Basic research for the treatment of psychological dependence on methamphetamine

冰毒心理依赖治疗基础研究

• 批准号: 15390085
• 负责人: SUZUKI Tsutomu
• 金额: $ 3.46万
• 依托单位: Hoshi University School of Pharmacy and Pharmaceutical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390085/
• 关键词: Methamphetamine; Psychological dependence; Ifenprodil; TRK-820; Glutamatergic system; κ-Opioidergic system; Mesolimbic dopamine neuron; Sensitization; κオピオイド受容体; NMDA受容体; 中脳辺縁ドパミン神経系; 報酬効果; 新規κ受容体作動薬; グルタミン酸神経系; NR2Bサブユニット; κオピオイド神経系

Repeated treatment with methamphetamine leads to an enhancement in the methamphetamine-induced dopamine release and its related behaviors. This phenomenon is called sensitization or reverse tolerance. In this study, I demonstrated the effect of N-methyl-D-aspartate(NMDA) receptor antagonist ifenprodil and κ-opioid receptor agonist TRK-820 on the development of sensitization to the methamphetamine-induced rewarding effect and dopamine release in rodents. The conditioned place preference paradigm and in vivo microdialysis assay were performed in the present study. The treatment with ifenprodil or TRK-820 abolished the enhancement of the methamphetamine-induced place preference following repeated treatment with methamphetamine. Furthermore, intra-nucleus accumbens (N.Acc.) injection of TRK-820 blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. These findings strongly indicate that treatment with ifenprodil or TRK-820 co … More uld be highly recommended for the cure of drug dependence.On the other hand, I investigated that intra-nucleus accumbens injection of a selective protein kinase C(PKC) inhibitor chelerythrine chloride blocked the development of sensitization to dopamine release in the N.Acc.induced by repeated methamphetamine treatment. Under these conditions, the immunoreactivity of the cytosolic phosphorylated-PKC in the limbic forebrain region including the N.Acc.was slightly, but significantly increased in methamphetamine-sensitized rats. Furthermore, it should be mentioned that the protein level of NR2B subunit was significantly increased in membrane preparations of the limbic forebrain obtained from methamphetamine-sensitized rats. Moreover, methamphetamine produced prolonged PKC-dependent astrocytic activation, whereas morphine caused a reversible activation of astrocytes in in vivo and in vitro study. In conclusion, the present study provides novel evidence that the development of sensitization to the methamphetamine-induced rewarding effects may be, at least in part, linked to the increased level of PKC, NR2B subunit and PKC-dependent astrocytic activation by methamphetamine in rodents. Less

重复使用甲基苯丙胺治疗会导致甲基苯丙胺诱导的多巴胺释放及其相关行为的增强，这种现象称为敏化或反向耐受，在这项研究中，我证明了 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的作用。艾芬地尔和 κ-阿片受体激动剂 TRK-820 对甲基苯丙胺诱导的奖赏效应和多巴胺释放的敏感性的发展在本研究中进行了条件性位置偏好范例和体内微透析，用艾芬地尔或 TRK-820 进行的测定治疗消除了重复注射 N.Acc. 治疗后甲基苯丙胺诱导的位置偏好的增强。 TRK-820 阻断重复甲基苯丙胺诱导的 N.Acc 中多巴胺释放敏化的发展这些发现强烈建议使用艾芬地尔或 TRK-820 联合治疗来治疗药物依赖。另一方面，我研究了伏核内注射选择性蛋白激酶 C (PKC) 抑制剂白屈菜红碱。在这些条件下，氯化物阻断了由重复甲基苯丙胺治疗诱导的 N.Acc. 中多巴胺释放的敏化的发展。在甲基苯丙胺致敏的大鼠中，边缘前脑区域（包括 N.Acc.）的胞质磷酸化-PKC 略有增加，但显着增加。此外，应该提到的是，边缘前脑膜制剂中 NR2B 亚基的蛋白水平显着增加。此外，甲基苯丙胺产生延长的 PKC 依赖性星形胶质细胞激活，而吗啡则引起可逆激活。总之，本研究提供了新的证据，表明对甲基苯丙胺奖励诱导效应的敏感性的发展可能至少部分与 PKC、NR2B 亚基和 PKC、NR2B 亚基水平的增加有关。啮齿类动物中甲基苯丙胺对 PKC 依赖性星形胶质细胞的激活作用较少。

项目成果

基礎からオピオイド使用を勧める理由 慢性疼痛下におけるオピオイド及びドパミン神経系に対する修飾ならびにオピオイドによる一過性のグリア細胞活性化及び神経細胞死に対する影響

从基础开始推荐使用阿片类药物的理由阿片类药物和慢性疼痛下多巴胺能神经系统的改变，以及阿片类药物对短暂性胶质细胞激活和神经元细胞死亡的影响

• 发表时间: 2004
• 期刊: ペインクリニック 25
• 作者: 成田 年;宮竹真由美;鈴木雅美;芝崎真裕;矢島義識;鈴木 勉
• 通讯作者: 鈴木 勉

Behavioral sensitization to the discriminative stimulus effects of methamphetamine in rats.

大鼠对甲基苯丙胺的歧视性刺激作用的行为敏感性。

• 发表时间: 2004
• 期刊: Eur.J.Pharmacol. 498
• 作者: T.Suzuki;Y.Fukuoka;T.Mori;M.Miyatake;M.Narita
• 通讯作者: M.Narita

J.Khotib, M.Narita, M.Suzuki, Y.Yajima, T.Suzuki: "Functional interaction among opioid receptor types : up-regulation of μ- and δ-opioid receptor functions after repeated stimulation of κ-opioid receptors."Neuropharmacology. 46. 531-540 (2004)

J.Khotib、M.Narita、M.Suzuki、Y.Yajima、T.Suzuki：“阿片受体类型之间的功能相互作用：重复刺激 κ-阿片受体后 μ- 和 δ-阿片受体功能上调。”神经药理学。46。531-540（2004）

Differential properties between TRK-820 and U-50,488H on the discriminative stimulus effects in rats.

• DOI: 10.1016/j.lfs.2004.05.017
• 发表时间: 2004-10
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Tomohisa Mori;M. Nomura;Kazumi Yoshizawa;H. Nagase;M. Narita;Tsutomu Suzuki

M.Narita, M.Suzuki, M.Narita, Y.Yajima, R.Suzuki, S.Shioda, T.Suzuki: "Neuronal protein kinase Cγ-dependent proliferation/hypertrophy of spinal cord astrocyte following repeated in vivo administration of morphine."Eur.J.Neurosci.. 19. 479-484 (2004)

M.Narita、M.Suzuki、M.Narita、Y.Yajima、R.Suzuki、S.Shioda、T.Suzuki：“体内反复给予吗啡后，脊髓星形胶质细胞的神经蛋白激酶 Cγ 依赖性增殖/肥大。 “欧洲神经科学杂志 19. 479-484 (2004)