PDF(Pubmed)
Abstract：
Alcohol use disorder (AUD) remains a major public health concern. The dynorphin (DYN)/κ-opioid receptor (KOP) system is involved in actions of alcohol, particularly its withdrawal-associated negative affective states. This study tested the ability of LY2444296, a selective, short-acting, KOP antagonist, to decrease alcohol self-administration in dependent male and female Wistar rats at 8 h abstinence. Animals were trained to orally self-administer 10% alcohol (30 min/day for 21 sessions) and were made dependent via chronic intermittent alcohol vapor exposure for 6 weeks or exposed to air (nondependent). After 6 weeks, the effect of LY2444296 (0, 3, and 10 mg/kg, p.o.) was tested on alcohol self-administration at 8 h of abstinence. A separate cohort of rats was prepared in parallel, and their somatic withdrawal signs and alcohol self-administration were measured after LY2444296 administration at 8 h, 2 weeks, and 4 weeks abstinence. LY2444296 at 3 and 10 mg/kg significantly reduced physical signs of withdrawal in dependent rats at 8 h abstinence, only. Furthermore, 3 and 10 mg/kg selectively decreased alcohol self-administration in dependent rats at only 8 h abstinence. These results highlight the DYN/KOP system in actions of alcohol during acute abstinence, suggesting KOP antagonism could be beneficial for mitigating acute withdrawal signs and, in turn, significantly reduce excessive alcohol consumption associated with AUD.
摘要：
酒精使用障碍（AUD）仍然是一个主要的公共卫生问题。强啡肽（DYN）/κ阿片受体（KOP）系统参与酒精的作用，特别是其与退缩相关的负面情感状态。这项研究测试了LY2444296的能力，短效,KOP拮抗剂，在8h禁欲时减少依赖性雄性和雌性Wistar大鼠的酒精自我给药。训练动物口服自我施用10％酒精（30分钟/天，共21个疗程），并通过长期间歇性酒精蒸气暴露6周或暴露于空气（非依赖性）使其依赖性。6周后,LY2444296（0、3和10mg/kg，p.o.）在禁欲8小时时对酒精自我给药进行了测试。平行准备了单独的大鼠队列，LY2444296给药后8小时测量其躯体戒断体征和酒精自我给药，2周,禁欲4周。3和10mg/kg的LY2444296显着降低了8h禁欲依赖性大鼠的戒断体征，only.此外，3和10mg/kg在仅禁欲8小时的依赖性大鼠中选择性地减少了酒精的自我给药。这些结果突出了DYN/KOP系统在急性禁欲期间酒精的作用，提示KOP拮抗作用可能有利于减轻急性戒断症状，反过来,显著减少与AUD相关的过量饮酒。
