5-HT receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression.

Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin receptor (5-HT) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT receptor knockout (5-HT ) mice of both sexes. 5-HT and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT mice of both sexes. 5-HT female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (), , FBJ osteosarcoma gene (), FBJ murine osteosarcoma viral oncogene homolog B (), Fos-like antigen 2 (), Homer scaffolding protein () 1-3 (), Jun proto-oncogene ()) in the PFC. Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT receptor deficiency. However, the loss of function of the 5-HT receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.