Clinical study of GIRK channel inhibitors as candidate medicines for drug dependence

Abstract

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.