Ayers-Ringler Jennifer R, Oliveros Alfredo, Qiu Yanyan, Lindberg Daniel M, Hinton David J, Moore Raymond M, Dasari Surendra, Choi Doo-Sup
Neurobiology of Disease PhD Program, Mayo Graduate School, Mayo Clinic Rochester, MN, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Graduate School, Mayo Clinic College of Medicine Rochester, MN, USA.
Front Behav Neurosci. 2016 Mar 11;10:46. doi: 10.3389/fnbeh.2016.00046. eCollection 2016.
The molecular mechanisms underlying the neuronal signaling changes in alcohol addiction and withdrawal are complex and multifaceted. The cortico-striatal circuit is highly implicated in these processes, and the striatum plays a significant role not only in the early stages of addiction, but in the developed-addictive state as well, including withdrawal symptoms. Transcriptional analysis is a useful method for determining changes in gene expression, however, the results do not always accurately correlate with protein levels. In this study, we employ label-free proteomic analysis to determine changes in protein expression within the striatum during chronic ethanol use and early withdrawal. The striatum, composed primarily of medium spiny GABAergic neurons, glutamatergic and dopaminergic nerve terminals and astrocytes, is relatively homogeneous for proteomic analysis. We were able to analyze more than 5000 proteins from both the dorsal (caudate and putamen) and ventral (nucleus accumbens) striatum and identified significant changes following chronic intermittent ethanol exposure and acute (8 h) withdrawal compared to ethanol naïve and ethanol exposure groups respectively. Our results showed significant changes in proteins involved in glutamate and opioid peptide signaling, and also uncovered novel pathways including mitochondrial function and lipid/cholesterol metabolism, as revealed by changes in electron transport chain proteins and RXR activation pathways. These results will be useful in the development of novel treatments for alcohol withdrawal and thereby aid in recovery from alcohol use disorder.
酒精成瘾和戒断过程中神经元信号变化的分子机制复杂且多方面。皮质 - 纹状体回路在这些过程中高度相关，纹状体不仅在成瘾的早期阶段起重要作用，在成瘾状态包括戒断症状方面也发挥着重要作用。转录分析是确定基因表达变化的有用方法，然而，结果并不总是与蛋白质水平准确相关。在本研究中，我们采用无标记蛋白质组学分析来确定慢性乙醇使用和早期戒断期间纹状体内蛋白质表达的变化。纹状体主要由中等棘状GABA能神经元、谷氨酸能和多巴胺能神经末梢以及星形胶质细胞组成，对于蛋白质组学分析来说相对均匀。我们能够分析来自背侧（尾状核和壳核）和腹侧（伏隔核）纹状体的5000多种蛋白质，并分别与未接触乙醇和接触乙醇的组相比，确定了慢性间歇性乙醇暴露和急性（8小时）戒断后的显著变化。我们的结果显示参与谷氨酸和阿片肽信号传导的蛋白质有显著变化，还发现了新的途径，包括线粒体功能和脂质/胆固醇代谢，这通过电子传递链蛋白和RXR激活途径的变化得以揭示。这些结果将有助于开发新的酒精戒断治疗方法，从而有助于从酒精使用障碍中恢复。
