羟基苯基）乙酸钠盐（CHPG）的伏隔核内给药，均恢复了辨别训练大鼠对酒精的敏感性。这些结果表明，mGluR5的激活可能减轻CORT诱导的mGluR5下调对酒精敏感性的功能影响。了解这种神经适应性变化对酒精内感受性效应的作用，可能会丰富我们对应激发作期间对酒精主观敏感性潜在变化的理解。
