Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Sweden.
Addict Biol. 2019 May;24(3):471-484. doi: 10.1111/adb.12613. Epub 2018 Feb 26.
Alcohol craving, in combination with impaired impulse control, often leads to relapse. The dopamine system mediates the rewarding properties of alcohol but is also involved in regulating impulsive behavior. The monoamine stabilizer (-)-OSU6162 (OSU6162) has the ability to stabilize dopamine activity depending on the prevailing dopaminergic tone and may therefore normalize the dopaminergic transmission regulating both alcohol use disorder and impulsivity. We have recently showed that OSU6162 attenuates voluntary alcohol consumption, operant alcohol self-administration, alcohol withdrawal symptoms and cue-induced reinstatement of alcohol seeking in rats. Here, we evaluated OSU6162's effects on motor impulsivity in Wistar rats that had voluntarily consumed alcohol or water for 10 weeks. The five-choice serial reaction time task was used to measure motor impulsivity, and a prolonged waiting period (changed from 5 to 7 seconds) was applied to induce premature responses. OSU6162-testing was conducted twice a week (Tuesdays and Fridays), every other week with regular baseline training sessions in between. We also tested OSU6162's effects on the alcohol deprivation effect in long-term alcohol drinking Wistar rats. The results showed that OSU6162 (30 mg/kg) pre-treatment significantly improved motor impulsivity in the five-choice serial reaction time task in both alcohol and alcohol-naïve rats. Moreover, OSU6162 (30 mg/kg) pre-treatment prevented the alcohol deprivation effect, i.e. relapse-like drinking behavior after a forced period of abstinence in long-term drinking rats. In conclusion, our results provide further support for OSU6162 as a novel treatment for alcohol use disorder. The results further indicate that improvement of motor impulse control might be one mechanism behind OSU6162's ability to attenuate alcohol-mediated behaviors.
酒精渴求，加上冲动控制受损，常导致复发。多巴胺系统介导酒精的奖赏特性，但也参与调节冲动行为。单胺稳定剂 (-)-OSU6162（OSU6162）具有根据多巴胺能张力稳定多巴胺活动的能力，因此可能使调节酒精使用障碍和冲动性的多巴胺传递正常化。我们最近表明，OSU6162 可减弱大鼠自愿饮酒、操作性酒精自我给药、酒精戒断症状和线索诱导的酒精寻求复吸。在这里，我们评估了 OSU6162 对自愿饮用酒精或水 10 周的 Wistar 大鼠的运动冲动性的影响。五选择序列反应时间任务用于测量运动冲动性，并应用延长的等待期（从 5 秒变为 7 秒）来诱导过早反应。OSU6162 测试每周进行两次（星期二和星期五），中间每隔一周进行常规基线训练。我们还测试了 OSU6162 在长期饮酒 Wistar 大鼠中的酒精剥夺效应。结果表明，OSU6162（30mg/kg）预处理可显著改善酒精和酒精未处理大鼠的五选择序列反应时间任务中的运动冲动性。此外，OSU6162（30mg/kg）预处理可预防酒精剥夺效应，即在长期饮酒大鼠中强制禁欲期后出现类似复发的饮酒行为。总之，我们的结果为 OSU6162 作为一种新型酒精使用障碍治疗方法提供了进一步的支持。结果进一步表明，改善运动冲动控制可能是 OSU6162 减弱酒精介导行为的能力的一种机制。
