Department of Psychology, Grand Valley State University, 1 Campus Drive, Allendale, MI 49401, USA.
Alcohol. 2013 Aug;47(5):359-65. doi: 10.1016/j.alcohol.2013.05.001. Epub 2013 May 31.
Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25-30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0-20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0-10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature.
尽管最近的研究表明，强啡肽/κ 阿片受体（DYN/KOR）系统可能是酒精相关应激效应的关键介质，但通过 DYN/KOR 系统调节与乙醇戒断延长相关的长期变化尚未得到探索。本研究的目的是确定 DYN/KOR 系统在具有乙醇依赖史的动物长期戒断乙醇期间调节焦虑相关行为中的作用。雄性 Wistar 大鼠（n=94）喂食乙醇或对照液体饮食 25-30 天。去除饮食 6 周后，大鼠暴露于 20 分钟的固定中，并用 KOR 拮抗剂诺丁啡（nor-BNI）（0-20mg/kg，腹腔内 [i.p.]）来研究慢性暴露于乙醇的大鼠应激反应增强的缓解作用，使用高架十字迷宫。此外，还研究了 U50,488（0-10mg/kg，i.p.）在延长戒断期间引发焦虑样行为的能力。与接受相同处理的对照组相比，具有乙醇依赖史的大鼠在暴露于束缚后，其开放臂探索明显减少，表明出现焦虑样状态，这一效应被 nor-BNI 阻断。nor-BNI 还选择性地减少了乙醇暴露大鼠的中央时间和开放臂接近。U50,488 的最高剂量降低了乙醇暴露和对照组大鼠的开放臂探索和总臂入口数。尽管较低剂量的 U50,488 对两组的开放臂探索都没有影响，但 0.1mg/kg 剂量选择性地降低了乙醇暴露大鼠的运动活性，与接受相同预处理的对照组相比。这些发现进一步支持了这样的假设，即与乙醇戒断相关的行为部分受 DYN/KOR 系统调节，并表明这些效应可能具有长期性质。
