5-HT2A receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression

Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin 2A receptor (5-HT 2A ) 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 2A 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 2A receptor knockout (5-HT 2A −/− ) mice of both sexes. Methods: 5-HT 2A −/− 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. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT 2A −/− mice of both sexes. 5-HT 2A −/− female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT 2A −/− male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor ( Bdnf ), Egr2, Egr4 , FBJ osteosarcoma gene ( Fos ), FBJ murine osteosarcoma viral oncogene homolog B ( Fosb ), Fos-like antigen 2 ( Fosl2 ), Homer scaffolding protein ( Homer ) 1-3 ( Homer1-3 ), Jun proto-oncogene ( Jun )) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT 2A receptor deficiency. However, the loss of function of the 5-HT 2A 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.