Anxiety-like behaviors and expression of SERT and TPH in the dorsal raphé of estrogen- and fluoxetine-treated ovariectomized rats.

The anxiolytic effect of fluoxetine (Flx) was often ineffective in postmenopausal and estrogen-deficient patients, but such effect had not been experimentally demonstrated, particularly in the female rat model of estrogen deficiency. Here we determined the anxiety-like behaviors in ovariectomized (Ovx) rats treated for 4weeks with 10μg/kg 17β-estradiol s.c. (Ovx+E2), 10mg/kg Flx p.o. (Ovx+Flx) or a combination of both (Ovx+E2+Flx). Since Flx is known to induce anxiolysis in males, we first evaluated the Flx regimen in male rats. The results showed that anxiety-like behaviors were reduced in Flx-treated male rats. In contrast, Ovx+Flx rats still exhibited the same anxiety-like behaviors as in Ovx rats. Both Ovx+E2 and Ovx+E2+Flx rats, however, showed comparable reductions in anxiety-like behaviors, suggesting that Flx had no anxiolytic-like effect. Furthermore, E2 and E2+Flx similarly upregulated the mRNA expression of serotonin reuptake transporter (SERT) and tryptophan hydroxylase-2 in the dorsal raphé of Ovx rats, while having no effect on SERT expression in the frontal cortex, hippocampus, septum, amygdala and periaqueductal gray. In conclusion, Flx induced anxiolytic-like action in male rats. In Ovx rats, it was E2 and not Flx that exerted the anxiolytic-like action, which was mediated, in part, by altering serotonin metabolism in the dorsal raphé.