Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Psychopharmacology (Berl). 2013 Jun;227(3):503-8. doi: 10.1007/s00213-013-2969-0. Epub 2013 Jan 24.
Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization.
The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST).
The inhibitor was administered intracerebroventricularly in liposomes.
L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST.
It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.
在过去的 60 年里,锂一直是治疗双相情感障碍的标准药物治疗方法;然而,锂发挥治疗作用的分子靶点仍未确定。抑制肌醇单磷酸酶(IMPase)导致的磷脂酰肌醇信号转导通路衰减,被认为是锂诱导情绪稳定的可能机制之一。
本研究旨在研究鞘内给予特异性竞争性 IMPase 抑制剂 L-690,330 对匹鲁卡品诱导的癫痫发作模型和强迫游泳试验(FST)中小鼠行为的影响。
抑制剂以脂质体形式鞘内给药。
L-690,330 增加了对亚惊厥剂量匹鲁卡品的敏感性,并减少了 FST 中的不动时间。
锂在匹鲁卡品诱导的癫痫发作和 FST 中的行为效应可能是通过抑制 IMPase 介导的,但用鞘内肌醇逆转抑制剂的作用将是进一步证明的重要步骤。