Involvement of the endocannabinoid system in the mechanism of relapse to drug craving

内源性大麻素系统参与药物渴望复发的机制

• 批准号: 14572056
• 负责人: YAMAMOTO Tsuneyuki
• 金额: $ 2.24万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572056/
• 关键词: methamphetamine; drug self-administration; drug-seeking behavior; drug-associated cue; priming injection; CB1 receptor; EP3 receptor; arachidonic acid cascade; 薬物自己投与実験; cocaine; methamphetamine; self-administration

[METHAMPHETAMINE (MAP)]1)MAP-seeking_behavior:Priming injection of MAP as well as re-exposure to light and tone previously paired with MAP-taking (MAP associated-cues) reinstated MAP-seeking behavior. The reinstatement induced by MAP-priming injection was potentiated by cannabinoid (CB) receptor agonist THC and antagonized by CB1 receptor antagonist SR141716A. Furthermore, COX inhibitor diclofenac attenuated both MAP-priming-and cue-induced reinstatement. In addition, MAP-priming-injection as well as MAP associated-cues induced reinstatement were attenuated by repeated THC-injection during MAP withdrawal. Not only MAP-priming-but also cue-induced reinstatement were attenuated by microinjection of local anesthetic lidocaine or SR141716A into basolateral amygdala (BLA).2)Change in the levels og the endogenous CB receptor ligand 2-AG:The contents of 2-AG in the rat whole brain following self-administration of MAP for 10 days were increased compared with non-treated group. However, on day … More 5 of MAP withdrawal, during which only saline was available, the contents of 2-AG tended to decrease.[cocaine]Re-exposure to cocaine-associated cues reinstated cocaine-seeking behavior, and SR141716A as well as diclofenac attenuated the reinstatement. CB1 receptor agonist HU210 also reinstated cocaine-seeking behavior, and this reinstatement was attenuated by diclofenac. Furthermore, during the expression of cue-induced cocaine-seeking behavior, the contents of prostaglandin E_2 (PGE_2), an end product of the arachidonic acid cascade (AAC), in the nucleus accumbens of the cocaine-self-administering rats were increased.The aforementioned evidence, clarifies that 1)MAP/cocaine-seeking behavior were due to activation of AAC, mediated by brain CB1 receptor, and 2)BLA is one of the substrates responsible for the expression of MAP-seeking behavior. Furthermore, 3)these results not only unveil the mechanisms of the expression of drug dependence, but also implicate that various kinds of psychiatric disorders are, in part, due to dysfunction of the brain reward system. Less

[甲安非他明（MAP）]1）MAP-寻求行为：MAP的启动注射以及重新暴露于先前与MAP-摄取配对的光和音调（MAP相关线索）恢复了MAP-寻求行为。大麻素（CB）受体激动剂THC可增强MAP预注诱导的再灌注，CB 1受体拮抗剂SR 141716 A可拮抗MAP预注诱导的再灌注。此外，考克斯抑制剂双氯芬酸减弱MAP引发和线索诱导的恢复。此外，MAP诱导注射以及MAP相关线索诱导的恢复被MAP撤药期间重复注射THC所减弱。2）内源性CB受体配体2-AG含量的变化：MAP自身给药10 d后，大鼠全脑2-AG含量较未给药组明显增加。然而，在一天 ...更多信息 MAP停药5分钟后，2-AG含量呈下降趋势。[可卡因]再次暴露于可卡因相关线索恢复了可卡因寻求行为，SR 141716 A以及双氯芬酸减弱了恢复。CB 1受体激动剂HU 210也恢复可卡因寻求行为，双氯芬酸减弱了这种恢复。此外，在提示性可卡因觅药行为的表达过程中，可卡因自身给药大鼠中脑延髓背核内花生四烯酸级联反应（AAC）终产物前列腺素E_2（PGE_2）的含量增加，提示：（1）MAP/可卡因觅药行为是由脑内CB 1受体介导的AAC激活所致，2）BLA是MAP-seeking行为表达的底物之一。3）这些结果不仅揭示了药物依赖的表现机制，而且还暗示了各种精神障碍的部分原因是由于大脑奖赏系统的功能障碍。少

项目成果

Tsuneyuki Yamamoto, et al.: "Front lines of studies for analgesics -opioids (Association for the studies on pain -opioid peptides, ed.), Role of the brain endocannabinoid system on drug dependence."Elsevier Science. 166 (2002)

Tsuneyuki Yamamoto 等人：“镇痛药阿片类药物研究的前沿（疼痛阿片肽研究协会编辑），大脑内源性大麻素系统对药物依赖的作用。”爱思唯尔科学。

Kusnandar Anggadiredja, et al.: "Prostaglandin E2 attenuates SR141716A-precipitated withdrawal in tetrahydrocannabinol-dependent mice"Brain Res. 966. 47-43 (2003)

Kusnandar Anggadiredja 等人：“前列腺素 E2 可减弱四氢大麻酚依赖性小鼠中 SR141716A 引发的戒断”Brain Res。

Anggadiredja, K. et al.: "Prostaglandin E_2 attenuates SR141716A-precipitated withdrawal in tetrahydrocannabinol-dependent mice"Brain Res.. (in press). (2003)

Anggadiredja, K. 等人：“前列腺素 E_2 减弱四氢大麻酚依赖性小鼠中 SR141716A 诱发的戒断”Brain Res..（正在出版）。

Tsuneyuki Yamamoto, et al.: "Psychostimulat-induced psychosis and narcotic,dependeice (Kogen Sato, ed.) Section 2. How does narcotic dependence happen Subsection 1. Can animals also depend on psychostimulant and narcotic drugs?"Publication Division of Toh

Tsuneyuki Yamamoto 等人：“精神刺激物引起的精神病和麻醉品依赖（佐藤高源主编）第 2 节。麻醉品依赖性如何发生第 1 节：动物也可以依赖精神兴奋剂和麻醉药品吗？”Toh 出版部

山本経之, 他: ""大麻"受容体と"唐辛子"受容体"脳21. 6巻2号(in press). (2003)

Nobuyuki Yamamoto 等人：“大麻受体和辣椒受体”Brain 21。第 6 卷，第 2 期（印刷中）。