薬物依存、乱用 Drug Addiction and Abuse
P3-2-218 NMDA受容体のGluN2Dサブユニットの遺伝子欠損はPCPによりおこる落胆した状態と類似したアンヘドニアと鬱状態をひきおこす Genetic deprivation of GluN2D subunit of the NMDA receptor induced anhedonia and depressive-like state similar to PCP-induced despair ○山本秀子1, 亀ヶ谷悦子1, 萩野洋子1, 高松幸雄1, 山本敏文2, 三品昌美3池田和隆1 ○Hideko Yamamoto1, Etsuko Kamegaya1, Yoko Hagino1, Yukio Takamatsu1, Toshifumi Yamamoto2, Masayoshi Mishina3, Kasper B. Hansen4, Stephen F. Traynelis4, Kazutaka Ikeda1 東京都医学研・依存性薬物1, 横浜市大・院・生命ナノシステム2, 立命館大・総合科学技術研究機構3, Emory大・医4 Addictive Substance, Tokyo Metropolitan Inst Med Sci, Tokyo1, Yokohama City Univ., Yokohama, Japan2, Ritsumeikan Univ, Kusatsu, Japan3, Emory Univ Sch Med, Atlanta, USA4 Background:Anhedonia is frequently seen during withdrawal in alcoholics and patients with addiction and is also an important factor involved in relapse. Phencyclidine (PCP) produces psychotomimetic symptoms in humans and produces moderate anhedonia in rodents. We had previously reported that GluN2D knockout (KO) mice showed reduced behavioral responses to PCP and PCP-induced dopamine release in the striatum and these mice often did not show sensitization to PCP. The aim of the present study was to determine if deprivation of the GluN2D subunit can induce anhedonia that is similar to chronic PCP treatment-induced anhedonia.Methods: We generated PCP withdrawal model mice by subchronic PCP administration (5 mg/kg, s.c.) followed by a drug-free period. Using GluN2D KO mice and PCP withdrawal mice, we performed behavioral measurements of despair by using the sucrose preference test (for anhedonia) and the tail-suspension test (for the depressive-like state).Results: The motility of the GluN2D KO mice and PCP withdrawal mice significantly decreased in the tail-suspension test. CDPPB, a metabotropic glutamate receptor 5 positive allosteric modulator, increased the motility of both groups of mice. Sucrose intake was lower in male GluN2D KO mice and also decreased in male wild-type mice during PCP withdrawal. Agomelatine, an antidepressant, improved the sucrose intake in GluN2D KO mice. The behavioral scores for anhedonia were not correlated with those for the depressive like state.Conclusions:These results show that GluN2D KO mice seem to develop a depressive-like state with anhedonia and that agomelatine therapy improves the behavioral scores for these conditions. Genetic deprivation of GluN2D subunits and subchronic inhibition of NMDA receptor function by PCP in wild-type mice produced similar emotional states, suggesting that GluN2D subunits are related to depression with anhedonia, it should be possible to develop efficacious therapies with new mechanisms.	P3-2-219 コカイン依存形成における背外側被蓋核－腹側被蓋野コリン作動性神経伝達の役割 Role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced addiction ○篠原史弥1, 木原由佳理1, 井手聡一郎1, 南雅文1, 金田勝幸1 ○Fumiya Shinohara1, Yukari Kihara1, Soichiro Ide1, Masabumi Minami1, Katsuyuki Kaneda1 北海道大院・薬・薬理1 Dept Pharmacol, Grad Sch Pharm Sci Hokkaido Univ, Sapporo1 The mesolimbic dopaminergic (DA) neurons in the ventral tegmental area (VTA) are important for addictive behaviors induced by drugs of abuse, including cocaine. The VTA DA neurons receive cholinergic inputs mainly from the laterodorsal tegmental nucleus (LDT) in the pons, which is critical for regulating the activity of VTA DA neurons. However, it remains unclear whether cholinergic transmission from the LDT to the VTA is involved in cocaine-induced addiction. We addressed this issue using a cocaine-induced place preference paradigm that consists of acquisition (i.e., conditioning session) and expression (i.e., post test session) phases. Intra-LDT injection of carbachol, which is known to inhibit the activity of LDT neurons, just before the cocaine conditioning significantly reduced the cocaine-induced place preference. Additionally, scopolamine or mecamylamine injected into the VTA prior to the cocaine conditioning also remarkably attenuated the place preference induced by cocaine. These results indicate that activity of LDT cholinergic neurons and accompanying signal transmission through muscarinic and nicotinic acetylcholine receptors in the VTA are necessary for the acquisition of cocaine-induced place preference. We also found that intra-VTA injection of scopolamine or mecamylamine immediately before the post test session significantly reduced the cocaine-induced place preference, indicating that the LDT-VTA cholinergic transmission is also critical for the expression of cocaine place preference. Thus, these results suggest that the brainstem cholinergic system may play a crucial role in developing cocaine-induced addiction.
P3-2-220 脳内報酬系におけるCCL2発現増加はメタンフェタミン精神依存形成に関与する Upregulation of CC-chemokine ligand 2 in the rewarding system participates in conditioned place preference to methamphetamine ○木口倫一1, 和木田直希1, 小林悠佳1, 雑賀史浩1, 岸岡史郎1 ○Norikazu Kiguchi1, Naoki Wakida1, Yuka Kobayashi1, Fumihiro Saika1, Shiroh Kishioka1 和歌山県立医大・医・薬理1 Dept Pharmacol, Wakayama Med Univ, Wakayama, Japan1 Methamphetamine is an addictive psychostimulant due to increase in dopamine in the synaptic cleft. This drug of abuse impairs the neural circuits such as rewarding system in the brain, and dysfunction of these regions persists over long term. Although the neural mechanisms underlying addiction to methamphetamine remain unclear, increasing evidence indicates the account of neuroinflammation. In general concepts, microglia and astrocytes produce several inflammatory molecules including cytokines and chemokines, and interact with neurons. These phenomena underlie neurodegenerative disorders in the central nervous system. In this study, we focused on the pathological roles of chemokines in addiction to methamphetamine using C57BL mice. Addictive behavior to methamphetamine was evaluated by conditioned place preference (CPP) test. Biological assays were performed according to conventional procedures. Subcutaneous administration of methamphetamine (0.3-3 mg/kg) caused CPP in a dose dependent manner. The mRNA expression of CC-chemokine ligand 2 (CCL2; also named monocyte chemoattractant protein-1) was markedly increased one hour after methamphetamine administration in the prefrontal cortex and nucleus accumbens. Expression of CC-chemokine receptor 2 (CCR2) which is principal receptor for CCL2 was observed in these brain regions. Minocycline (40 mg/kg), an inhibitor of microglia activation, prevented the upregulation of CCL2 and the CPP to methamphetamine. Furthermore, CCR2 antagonist RS504393 diminished the CPP to methamphetamine. Taken together, we hypothesize that exposure to methamphetamine increased in the amount of CCL2 in rewarding system, and the CCL2 participates in the development of addiction to methamphetamine through CCR2. Therefore, blockade of CCL2/CCR2 cascade in the brain might be effective therapeutic approach for drug abuse.	P3-2-221 グルタチオン合成阻害剤はコカイン逆耐性現象において、移所運動量と常同行動のそれぞれに異なった効果を示す Dissociable effects of a glutathione synthesis inhibitor on locomotor activity and stereotypy of cocaine sensitization ○戸田重誠1, 小杉桜子1, 井口善生1, 三邉義雄1 ○Shigenobu Toda1, Sakurako Kosugi1, Yoshio Iguchi1, Yoshio Minabe1 金沢大学附属病院神経科精神科1 Dept Psychiatry and Neurobiology, Kanazawa University, Kanazawa1 It is postulated that mild oxidative stress induced by social or physical stress may not induce cell death but contribute to numerous cellular events. Acute cocaine administration at moderate dose also induces a mild and transient oxidative stress in the striatum, and the combination of cocaine administration and social/physical stress promotes cocaine addiction. However, how mild oxidative stress is involved in cocaine-induced pathophysiology needs to be clarified. In this study, we tried to address issue by transiently reducing the most abundant endogenous antioxidant in the brain, glutathione (GSH) using a GSH synthesis inhibitor, 2-cyclohexene-1-one (CHX). We tried to examine the effect of CHX that reduced the level of GSH around 20% on cocaine-induced locomotor activity and stereotypy. Pretreatment of CHX (25 mg/kg, i.p.) 1hr before cocaine challenge (15 mg/kg, i.p.) enhanced locomotor activity compared to vehicle-pretreated rats, but stereotypy was not affected. As cocaine was repeatedly administrated for consecutive 7 days, both locomotor activity and stereotype were sensitized in the control group, whereas in the CHX group locomotor activity was not sensitized any more while stereotypy was sensitized as the control group. At this point, there was no difference of stereotypy between two groups. After 3 weeks of withdrawal period, both locomotor activity and stereotype were still sensitized in both groups, however, stereotypy was more enhanced in CHX-pretreated rats compared to control rats. Of note, the basal level of GSH in CHX group was not affected 1 day after the last CHX + cocaine administration compared to the control group. Thus, a single CHX administration immediately sensitized cocaine-induced locomotor activity, but not stereotypy. Meanwhile, the effect of repeated CHX pretreatment later appeared only on stereotypy, suggesting dissociable effects of mild and short-term oxidative stress on locomotor activity and stereotypy.
P3-2-222 マウウ側坐核または線条体へShati/nat8lを過剰発現させた場合のメタンフェタミン応答性の差異とそのメカニズムについて Different effects of shati/nat8l-overexpression on the responses to methamphetamine between in mice nucleus accumbens and dorsal striatum ○新田淳美1, 石川雄大1, 家垣典幸1, 鷲見和之1, 日比陽子2, 村松慎一3, 鍋島俊隆4, 宇野恭介1, 宮本嘉明1 ○Atsumi Nitta1, Yudai Ishikawa1, Noriyuki Iegaki1, Kazuyuki Sumi1, Yoko Furukawa-Hibi2, Shin-ichi Muramatsu3, Toshitaka Nabeshima4, Kyosuke Uno1, Yoshiaki Miyamoto1 富山大学大学院医学薬学研究部（薬学）薬物治療学研究室1, 名古屋大学大学院医学系研究科・医療薬学・附属病院・薬剤部2, 自治医科大学・神経内科学3, 名城大学薬学部・地域医療薬局学講座4 Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences,Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama,Toyama, Japan1, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine,Nagoya, Japan2, Division of Neurology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan3, Department of Regional Pharmaceutical Care and Science, Meijo University, Nagoya, Japan4 The abuse of methamphetamine (Meth) has significantly psychiatric and medical consequences, including dependence, psychosis and even death. A novel molecule shati/nat8l has been identified from the nucleus accumbens (NAc) of mice treated with Meth. We have reported that shati depresses Meth-induced hyperlocomotion and preference via dopaminergic neuronal regulations. However, it is not clear where and/or how shati/nat8l works for anti-addictive action of in the brain. In this study, overexpression of shati/nat8l in the NAc or dorsal striatum (dS) of mice with limited area of brain using adenoassociated virus (AAV) vectors. Only in NAc-overexpressed-shati suppressed Meth-induced hyperlocomotion, sensitization and place preference in mice, not in dS. Moreover, in vivo microdialysis method revealed that overexpression of shati in the NAc inhibits Meth-induced increase of DA release. These effects of inducible shati were canceled by the selective group 2 metabotropic glutamate receptor (mGluR2 and mGluR3) antagonist LY341495. Elevations of N-acetylaspartate and N-acetylaspartylglutamate (NAAG) contents were observed in the AAV vectors injected NAc. Injection of NAAG itself or its inhibitors, reduced DA release from the NAc by using microdialysis. These results indicate that shati in the NAc, but not in the dS, plays an important suppressive role in the action of Meth-induced behaviors by mediating extracellular DA levels via mGluR3.Keywords: drug dependence, methamphetamine, shati, nucleus accumbens, dorsal striatum, dopamine, metabotropic glutamate receptor 3, N-acetylaspartate, N-acetylaspartylglutamate.	P3-2-223 PET検査を用いた向知性薬のドーピング効果評価 Evaluation of doping effect of nootropics by positron emission tomography ○金禹瑣1, 舘野周1, 坂寄健1, 荒川亮介3, 池田裕美子2, 鈴木秀典2, 大久保善朗1 ○WooChan Kim1, Amane Tateno1, Takeshi Sakayori1, Ryosuke Arakawa3, Yumiko Ikeda2, Hidenori Suzuki2, Yoshiro Okubo1 日本医大院・医・精神医学1, 日本医大院・医・薬理学2, 国立精神・神経医療研究センター3 Dept Psychl, Nippon Medical School, Tokyo1, Dept Pharm, Nippon Medical School, Tokyo2, National Center of Neurology and Psychiatry, Tokyo3 [Purpose] Although many athletes and addicts use nootropics in anticipation of improving brain function, few brain-imaging studies have examined either the effects or adverse effects of nootropics. Such data might represent objective evaluations that could support decisions to prohibit or regulate the use of noortropics in the field of athletics. [Methods] In this study we estimated the change of binding potential (BP) of dopamine D2 receptor in the striatum by [11C]raclopride in direct measurement of dopamine release of mazindol (N=10) and caffeine (N=5), and the change in BP of dopamine transporter (DAT) in the striatum by [18F] FE-PE2I as measurement of the inhibitory effect of DAT by bupropion (N=5) and modafinil (N=9). All subjects gave written informed consent prior to participation in the study. All participants underwent positron emission tomography (PET) scan two times (baseline and during medication). In medicated condition, PET scan was started at the time of maximum concentration. All subjects underwent structural magnetic resonance imaging (MRI) for analysis of PET. BP change was calculated by the following equation: change of BP(%)=(BPbase-BPdrug)-BPbasex100. The present study was approved by the Institutional Review Board of Nippon Medical School. [Results] The change in BP of dopamine D2 receptor was 0.3% by 186mg of caffeine, -2.0% by 0.5mg of mazindol, and -7.8% by 1.5mg of mazindol. The change in BP of DAT was -18.2% by 150mg of bupropion, -47.2% by 200mg of modafinil, and -67.0% by 300mg of modafinil.[Discussion] In this study, we could detect the effect of nootropics on dopaminergic pathways. Thus nootropics, even if given at a single oral dose, affected brain function. This method of evaluating dopaminergic neurotransmission may lead to major progresses in understanding the effects and risks of doping by nootropics.
P3-2-224 ocotillol型サポニンpseudoginsenoside-F11はマウスにおけるメタンフェタミン誘発中毒を抑制する An ocotillol type saponin pseudoginsenoside-F11 inhibits methamphetamine-induced addiction in mice ○林慧洋1,2, 宮本嘉明1, 宇野恭介1, 呉春福2, 楊静玉2, 新田淳美1 ○Huiyang Lin1,2, Yoshiaki Miyamoto1, Kyosuke Uno1, Chunfu Wu2, Jingyu Yang2, Atsumi Nitta1 富山大院・医薬（薬）・薬物治療学1, 瀋陽薬科大学2 Dept of Pharm Therapy and Neuropharmacol, Fac of Pharm Sci, Grad Sch of Med and Pharm Sci, Univ of Toyama, Toyama, Japan1, Dept of Pharm, Shenyang Pharm Univ, Shenyang, China2 Addiction of methamphetamine (METH) is worldwide health and social problems to relate serious psychiatric and medical symptoms. Nevertheless, there is currently no effective pharmacological treatment for METH-induced addiction. Pseudoginsenoside-F11 (PF11), an ocotillol type saponin, isolated from Panax quinquefolium L (American ginseng). The previous study has demonstrated that PF11 has neuronal protective effect, and promoted learning and memory. It has been also reported that PF11 antagonized pharmacological effects of morphine, such as analgesia and analgesia tolerance. However, the effect of PF11 on drug addiction is still unknown. In this study, we investigated to clarify the effect of PF11 on METH-induced dependence in mice. Single pretreatment with PF11 (4 and 8 mg/kg, p.o.) failed to attenuate hyperlocomotion induced by single METH administration (1 mg/kg, s.c.). On the other hand, repeated pretreatment with PF11 (4 and 8 mg/kg/day, p.o.) prior to continuous METH administration (1 mg/kg/day, s.c., for 6 days) showed the tendency to attenuate METH-induced locomotor sensitization. In the conditioned place preference test, the pretreatment with PF11 (4 and 8 mg/kg/day, p.o.) inhibited METH (1 mg/kg, s.c.)-induced place preference. These results suggest that PF11 possesses the inhibitive effect on METH-induced addiction. We have next plan to test the change of extracellular neurotransmitter level after repeated co-administration of PF11 and METH administration.	P3-2-225 Expression of BDNF and reinstatement of amphetamine induced conditioned place preference in rats ○Ying-Ling Shen1, Tin-Yuan Chang2, Ya-Chu Chang1, Hsin-Hua Tien1, Ruey-Ming Liao1,2,3 Department of Psychology, National ChengChi University1, Institute of Neuroscience, National ChengChi University, Taipei, Taiwan2, Research Center for Mind, Brain and Learning, National ChengChi University, Taipei, Taiwan3 Drug addiction is a brain disease, which behavioral formation or expression is thought to have certain neurobiological mechanisms of synaptic plasticity subserve the corresponding neuroadaptation. Most of the addictive drugs exert their effects in the mesocorticolimbic dopamine system in the brain. Nowadays, besides the search for functional roles of dopamine in the development of drug addiction, brain-derived neurotrophic factor (BDNF) is also thought to be participated in this drug-induced behavioral changes and synaptic plasticity. In order to investigate the interactions between the dopamine and BDNF involved in drug addiction behavior, the amphetamine (1.0 mg/kg; ip) induce conditioned place preference (CPP) was used in the present study. Then, the expressions of BDNF mRNA in the medial prefrontal cortex, caudate nucleus, nucleus accumbens, hippocampus and amygdala were examined at two stages: the CPP performance and the reinstatement of CPP after lower doses of amphetamine challenge (0, 0.5, 0.75 mg/kg; ip). Results showed that the amphetamine CPP was significantly formed via the association of drug effect paired with a specific context as preferred in comparing to saline vehicle pairing the other context. Following an extinction protocol, the extinguished CPP was reinstated by amphetamine given at 0.75 mg/kg but not 0.5 mg/kg. BDNF expression, over all regions tested, was not changed at the stage of CPP performance. In contrast, the BDNF mRNA significantly increased in the medial prefrontal cortex after the CPP reinstatement test. Such effect was not found in other regions. Taken together, these data indicate that the endogenous BDNF mRNA in the medial prefrontal cortex is involved in the drug-priming reinstatement of amphetamine CPP.
P3-2-226 Modulation of opiate-induced locomotion by hippocampal NMDA receptors and environmental experience ○Adam Weitemier1, Thomas J. McHugh1 RIKEN Brain Science Institute1 The behavioral actions of opiates can be modulated by behavioral state, number of exposures and associative learning. To understand the role of hippocampal NMDA glutamate receptors in the acute and chronic actions of opiates with or without prior environmental experience, we monitored locomotor activity after administration of saline vehicle or 0.2 mg/kg fentanyl, a mu-opioid receptor agonist, in mice lacking the NR1 subunit of the NMDA receptor in the hippocampal CA3 region (CA3-NR1 KO) and wildtype littermates. After saline injection CA3-NR1 KO mice exhibited generally higher locomotor activity than littermate control mice over all daily 30-minute sessions. After fentanyl administration CA3-NR1 KO mice exhibited an exaggerated acute locomotor response and were also more prone to develop locomotor sensitization, a form of behavioral adaptation after chronic exposure to addictive drugs. After four daily habituation trials to the experimental arena, the locomotor response to first-exposure fentanyl was increased in control mice, but not CA3-NR1 KO mice. These results suggest that hippocampal NMDA receptors can modulate the acute behavioral effects of opiate drugs and also adaptations to chronic opiate exposure. Environmental experience can modulate the acute opiate response as well. Functional interactions between the hippocampus and brain systems more directly implicated in opiate effects such as the mesolimbic dopamine system and striatal circuitry may underlie these results.	P3-2-227 Withdrawn

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