Mechanisms Of Action Of Lithium And Other Drugs In Bipol

锂和其他药物在 Bipol 中的作用机制

• 批准号: 6968662
• 负责人: Stanley I. Rapoport
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6968662
• 关键词: aging; arachidonate; biological signal transduction; bipolar depression; brain metabolism; fatty acids; laboratory rat; lithium; neurotransmitter antagonist; pharmacokinetics; phospholipids; psychopharmacology; serotonin receptor

1. Using our in vivo fatty acid method (AG000134-20 BPMS), we demonstrated that chronic lithium administration to rats enhanced brain cholinergic muscarinic receptor-mediated activation of PLA2, to release the second messenger, AA from membrane phospholipids. Such enhancement is consistent with lithium?s reported ability to reduce the convulsant threshold to cholinomimetics in rodents and the reported therapeutic efficacy of cholinomimetics in human bipolar disorder. 2. With our fatty acid method (AG000134-20 BPMS), we imaged serotonergic (5-HT) signal transduction involving arachidonic acid (AA) in awake rats. Acute administration of the 5-HT2A/2C receptor agonist, (+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), or of fluoxetine (Prozac, an antidepressant that increases 5-HT in the synaptic cleft), stimulated brain incorporation of intravenously-injected radiolabeled AA, a marker of phospholipase A2 (PLA2) activation. The effect was blocked by pre-administration of a 5-HT2A/2C receptor antagonist. These results are consistent with fluoxetine being effective in depression by increasing AA release from membrane phospholipids through the 5-HT2A/2C - mediated activation of PLA2.

1.使用我们的体内脂肪酸方法（AG 000134 -20 BPMS），我们证明了大鼠长期锂给药增强了脑胆碱能毒蕈碱受体介导的PLA 2活化，从而从膜磷脂中释放第二信使AA。这种增强与锂元素一致吗？的能力，以减少惊厥阈值拟胆碱类药物在啮齿动物和拟胆碱类药物在人类双相情感障碍的疗效报告。 2.用我们的脂肪酸方法（AG 000134 -20 BPMS），我们成像了清醒大鼠中涉及花生四烯酸（AA）的多巴胺能（5-HT）信号转导。急性给予5-HT 2A/2C受体激动剂，（±）-2，5-二甲氧基-4-碘苯基-2-氨基丙烷（DOI）或氟西汀（百忧解，一种增加突触间隙中5-HT的抗抑郁药），刺激静脉注射的放射性标记AA（磷脂酶A2（PLA 2）活化的标志物）的脑掺入。预先给予5-HT 2A/2C受体拮抗剂可阻断该作用。这些结果与氟西汀通过5-HT 2A/2C介导的PLA 2活化增加AA从膜磷脂释放而有效治疗抑郁症一致。