RESUMEN
RATIONALE: Glibenclamide (GD) is a widely used medical drug; therefore, identifying the mechanisms underlying its pleiotropic effects in the central nervous system is urgent. OBJECTIVES: The aim of this work was to determine the ability of GD to modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) transmission and to assess the dose-dependent effect of GD on cognitive function in rats during natural ageing. METHODS: In Experiment 1, rats received 10, 25, or 50 µg/kg GD intraperitoneally for 10 days. In Experiment 2, rats received 50 µg/kg GD intraperitoneally for 30 days. Spatial and working memory was assessed in the MWM and Y-maze tests, respectively. In both experiments, the levels of DA and 5-HT, their metabolites, and turnover rate were analysed by HPLC-ED in the rat hippocampus and striatum. RESULTS: Changes in DA and 5-HT levels occurred only with a dose of 50 µg/kg GD. Therefore, in the second experiment, we administered a dose of 50 µg/kg GD. At this dose, GD prevented the development of impairments in spatial and working memory. The hippocampal concentrations of DA and DOPAC decreased, and the striatal concentrations of DA, DOPAC, 5-HT, and 5-HIAA increased. CONCLUSION: One of the possible mechanisms of the precognitive effect of GD is its ability to modulate monoamine transmission. Thus, in translating our results to humans, GD can be recommended as a prophylactic agent for natural ageing to reduce the risk of developing cognitive impairments.