Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
Biol Psychiatry. 2012 Nov 15;72(10):823-31. doi: 10.1016/j.biopsych.2012.06.018. Epub 2012 Jul 18.
New medications for alcohol use disorder (AUD) are needed. Long-term alcohol consumption leads to a dysregulated dopamine system. A novel approach to normalize these dysregulations might be treatment with "monoamine stabilizers," a novel class of compounds characterized by the ability to either suppress, stimulate, or not influence dopamine activity depending on the prevailing dopaminergic tone.
The effects of the monoamine stabilizer (-)-OSU6162 (OSU6162) on voluntary ethanol intake and ethanol withdrawal symptoms were evaluated in rats voluntarily consuming ethanol for at least 3 months before testing. Furthermore, effects of OSU6162 on ethanol seeking behavior were evaluated with the progressive ratio and cue-induced reinstatement paradigms. Finally, the interaction of OSU6162 with ethanol on dopamine output and metabolism was studied with microdialysis.
The OSU6162 attenuated several ethanol-mediated behaviors, including voluntary ethanol consumption, ethanol withdrawal symptoms, operant ethanol self-administration under progressive ratio schedule, and cue-induced reinstatement of ethanol seeking in rats that had voluntarily consumed ethanol for at least 3 months before treatment. In addition, OSU6162 blunted ethanol-induced dopamine output in nucleus accumbens of ethanol-naïve rats.
These results highlight the ability of OSU6162 to stabilize dopamine activity depending on the prevailing dopaminergic tone and indicate that OSU6162 might decrease ethanol intake by attenuating the acute rewarding properties of ethanol. In addition, OSU6162 might have potential to prevent relapse triggered by alcohol craving, alcohol related cues, and or an urge to relieve abstinence symptoms. The present study is to our knowledge the first indicating that OSU6162 might serve as a novel medication for AUD.
需要新的药物来治疗酒精使用障碍（AUD）。长期饮酒会导致多巴胺系统失调。一种使这些失调正常化的新方法可能是使用“单胺稳定剂”进行治疗，这是一类新型化合物，其特点是根据多巴胺能张力的变化，具有抑制、刺激或不影响多巴胺活性的能力。
在测试前，至少有 3 个月自愿摄入乙醇的大鼠中，评估单胺稳定剂（-）-OSU6162（OSU6162）对自愿摄入乙醇和乙醇戒断症状的影响。此外，还通过递增比率和线索诱导复吸范式评估了 OSU6162 对乙醇寻求行为的影响。最后，通过微透析研究了 OSU6162 与乙醇对多巴胺输出和代谢的相互作用。
OSU6162 减弱了几种乙醇介导的行为，包括自愿摄入乙醇、乙醇戒断症状、在递增比率方案下进行的操作性乙醇自我给药，以及在治疗前至少有 3 个月自愿摄入乙醇的大鼠中诱导的线索复吸。此外，OSU6162 减弱了乙醇诱导的伏隔核中多巴胺的输出。
这些结果突出了 OSU6162 根据多巴胺能张力稳定多巴胺活动的能力，并表明 OSU6162 可能通过减弱乙醇的急性奖赏特性来减少乙醇的摄入。此外，OSU6162 可能具有预防由酒精渴望、酒精相关线索和/或缓解戒断症状的冲动引发的复发的潜力。本研究首次表明，OSU6162 可能作为一种治疗 AUD 的新型药物。
