Subchronic oral administration of Tamoxifen in hormonally intact female rats induces dose-dependent maladaptive behavioral phenotypes

Tamoxifen (TAM), the gold standard treatment for hormone-responsive breast cancer, is the most widely used Selective Estrogen Receptor Modulator (SERM). Based on the premise that subchronic oral administration of TAM may induce neurotoxic effects, we hypothesize that TAM triggers maladaptive behavior in intact female Wistar rats. The contribution of hippocampal apoptosis, inflammation, and of the hypothalamic-pituitary-adrenal (HPA) axis parameters to the maladaptive behavior was also investigated. Intact female rats (60-day-old) were treated intragastrically with TAM (0.25 and 2.5 mg/kg) for 59 days. Behavioral tests were conducted from day 120 to 125, after which the rats were euthanized. Different phenotypic manifestations of maladaptive behavior were observed in female rats treated with TAM. Psychomotor agitation and anxiety-like behavior appeared only in those receiving the lowest TAM dose. In contrast, anhedonia was observed only in female rats treated with the highest TAM dose. Behaviors, such as despair, apathy, and thigmotaxis were observed in female rats treated with both TAM doses. In ex vivo analysis, inflammatory markers in hippocampus of hormonally intact female rats were found to vary depending on the TAM dose. While the relative weight of the uterus decreased in TAM-exposed rats, only the highest TAM dose increased plasma corticosterone and hippocampal glucocorticoid receptor levels. Only the lowest TAM dose increased hippocampal p75NTR and Bax levels and decreased Bcl2, apoptosis markers. Summarizing, TAM subchronic oral administration, dependent on the dose, induced maladaptive behavior in intact female rats, which were associated with the hippocampal modulation of apoptosis, HPA axis markers, and inflammation.