Neurosteroid dehydroepiandrosterone improves active avoidance retrieval and induces antidepressant-like behavior in rats

Various studies reported beneficial effects of dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), the neurosteroids involved in various brain functions, on synaptic plasticity, neuronal survival, memory, learning and behavior. This study aimed to investigate the behavioral profile of acute DHEA treatment by using active avoidance (AA) task, primarily predictive of the effects on the retrieval-based learning, and by applying forced swim test (FST), for assessment of antidepressant-like potential. Adult male Wistar rats received intraperitoneal injections of either DHEA (2, 10, 20 mg/kg) or solvent, 30 min prior to testing. DHEA, in a manner resembling an inverted U shape, influenced the retrieval imposed to rats in AA paradigm. The significant improvement of the performance in the retention session was observed following 10 mg/kg DHEA treatment and it was not due to the changes in the motor activity, as indicated by unaltered locomotor parameters (inter-trial crossing). Moreover, 10 mg/kg of DHEA significantly decreased the duration of immobility in FST, demonstrating antidepressant-like effects. The capability of bicuculline (2 mg/kg) to antagonize the effects of DHEA has been evaluated simultaneously. The retrieval-facilitating as well as antidepressant-like effects of 10 mg/kg DHEA were counteracted by bicuculline, a competitive antagonist of GABAA receptors, suggesting involvement of GABAergic system. These results support administration of DHEA as potential therapeutic strategy for treating depression and related cognitive impairments, but emphasized the importance of adequate dosing, as DHEA levels that are too high or too low may not be beneficial.