Neuroprotective effects of aripiprazole in stress-induced depressive-like behavior: Possible role of CACNA1C

Background: Depression is the most common psychiatric disorder. Recently, aripiprazole, a novel antipsychotic drug, has been approved as the adjunctive therapy for the Treatment-Resistant Depression (TRD). However, the mechanisms underlying the antidepressant effects of aripiprazole are not fully known. Besides the involvement of calcium signaling dysregulations in the pathophysiology of depression, there is some evidence of overexpressed CACNA1C (the gene encoding the Cav1.2 channels) following chronic stress in the brain regions, which involved in emotional and stress responses. Based on the data indicating the aripiprazole's effects on intracellular calcium levels, this study aimed to investigate the mechanisms of therapeutic effects of aripiprazole, by a focus on the modulation of CACNA1C expression, in the rat stress-induced model of depression.

Methods: Using Chronic Unpredictable Mild Stress (CUMS) model of depression, we examined the effects of aripiprazole on depressive and anxiety-like behaviors (by forced swimming test and elevated plus maze), serum IL-6 (Elisa), and cell survival (Nissl staining). In addition, CACNA1C, BDNF, and TrkB expression in the PFC and hippocampus (RT-qPCR), as well as BDNF and GAP-43 protein levels in the hippocampus (Immunohistofluorescence), have been assayed.

Results: Our data indicated that aripiprazole could improve anxiety and depressive-like behaviors, decrease the serum levels of IL-6 and hippocampal cell death following CUMS. In addition, we showed the significant modulation on overexpressed CACNA1C, as well as downregulated BDNF and GAP-43 expression DISCUSSION: These results demonstrate that aripiprazole may promote synaptic plasticity by improving the expression of BDNF and gap-43. In addition, inflammation reduction and CACNA1C expression downregulation may be some of mechanisms by which aripiprazole alleviates chronic stress-induced hippocampal cell death and play its pivotal antidepressant role.