Neuroscience Institute, National Research Council of Italy, Section of Cagliari, I-09042 Monserrato CA, Italy.
Alcohol. 2013 Feb;47(1):69-73. doi: 10.1016/j.alcohol.2012.11.002. Epub 2012 Dec 6.
Previous research has demonstrated that treatment with the positive allosteric modulator (PAM) of the GABA(B) receptor (GABA(B) PAM), rac-BHFF, suppressed lever-responding for alcohol and amount of self-administered alcohol in Sardinian alcohol-preferring (sP) rats. The present study was designed to extend the investigation on the anti-alcohol effects of rac-BHFF to alcohol drinking behavior. To this end, sP rats were exposed to the homecage, 2-bottle "alcohol (10%, v/v) vs water" choice regimen, with unlimited access for 24 h/day. rac-BHFF was administered once daily and for 7 consecutive days at the doses of 0, 50, 100, and 200 mg/kg (i.g.). Treatment with rac-BHFF resulted in an immediate, stable, and dose-related reduction in daily alcohol intake; the overall magnitude of reduction in alcohol intake averaged approximately 25%, 40%, and 65% in 50, 100, and 200 mg/kg rac-BHFF-treated rat groups, respectively. An increase in daily water intake fully compensated the reduction in alcohol intake, so that daily total fluid intake was unaffected by treatment with rac-BHFF. Daily food intake tended to be reduced only by the highest dose of rac-BHFF. These results complement closely with previous data indicating that (a) rac-BHFF suppressed operant, oral alcohol self-administration in sP rats and (b) the prototypic GABA(B) PAMs, CGP7930 and GS39783, reduced alcohol drinking in sP rats. However, while the reducing effect of CGP7930 and GS39783 on the daily alcohol intake tended to vanish after the first 2-3 days of treatment, the reducing effect of rac-BHFF on daily alcohol intake remained unchanged over the entire 7-day treatment period. These data strengthen the hypothesis that GABA(B) PAMs may represent a step forward in the search for GABA(B) receptor ligands with therapeutic potential for alcoholism.
先前的研究表明，GABA(B) 受体的正变构调节剂（PAM），rac-BHFF 的治疗抑制了酒精偏好（sP）大鼠的酒精和自我给药的酒精量。本研究旨在将 rac-BHFF 对酒精的抗作用扩展到酒精饮用行为。为此，sP 大鼠暴露于笼中，2 瓶“酒精（10%，v/v）与水”选择方案，每天 24 小时无限制访问。rac-BHFF 每天给药一次，连续 7 天，剂量为 0、50、100 和 200mg/kg（ig）。rac-BHFF 治疗导致每日酒精摄入量立即、稳定且剂量相关的减少；在 50、100 和 200mg/kg rac-BHFF 治疗大鼠组中，酒精摄入量的总体减少幅度分别约为 25%、40%和 65%。每日饮水量的增加完全补偿了酒精摄入量的减少，因此 rac-BHFF 治疗对每日总液体摄入量没有影响。每日食物摄入量仅因 rac-BHFF 的最高剂量而减少。这些结果与之前的数据密切互补，表明（a）rac-BHFF 抑制了 sP 大鼠的操作性、口服酒精自我给药，（b）原型 GABA(B)PAMs，CGP7930 和 GS39783，减少了 sP 大鼠的酒精摄入量。然而，虽然 CGP7930 和 GS39783 对每日酒精摄入量的减少作用在治疗的前 2-3 天趋于消失，但 rac-BHFF 对每日酒精摄入量的减少作用在整个 7 天的治疗期间保持不变。这些数据加强了 GABA(B)PAMs 可能代表治疗酒精中毒的 GABA(B) 受体配体的治疗潜力向前迈出了一步的假设。
