Gould Todd D, Einat Haim, Bhat Ratan, Manji Husseini K
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-3711, USA.
Int J Neuropsychopharmacol. 2004 Dec;7(4):387-90. doi: 10.1017/S1461145704004535. Epub 2004 Jul 26.
The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect is supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity. Taken together, these data support the hypothesis that lithium may exert its antidepressant effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may be useful for the treatment of bipolar disorder and depression.
锂发挥其抗躁狂或抗抑郁作用的机制仍有待充分阐明。尽管锂在与双相情感障碍治疗相关的浓度下可抑制糖原合酶激酶-3（GSK-3），但尚不清楚与GSK-3相关的机制是否是其治疗该疾病的疗效原因。我们报告称，AR-A014418（一种选择性GSK-3抑制剂）可诱导与抗抑郁药物作用一致的行为变化。亚急性腹腔注射AR-A014418可减少暴露于强迫游泳试验中的大鼠的不动时间，强迫游泳试验是一种确立的抗抑郁疗效模型。此外，我们发现AR-A014418可降低自发活动以及苯丙胺诱导的活动，这支持了该效应的特异性。综上所述，这些数据支持以下假设：锂可能通过抑制GSK-3发挥其抗抑郁作用，新型小分子GSK-3抑制剂可能对双相情感障碍和抑郁症的治疗有用。
