Oliva José M, Manzanares Jorge
Institute of Physiological Chemistry and Pathobiochemistry, School of Medicine, Johannes-Gutemberg University of Mainz, Mainz, Germany.
Neuropsychopharmacology. 2007 Jun;32(6):1358-69. doi: 10.1038/sj.npp.1301237. Epub 2006 Oct 25.
Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mu-opioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB(1) receptor (CB1-R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the mu-opioid receptor, TH, PENK, CRF, CB1-R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone.
临床前和临床研究表明，给予阿片类拮抗剂纳曲酮可减少乙醇摄入量。然而，与乙醇摄入量减少相关的大脑神经可塑性适应仍有待阐明。本研究的目的是确定在大鼠中给予纳曲酮后，自愿乙醇摄入量减少背后的基因转录改变。给已养成高乙醇偏好（>3.5克乙醇/千克/天）的大鼠递增剂量的纳曲酮（0.7毫克/千克，4天；以及1.4毫克/千克/天，4天），可使自愿乙醇摄入量减少50%。自愿乙醇摄入改变了扣带回皮质、尾状核-壳核（CPu）、伏隔核核心（Acb C）和壳部（Acb S）中的μ-阿片受体功能，腹侧被盖区和黑质中酪氨酸羟化酶（TH）的表达，梨状皮质、嗅结节、CPu、Acb C和Acb S、下丘脑腹内侧核（VMN）和室旁核（PVN）中前脑啡肽（PENK）的表达，PVN中促肾上腺皮质激素释放因子（CRF）的表达，CPu、海马体和VMN中大麻素CB(1)受体（CB1-R）的表达，以及背侧和中缝核中5-羟色胺转运体（5-HTT）的表达。纳曲酮诱导的乙醇摄入量减少与乙醇在这些与药物依赖相关的关键区域基因表达中所产生变化的阻断或显著减少有关。这些结果表明，μ-阿片受体、TH、PENK、CRF、CB1-R和5-HTT基因在特定脑区对与纳曲酮诱导的乙醇摄入量减少相关的神经适应性机制的调节中发挥作用。
