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RGS4 as a regulator of the antidepressant effects of SSRIs

Previously, we showed that RGS‐insensitive Gαi2G184S (Gαi2GS) mice exhibit basal and serotonin‐dependent antidepressant (AD) phenotypes. Here we show that acute (3‐day) administration of the serotonin selective reuptake inhibitor (SSRI) fluoxetine (FLX) produced AD‐like responses in Gαi2GS mice in the novelty‐induced hypophagia test, which requires chronic (21‐day) FLX to produce AD effects in wild‐type (WT) animals. In contrast, acute desipramine, a norepinephrine‐based antidepressant, had no effect. The AD efficacy of FLX in acutely treated Gαi2GS mice was twice that of chronically treated WT littermates. Also, Gαi2GS mice exhibited basal and selective 4‐fold upregulation of cortical RGS4 vs. WT mice. mRNA expression of eleven RGS proteins in the cortex and hippocampus by RT‐PCR showed chronic FLX selectively upregulated cortical RGS4 in WT mice. Notably, vehicle‐treated Gαi2GS mice showed similar regional and RGS‐selective upregulation of cortical RGS4 mRNA and protein. These are the first studies of which we are aware to show altered expression of RGS proteins in response to SSRIs. Overall, these data suggest RGS insensitivity improves the efficacy and onset of action of SSRIs in animal models of mood. Moreover, upregulation of cortical RGS4 may contribute to the AD phenotype of Gαi2GS animals and to the therapeutic effects of SSRIs. Supported by DA04087 and the Bower Bennett Bennett Endowment.