Estrogen decreases 5-HT1B autoreceptor mRNA in selective subregion of rat dorsal raphe nucleus: Inverse association between gene expression and anxiety behavior in the open field

We have recently shown that estrogen decreases anxiety and increases expression of tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme for 5-HT synthesis. However, the effects of estrogen on 5-HT release and reuptake may also affect the overall availability of 5-HT in the forebrain. Estrogen has been previously shown to have no effect on the inhibitory 5-HT 1A autoreceptor (5-HT1A) in the rat dorsal raphe nuclei (DRN); however the regulation of the inhibitory 5-HT 1B autoreceptor (5-HT1B) in the midbrain raphe by estrogen has not yet been investigated. Therefore, we examined the effects of estrogen on 5-HT1B mRNA in the rat DRN, focusing on specific subregions, and whether 5-HT1B mRNA levels correlated with TPH2 mRNA levels and with anxiety-like behavior. Ovariectomized rats were treated for 2 weeks with estrogen or placebo, exposed to the open field test, and 5-HT1A and 5-HT1B mRNA was quantified by in situ hybridization histochemistry. Estrogen had no effect on 5HT1A mRNA in any of the DRN subregions examined, confirming a previous report. In contrast, estrogen selectively decreased 5-HT1B mRNA in the mid-ventromedial subregion of the DRN, where 5-HT1B mRNA was associated with higher anxiety-like behavior and inversely correlated with TPH2 mRNA levels. These results suggest that estrogen may reduce 5-HT1B autoreceptor and increase TPH2 synthesis in a coordinated fashion, thereby increasing the capacity for 5-HT synthesis and release in distinct forebrain regions that modulate specific components of anxiety behavior.