CNR Neuroscience Institute, Viale Diaz 182, I-09126 Cagliari, Italy.
Drug Alcohol Depend. 2010 Jun 1;109(1-3):96-103. doi: 10.1016/j.drugalcdep.2009.12.019. Epub 2010 Jan 20.
The present study was designed to extend to the newly synthesized rac-BHFF [(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one] the investigation on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol self-administration in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (0.7%, w/v) in daily 30-min sessions. Once responding reached stable levels, the effect of rac-BHFF (0, 50, 100, and 200mg/kg; i.g.) on responding for alcohol and sucrose was determined. Pretreatment with rac-BHFF produced a dose-dependent suppression in responding for alcohol; reduction in the total number of responses for alcohol, in comparison to vehicle-treated rats, averaged approximately 30%, 65%, and 90% in 50, 100, and 200mg/kg rac-BHFF-treated rats, respectively. Pretreatment with 200mg/kg rac-BHFF markedly increased the latency to the first response on the alcohol lever. The effect of pretreatment with rac-BHFF on alcohol self-administration was highly specific, since (a) responding for sucrose was reduced (to approximately 50%, in comparison to vehicle-treated rats) only by pretreatment with 200mg/kg rac-BHFF, and (b) latency to the first response on the sucrose lever was completely unaltered by any rac-BHFF dose. Treatment with rac-BHFF did not alter spontaneous locomotor activity in an independent group of sP rats. The present data constitute a further piece of evidence on the capacity of positive allosteric modulators of the GABA(B) receptor to reduce alcohol's reinforcing properties in rats.
本研究旨在将新合成的 rac-BHFF[(R,S)-5,7-二叔丁基-3-羟基-3-三氟甲基-3H-苯并呋喃-2-酮]的研究扩展到 GABA(B)受体的正变构调节剂降低大鼠酒精自我给药的能力。为此，最初对选择性繁殖的撒丁岛酒精偏好（sP）大鼠进行训练，使其通过操纵杆对酒精（15%，v/v）或蔗糖（0.7%，w/v）进行口服自我给药，每日 30 分钟。一旦反应达到稳定水平，就确定 rac-BHFF（0、50、100 和 200mg/kg；ig）对酒精和蔗糖的反应的影响。rac-BHFF 预处理产生了剂量依赖性的酒精反应抑制；与 vehicle 处理的大鼠相比，50、100 和 200mg/kg rac-BHFF 处理的大鼠中，酒精总反应数减少了约 30%、65%和 90%。200mg/kg rac-BHFF 预处理显著增加了对酒精操纵杆的第一次反应的潜伏期。rac-BHFF 预处理对酒精自我给药的影响具有高度特异性，因为 (a) 只有在 200mg/kg rac-BHFF 预处理时，蔗糖的反应才会减少（与 vehicle 处理的大鼠相比，减少约 50%），而 (b) 任何 rac-BHFF 剂量都不会改变对蔗糖操纵杆的第一次反应的潜伏期。rac-BHFF 治疗并未改变 sP 大鼠独立组的自发运动活动。目前的数据构成了 GABA(B)受体的正变构调节剂降低大鼠酒精强化特性的能力的进一步证据。
