Laboratory of Behavioral Neurobiology, The Rockefeller University, New York, New York 10065, USA.
Alcohol Clin Exp Res. 2013 Jan;37 Suppl 1(0 1):E141-51. doi: 10.1111/j.1530-0277.2012.01858.x. Epub 2012 Jun 22.
Alcoholism is a heterogeneous disease, with subjects possibly differing both in the best measure that predicts their excess consumption and in their most effective pharmacotherapy. Two different measures, high novelty-induced activity and high-fat-induced triglycerides (TGs), are known to identify subgroups of animals prone to consuming higher amounts of ethanol (EtOH). The question investigated here is whether these subgroups are, in fact, similar in their neurochemical phenotype that may contribute to their overconsumption.
EtOH-naïve, Sprague-Dawley rats were subgrouped based on the 2 predictor measures of activity or TG levels, and then quantitative real-time polymerase chain reaction and digoxigenin-labeled in situ hybridization were used to measure their expression of hypothalamic peptides that affect EtOH intake. In additional subgroups subsequently trained to drink 9% EtOH, the opioid antagonist and alcoholism medication, naltrexone, was tested at a low dose (0.02 mg/kg, s.c.) to determine the rats' sensitivity to its effects.
The 2 measures, while both effective in predicting amount of EtOH intake, were found to identify distinctive subgroups. Rats with high compared to low activity exhibited significantly greater expression of galanin and enkephalin in the paraventricular nucleus (PVN) and of orexin in the perifornical lateral hypothalamus (PFLH), but no difference in melanin-concentrating hormone in PFLH or neuropeptide Y in arcuate nucleus. This contrasts with rats having high TG, which exhibited greater expression only of PVN galanin, along with reduced PFLH orexin. The high-activity rats with elevated enkephalin, but not high-TG rats, were also unusually sensitive to naltrexone, which significantly reduced their alcohol intake.
In addition to revealing differences in endogenous peptides and drug responsiveness in predicted high EtOH drinkers, this study demonstrates that these disturbances differ markedly between the 2 at-risk subgroups. This indicates that simple tests may be effective in identifying subjects most responsive to a specific pharmacotherapy.
酗酒是一种异质性疾病，研究对象在预测其过量饮酒的最佳指标以及最有效的药物治疗方面可能存在差异。高新奇性诱导的活动和高脂肪诱导的甘油三酯（TGs）是已知的可识别易摄入大量乙醇（EtOH）的动物亚组的两种不同指标。本文探讨的问题是，这些亚组实际上是否在可能导致其过度饮酒的神经化学表型上相似。
根据活动或 TG 水平的两个预测指标，将 EtOH 初筛的 Sprague-Dawley 大鼠进行分组，然后使用定量实时聚合酶链反应和地高辛标记原位杂交技术测量影响 EtOH 摄入的下丘脑肽的表达。在随后接受 9% EtOH 训练的亚组中，测试阿片受体拮抗剂和酒精中毒药物纳曲酮的低剂量（0.02 mg/kg，皮下注射），以确定大鼠对其作用的敏感性。
虽然这两个指标都能有效地预测 EtOH 摄入量，但发现它们能识别出不同的亚组。与低活动大鼠相比，高活动大鼠的室旁核（PVN）中甘丙肽和脑啡肽表达显著增加，而在外侧下丘脑的穹窿周（PFLH）中食欲素表达增加，但 PFLH 中的黑皮质素集中激素或弓状核中的神经肽 Y 无差异。这与 TG 较高的大鼠形成对比，后者仅表现出 PVN 甘丙肽表达增加，同时 PFLH 食欲素表达减少。高活性大鼠的脑啡肽升高，但高 TG 大鼠没有，对纳曲酮也异常敏感，纳曲酮显著减少了它们的酒精摄入量。
除了揭示预测高 EtOH 饮酒者内源性肽和药物反应性的差异外，本研究还表明，这两个亚组之间存在明显的差异。这表明简单的测试可能有效识别对特定药物治疗反应最敏感的个体。
