Kotajima-Murakami Hiroko, Ikeda Kazutaka
Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science.
Nihon Yakurigaku Zasshi. 2020;155(3):130-134. doi: 10.1254/fpj.19134.
Recently, topics related to substance dependence and behavioral addiction have been reported through the media. Therapeutic treatment for substance dependence and behavioral addiction is one of the challenges in a clinical practice. This is because there is no therapeutic treatment for a complete cure, and reuses and repetitive hospitalization occur in patients. Therefore, it is an urgent need to develop new treatments for substance dependence and behavioral addiction. In the present review, we outline associations between dependence and G-protein-activated inwardly rectifying potassium (GIRK) channels which we focus on as therapeutic targets, and introduce ongoing clinical study using an inhibitor of GIRK channels. Previous studies including animals and patients have accumulated the results that GIRK channels have a key role for mediating signals from addictive substances. GIRK channels are expressed in various rodent brain regions including the reward system. The activation of G protein-coupled receptors (GPCRs) that activates GIRK channels through G-protein βγ subunits and activated GIRK channels contribute to control of neuronal excitability. Pretreatment with ifenprodil that is one of the GIRK channel blockers suppressed addictive substance-induced behaviors in animals. Ifenprodil is safe and broadly used as a cerebral circulation/metabolism ameliorator that is covered by medical insurance in Japan. The authors reported that ifenprodil treatment for 3 months decreased alcohol use scores in patients with alcohol dependence compared with patients who received the control medication. We currently conduct a clinical trial to investigate the outcomes of ifenprodil treatment for methamphetamine dependence. In the future, we will expand clinical studies using ifenprodil for patients with other substance dependence and behavioral addiction.
最近，与物质依赖和行为成瘾相关的话题已通过媒体进行了报道。物质依赖和行为成瘾的治疗是临床实践中的挑战之一。这是因为目前尚无能够完全治愈的治疗方法，患者会出现复发和反复住院的情况。因此，迫切需要开发针对物质依赖和行为成瘾的新治疗方法。在本综述中，我们概述了作为治疗靶点的依赖与G蛋白激活内向整流钾通道（GIRK通道）之间的关联，并介绍了正在进行的使用GIRK通道抑制剂的临床研究。包括动物和患者在内的先前研究积累的结果表明，GIRK通道在介导成瘾物质信号方面起关键作用。GIRK通道在包括奖赏系统在内的各种啮齿动物脑区中表达。通过G蛋白βγ亚基激活GIRK通道的G蛋白偶联受体（GPCR）的激活以及激活的GIRK通道有助于控制神经元兴奋性。作为GIRK通道阻滞剂之一的艾芬地尔预处理可抑制动物中成瘾物质诱导的行为。艾芬地尔是安全的，在日本作为脑循环/代谢改善剂广泛使用且被医疗保险覆盖。作者报告称，与接受对照药物治疗的患者相比，艾芬地尔治疗3个月可降低酒精依赖患者的酒精使用评分。我们目前正在进行一项临床试验，以研究艾芬地尔治疗甲基苯丙胺依赖的效果。未来，我们将扩大使用艾芬地尔对其他物质依赖和行为成瘾患者的临床研究。
