Selective estrogen receptor modifiers on the antidepressant-like effects of electroconvulsive seizures in adolescent rats

During the past decade, our group has induced electroconvulsive seizures (ECS) in rodent models of early-life stress to prove clear differences in antidepressant-like efficacy mainly driven by sex and age, with females and adolescents showing diminished responses (as opposed to males and adult rodents). Moreover, we have proven a role for sex hormones in this response, since letrozole, an inhibitor of the biosynthesis of estrogens, improved the antidepressant-like efficacy of ECS in adolescent female rats. In this follow-up study, we utilized selective estrogen receptor modifiers (tamoxifen and clomiphene) to evaluate how they interact with the antidepressant-like response induced by ECS in male and female adolescent rats. Early-life stressed Sprague-Dawley rats through maternal separation were treated during adolescence with tamoxifen (1 mg/kg, 7 days) or clomiphene (10 mg/kg, 5 days) and/or with ECS (95 mA, 0.6 s, 100 Hz, 1 session/day, 5 days). Antidepressant-like responses were measured behaviorally under the stress of the forced-swim test, and through hippocampal markers (cell proliferation and neurogenic differentiation, and BDNF protein level). The main results proved that tamoxifen improved the expected antidepressant-like response of ECS in adolescent rats, as observed in the forced-swim test, while boosted hippocampal proliferation and neurogenic differentiation. Contrarily, clomiphene did not alter ECS' response at the behavioral level and even showed some negative signs on the neuroplasticity markers evaluated (decreased neurogenic differentiation and BDNF content). Therefore, when considering an estrogen receptor modifier to enhance the antidepressant-like potential of ECS in adolescence, tamoxifen emerges as a promising option due to its positive behavioral and neuroplastic effects.