Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain.
Alcohol Clin Exp Res. 2010 Jan;34(1):131-41. doi: 10.1111/j.1530-0277.2009.01074.x. Epub 2009 Oct 23.
This study was undertaken to identify the neurochemical changes underlying the attenuation of voluntary ethanol intake induced by the cannabinoid CB1 receptor antagonist AM251 in fawn-hooded rats.
Rats were exposed to the 2-bottle-choice paradigm (ethanol 10% v/v or water) for 15 days. After this period, rats received AM251 (3 to 6 mg/kg, i.p.) or vehicle.
Voluntary ethanol intake decreased (30%) with the administration of incremental dosages of AM251 (3 mg/kg, 5 days and 6 mg/kg, 5 days) in rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/d). Ethanol intake significantly decreased proopiomelanocortin expression in the arcuate nucleus (38.31%) and micro-opioid-DAMGO-stimulated [(35)S]-GTPgamma binding in the caudate-putamen (40%), nucleus accumbens core (AccC) (32.87%), and shell (AccS) (34.21%). Moreover, ethanol intake increased tyrosine hydroxylase (TH) gene expression in the substantia nigra (24%) and ventral tegmental area (23%) and corticotrophin-releasing gene expression in the paraventricular hypothalamic nucleus (41.6%). The reduction of ethanol intake induced by AM251 was associated with blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. Interestingly, treatment with AM251 reduced (20%) TH gene expression in rats drinking only water. In this respect, the action of AM251 in reducing TH gene expression may not be specific.
Taken together, these results revealed that blockade of cannabinoid CB1 receptors (CB1r) decreased voluntary ethanol intake in ethanol-habituated rats by normalizing the neurochemical alterations induced by ethanol.
本研究旨在确定大麻素 CB1 受体拮抗剂 AM251 减弱 fawn-hooded 大鼠自愿性乙醇摄入的神经化学变化基础。
大鼠暴露于 2 瓶选择范式（10%乙醇 v/v 或水）15 天。在此期间，大鼠接受 AM251（3 至 6 mg/kg，ip）或载体。
在获得高偏爱乙醇消耗（>3.5 g/kg/d）的大鼠中，递增剂量的 AM251（3 mg/kg，5 天和 6 mg/kg，5 天）给药可降低自愿性乙醇摄入（30%）。乙醇摄入显著降低弓状核中的促阿黑皮素原（POMC）表达（38.31%）和尾壳核（caudate-putamen）（40%）、伏隔核核心（AccC）（32.87%）和壳（AccS）（34.21%）中微阿片-DAMGO 刺激的[(35)S]-GTPγ结合。此外，乙醇摄入增加了黑质（ substantia nigra ）（24%）和腹侧被盖区（ ventral tegmental area ）（23%）中的酪氨酸羟化酶（TH）基因表达和室旁下丘脑核（ paraventricular hypothalamic nucleus ）中的促肾上腺皮质释放基因表达（41.6%）。AM251 诱导的乙醇摄入减少与这些基因在与药物依赖相关的关键区域中的表达变化相关的乙醇诱导的阻断或显著减少有关。有趣的是，AM251 治疗降低了仅饮水大鼠的 TH 基因表达（20%）。在这方面，AM251 降低 TH 基因表达的作用可能不具有特异性。
综上所述，这些结果表明，大麻素 CB1 受体（CB1r）阻断通过使乙醇诱导的神经化学变化正常化，减少乙醇习惯大鼠的自愿性乙醇摄入。
