1-S08-1
薬物依存治療候補薬としてのGIRKチャネル阻害剤の臨床研究
Clinical study of GIRK channel inhibitors as candidate medicines for drug dependence
〇池田和隆1
KazutakaIkeda1
1東京都医学総合研
1Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science
G-protein activated inwardly rectifying potassium (GIRK, Kir3) channel is one of the effectors in signal pathways from ethanol, opioid, dopamine, and other addictive substances. We found associations between genetic polymorphisms in the GIRK subunit genes and sensitivity to addictive substances in mice and humans. We found that fluoxetine and paroxetine, selective serotonin reuptake inhibitors (SSRIs), but not fluvoxamine, another SSRI, inhibited GIRK channels in vitro and reduced preference for methamphetamine in mice. In addition, we found that ifenprodil, a widely used drug for dizziness, also inhibited GIRK channels in vitro. Another research group has shown that ifenprodil reduced preference for addictive substances using rodents. Furthermore, we found that relapse rate and relapse risk scores were lower in alcoholics who were treated with GIRK inhibitors. We also demonstrated an inhibitory effect of ifenprodil on alcohol use in patients with alcohol dependence in a prospective, randomized, controlled, rater-blinded study. These results suggest that GIRK channels are important molecules in the reward system and candidate targets for pharmacotherapy of drug dependence.
1-S08-2
薬物依存関連遺伝子Shati/Nat8l、Piccolo およびTMEM168の生理機能および薬物依存治療薬標的としての有用性
New three molecule regulate the dependece by methanphetamine
〇新田淳美1
AtsumiNitta1
1富山大学大学院医学薬学研究部(薬学)薬物治療学研究室
1Dept. Neuropharmacol. & Pharma Ther., Grad. Sch. Med. Pharm. Univ of Toyama
We found and study new three molecules related methamphetamine dependence, Shati/Nat8L, Piccolo and TMEM168. Accumbal Shati rescue the dependence-induced by methamphetamine via mGluR3, and dopaminergic deficiency. Reduce of Piccolo can inhibit methamphetamine dependence via GABA regulation. TMEM168 also inhibit the methamphetamine dependence via osteopontin pathways. We found some pathway to establish drug dependence. We expected them for the new medical target for the drug dependence.
Recently, we attempt to find these molecular regulation system to develop new medical tool. Here we would like to recent our results
1-S08-3
ストレスによるコカイン報酬の増強機構
Neural mechanisms underlying stress-induced enhancement of cocaine rewarding properties
〇金田勝幸1
KatsuyukiKaneda1
1金沢大・医薬保・薬・薬理
1Lab. Mol. Pharm., Kanazawa Univ.
Stress potentiates rewarding properties of cocaine. To elucidate neural mechanisms underlying this effect of stress, we developed an experimental paradigm combining cocaine-induced conditioned place preference (CPP) with a restraint stress. Acute restraint stress exposure immediately before posttest significantly increased cocaine CPP scores. It has been suggested that the extracellular noradrenaline (NA) level is increased by stress in the laterodorsal tegmental nucleus (LDT), which sends cholinergic projections to dopamine (DA) neurons in the ventral tegmental area (VTA), and in the medial prefrontal cortex (mPFC), which receives DA input from the VTA. Thus, we investigated the roles of NA in these brain regions. Intra-LDT injection of an α2 adrenoceptor antagonist or intra-mPFC injection of an α1 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. In vitro whole-cell recordings revealed that α2 adrenoceptor stimulation reduced GABAergic inputs to LDT cholinergic neurons and that α1 adrenoceptor stimulation directly excited mPFC pyramidal neurons. These findings suggest that stress-induced increases in neuronal activity of the LDT and mPFC contribute to the enhancement of rewarding properties of cocaine.
1-S08-4
飲酒量低減薬ナルメフェンの薬理学的特徴
Pharmacological profile of nalmefene for reducing alcohol consumption
〇大木雄太1
YutaOhgi1
1大塚製薬株式会社 中枢神経疾患研究所
1Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd.
Nalmefene, an opioid system modulator, is approved in the EU and other countries for as-needed use to reduce alcohol consumption in patients with alcohol dependence. Accumulating evidence indicates that the endogenous opioid system has important roles in alcohol dependence. Alcohol stimulates the release of endogenous opioid peptides such as β-endorphin and dynorphin in the brain. β-endorphin activates μ-opioid receptor leading to euphoric mood and positive reinforcement, while dynorphin activates κ-opioid receptor leading to dysphoric mood and negative reinforcement. These euphoric/dysphoric mood and reinforcement effects via endogenous opioid systems are suggested to be implicated in repeated alcohol intake in patients with alcohol dependence.
Nalmefene acts as an antagonist at μ- and δ-opioid receptor and a partial agonist at κ-opioid receptor. Preclinical studies have shown that nalmefene reduced the alcohol intake in alcohol preference rats. In clinical trials, as-needed use of nalmefene with psychosocial support reduced the number of heavy-drinking days and total alcohol consumption. These results suggest that nalmefene modulates the alcohol-induced euphoric/dysphoric mood via opioid system and thereby contribute to reduction in alcohol consumption in patients with alcohol dependence.
In this symposium, we will discuss the implications of opioid system in alcohol dependence and pharmacological profiles of nalmefene in preclinical and clinical studies.