The antidepressant-like effect of ethynyl estradiol is mediated by both serotonergic and noradrenergic systems in the forced swimming test.

Abstract 17α-Ethynyl-estradiol (EE 2 , a synthetic steroidal estrogen) induces antidepressant-like effects in the forced swimming test (FST) similar to those induced by 5-HT and noradrenaline reuptake inhibitors (dual antidepressants). However, the precise mechanism of action of EE 2 has not been studied. In the present study, the participation of estrogen receptors (ERs) and the serotonergic and the noradrenergic presynaptic sites in the antidepressant-like action of EE 2 was evaluated in the FST. The effects of the ER antagonist ICI 182,780 (10 μg/rat; i.c.v.), the serotonergic and noradrenergic terminal destruction with 5,7-dihydroxytryptamine (5,7-DHT; 200 μg/rat, i.c.v.), and N-(2-chloro-ethyl)-N-ethyl-2-bromobenzylamine (DSP 4 ; 10 mg/kg, i.p.) were studied in ovariectomized rats treated with EE 2 and subjected to the FST. In addition, the participation of α 2 -adrenergic receptors in the antidepressant-like action of EE 2 was explored using the selective α 2 -receptor antagonist idazoxan (0.25, 0.5 and 1.0 mg/kg, i.p.). EE 2 induced an antidepressant-like action characterized by a decrease in immobility behavior with a concomitant increase in swimming and climbing behaviors. The ER antagonist, 5,7-DHT, DSP 4 , and idazoxan blocked the effects of EE 2 on the immobility behavior, whereas ICI 182,780 and 5,7-DHT affected swimming behavior. The noradrenergic compound DSP 4 altered climbing behavior, while Idazoxan inhibited the increase of swimming and climbing behaviors induced by EE 2 . Our results suggest that the antidepressant-like action of EE 2 implies a complex mechanism of action on monoaminergic systems and estrogen receptors.