Mechanisms Of Action Of Lithium And Other Drugs In Bipol

1.利用我们的体内脂肪酸法(AG000134-20BPMS)，我们证明了慢性锂对大鼠脑内胆碱能M受体介导的PLA2的激活有促进作用，从而使第二信使AA从膜磷脂中释放出来。这种增强与锂-S报告的能够降低啮齿动物对类胆碱能药的惊厥阈值以及已报道的类胆碱能药对人类双相情感障碍的治疗效果是一致的。 2.用我们的脂肪酸法(AG000134-20BPMS)，我们对清醒大鼠5-羟色胺能(5-HT)信号转导涉及花生四烯酸(AA)进行了成像。急性给予5-HT2A/2C受体激动剂(+-)-2，5-dimethoxy-4-iodophenyl-2-aminopropane(DOI)或氟西汀(百忧解，一种增加突触间隙中5-羟色胺的抗抑郁剂)，可刺激静脉注射的放射性标记AA(磷脂酶A2激活的标志)的脑内掺入。此作用可被预先给予5-HT2A/2C受体拮抗剂阻断。这些结果与氟西汀通过5-HT2A/2C介导的PLA2激活增加膜磷脂释放AA而有效地治疗抑郁症相一致。

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.