AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test
AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test
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DOI：
10.1017/s1461145704004535
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发表时间：
2004-12-01
影响因子：
4.8
通讯作者：
Manji, HK
中科院分区：
文献类型：
--
作者：
Gould, TD;Einat, H;Manji, HK
锂发挥其抗躁狂或抗抑郁作用的机制仍有待充分阐明。尽管锂在与治疗双相情感障碍相关的浓度下抑制糖原合成酶激酶-3（GSK-3），但尚不清楚GSK-3相关机制是否是其治疗该疾病的治疗作用的原因。我们报告说，AR-A014418（一种选择性GSK-3抑制剂）诱导的行为变化与抗抑郁药物的作用一致。亚急性腹膜内注射AR-A014418减少了暴露于强迫游泳试验的大鼠的不动时间，强迫游泳试验是一种良好的抗抑郁疗效模型。此外，我们发现AR-A014418降低自发活动和安非他明诱导的活动，这也支持了这种作用的特异性。总之，这些数据支持锂可能通过抑制GSK-3发挥其抗抑郁作用的假设，并且新型小分子GSK-3抑制剂可能用于治疗双相情感障碍和抑郁症。
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.