Figure 5. In vivo assessment of 5-HT1A and 5-HT2 post-synaptic receptor function using 8-OH-DPAT-induced change of corticosterone levels and DOI-induced head-twitches. Compared to paired-saline injected animals, administration of the 5-HT1A agonist 8-OH- DPAT (0.3 mg/kg, s.c.) significantly increased corticosterone levels in both (A) male and (B) female mice, regardless of the genotype. In the DOI- induced head-twitches experiment (bottom panel), there was a significant effect of genotype in both sexes. Indeed, the number of head-twitches following DOI (1 mg/kg) were decreased in (C) HD male and (D) HD female mice when compared to WT animals. Values represent means (6 SEM) of n = 5–10 mice per group. Saline vs. DPAT0.3: (+) p,0.05, (++) p,0.01, (+++) p,0.001 WT vs. HD: (*) p,0.05, (**) p,0.01, (***) p,0.001. doi:10.1371/journal.pone.0022133.g005 Sertraline decreased FST/TST immobility times of female HD mice to the same extent as WT controls. A similar antidepressant effect seemed to occur in male animals exposed to TST in which both genotypes responded to the drug. In contrast, but consistent with previous findings at 12 weeks of age [27], acute sertraline elicited an antidepressant-like effect in WT but not HD male mice in FST, once again suggesting distinct pathways for response to FST versus TST. Sex-differences in response to sertraline have been described in chronic depression, with women being more likely to show a favorable response to SSRIs compared to men [45]. Several targets have been proposed in mediating the antidepressant-like effect of acute sertraline [46,47,48] and it would be too simplistic to draw conclusions based on the correlation between immobility times in FST and 5-HTT mRNA levels within a unique brain region. Indeed, we found that WT females had lower 5-HTT mRNA levels than WT males in the raphe but still responded to acute sertraline (however we previously reported no sex differences for hippocampal and cortical 5-HTT expression, [27]). All together our findings suggest that lower 5-HTT gene expression may be associated with vulnerability to depression in female mice but could have opposite effects on male animals. Similarly women and men carrying the less transcriptionally efficient 5-HTTLPR short allele display opposite responses to environmental stress factors, suggesting that the molecular mechanisms underlying depression may differ between sexes [8,10–11]. Another present finding which helps explain the female-specific depression-related behaviors, is the enhanced hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT in female but not in male HD mice. The desensitization of the 5-HT1A autoreceptor localized in the dorsal raphe nucleus (DRN) is essential for enhancement of 5-HT transmission following chronic SSRI treatment [21,49] and sex differences in the adaptive regulation of the 5-HT1A receptor-mediated responses have been previously observed in mice [50,51,52]. In mice, 8-OH-DPAT- induced hypothermia seems to be mediated by somato-dendritic 5- HT1A autoreceptors [35]. However some data suggest that the model may be more complex [36,37] and that other receptor(s) and/or region(s) might be involved. In that regard change in mRNA levels was not consistent with the increased response to 5- HT1A agonist we observed in female HD mice, however 5-HT1A receptor protein or binding was not examined in this present study and may not have necessarily changed in the same direction as the mRNA levels. Additional experiments (e.g. GTPgammaS or electrophysiology) would be required to assess the 5-HT1A autoreceptor function specifically in the raphe. PLoS ONE | www.plosone.org 5 July 2011 | Volume 6 | Issue 7 | e22133