Abstract
We have shown previously that chronic administration of adrenocorticotropic hormone (ACTH) causes a significant decrease in hippocampal cell proliferation and neurogenesis. This effect in rats treated chronically with ACTH was not influenced by the chronic administration of imipramine, but was reversed by coadministration of imipramine and lithium. The present study was undertaken to further characterize the mechanism underlying the effect of imipramine and lithium on hippocampal cell proliferation and neurogenesis, by investigating the effects of treatment on the expression of brain-derived neurotrophic factor (BDNF), total cyclic adenosine monophosphate response element-binding protein (CREB), and phosphorylated CREB (pCREB) of the CREB signaling system, as well as Wnt 3a and cyclin D1 of the Wnt signaling pathway in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1. Treatment with imipramine and lithium increased the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF, CREB, pCREB, and Wnt 3a did not change in either saline-treated or ACTH-treated rats. These findings suggest that the antidepressant effect of imipramine and lithium in ACTH-treatment-resistant rats may be attributed, at least in part, to an enhancement of cyclin D1 expression.
Highlights
We already reported that the effect of tricyclic antidepressants to decrease immobility is blocked by repeated adrenocorticotropic hormone (ACTH) treatment in the forced swim test, a behavioral test widely used as a predictor of antidepressant activity [1]
We examined the effect of treatment with imipramine and lithium on the expressions of brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element-binding protein (CREB), and Wnt 3a, a strong nuclear signal for cyclin D1 transcription, to elucidate the involvement of CREB-BDNF and Wnt/β-catenin signaling in hippocampal cell proliferation in ACTH-treated rats
Western blotting was performed to examine whether concomitant treatment with imipramine and lithium changes the expression of CREB and phosphorylated CREB (pCREB) in the hippocampus
Summary
We already reported that the effect of tricyclic antidepressants to decrease immobility is blocked by repeated adrenocorticotropic hormone (ACTH) treatment in the forced swim test, a behavioral test widely used as a predictor of antidepressant activity [1]. The chronic administration of ACTH (100 μg/rat subcutaneously for 14 days) was found to significantly decrease the number of 5-bromo-2’-deoxyuridine and Ki-67 (an endogenous marker of cell proliferation)—positive cells compared with control values in the subgranular zone (SGZ) of the hippocampal dentate gyrus [8] [9]. This effect of ACTH treatment was not influenced by the chronic administration of imipramine, but was reversed by the coadministration of imipramine and lithium for 14 days [9]. These results suggest that imipramine and lithium improve the efficacy of treatment for resistant depression by triggering cell proliferation
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