RGS4 Differentially Regulates Antidepressant and Locomotor Behaviors In Vivo

Abstract

Evidence suggests the antidepressant actions of serotonin (5‐HT) are modulated by regulators of G protein signaling (RGS) proteins. Specifically, we have shown that upregulation of cortical RGS4 (mRNA and protein) occurs in response to genetic disruption of RGS protein activity at the GTP‐binding protein Gαi2 and following chronic administration of serotonin‐selective reuptake inhibitors (SSRIs). Genetic deletion of RGS4 (RGS4(‐/‐)) had no effect on basal antidepressant‐like behaviors or generalized locomotor activity. However, RGS4(‐/‐) mice exhibited decreased antidepressant‐like responses to the SSRI fluoxetine, whereas desipramine, a selective inhibitor of norepinephrine reuptake, was fully efficacious. Conversely, the regulation of locomotor activity by desipramine was augmented in RGS4(‐/‐) animals relative to vehicle‐treated controls. RGS4 expression had no effect on locomotor activity following fluoxetine administration. Overall, these data suggest altered expression of RGS4 differentially influence antidepressant‐like behaviors in animal models of mood and potentially the therapeutic effects of SSRIs and are consistent with studies showing RGS4 positively regulates the efficacy of serotonin‐mediated antidepressants.