ドパミンD1受容体によるcAMP産生におけるプロスタグランジンE受容体EP1の促進的作用を担う分子機構の解明

京都大学0048新制・課程博士博士(生命科学)甲第17931号生博第294号新制||生||38(附属図書館)30751京都大学大学院生命科学研究科高次生命科学専攻(主査)教授 垣塚 彰, 教授 渡邉 大, 教授 松崎 文雄学位規則第4条第1項該当Doctor of Philosophy in Life SciencesKyoto UniversityDFA

Mu opioid receptors in the medial habenula contribute to naloxone aversion

The medial habenula (MHb) is considered a brain center regulating aversive states. The mu opioid receptor (MOR) has been traditionally studied at the level of nociceptive and mesolimbic circuits, for key roles in pain relief and reward processing. MOR is also densely expressed in MHb, however, MOR function at this brain site is virtually unknown. Here we tested the hypothesis that MOR in the MHb (MHb-MOR) also regulates aversion processing. We used chnrb4-Cre driver mice to delete the Oprm1 gene in chnrb4-neurons, predominantly expressed in the MHb. Conditional mutant (B4MOR) mice showed habenula-specific reduction of MOR expression, restricted to chnrb4-neurons (50% MHb-MORs). We tested B4MOR mice in behavioral assays to evaluate effects of MOR activation by morphine, and MOR blockade by naloxone. Locomotor, analgesic, rewarding, and motivational effects of morphine were preserved in conditional mutants. In contrast, conditioned place aversion (CPA) elicited by naloxone was reduced in both naive (high dose) and morphine-dependent (low dose) B4MOR mice. Further, physical signs of withdrawal precipitated by either MOR (naloxone) or nicotinic receptor (mecamylamine) blockade were attenuated. These data suggest that MORs expressed in MHb B4-neurons contribute to aversive effects of naloxone, including negative effect and aversive effects of opioid withdrawal. MORs are inhibitory receptors, therefore we propose that endogenous MOR signaling normally inhibits chnrb4-neurons of the MHb and moderates their known aversive activity, which is unmasked upon receptor blockade. Thus, in addition to facilitating reward at several brain sites, tonic MOR activity may also limit aversion within the MHb circuitry

Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks

Backgound: Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. Methods: We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging. Results: Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced. Conclusions: Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment.This work was supported by National Institutes of Health/National Institute of Drug Abuse Grant No. 05010 (to BLK); National Institute on Alcohol Abuse and Alcoholism Grant No. 16658 (to BLK); the Canada Fund for Innovation and the Canada Research Chairs (to BLK); Spanish Ministerio de Economía y Competitividad-MINECO Grant No. #SAF2014-59648-P/FEDER (to RM); Instituto de Salud Carlos III RETICS-RTA Grant No. RD12/0028/0023/FEDER (to RM); Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional sobre Drogas Grant No. PNSD-2013-068 (to RM); Generalitat de Catalunya AGAUR Grant No. 2014-SGR-1547 (to RM); a 2015 Catalan Institution for Research and Advanced Studies Academia Award (to RM); the Brazilian government's CAAP scholarship (Programa Ciência Sem Froteiras) (to SM-N); and the NeuroTime Erasmus+: Erasmus Mundus program of the European Commission. This publication/communication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein