Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam

Several recent studies have demonstrated that alprazolam and lorazepam, adm inistered at low doses to healthy volunteers, improve cognitive functions a nd psychomotor performances. Paradoxical effects of low-dose benzodiazepine s have been also observed in mice, in experimental pharmacology. The aim of this work was to determine, in rat, the effect of similar low-doses of ben zodiazepines on spontaneous locomotor activity and performance in the eleva ted zero-maze, and to investigate the underlying neurobiological mechanisms . The dose-effect and the time-course of the action were studied for both c ompounds. Spontaneous locomotor activity was measured using a photoelectric actimeter. The level of anxiety of the animals was assessed in the elevate d zero-maze. Dopamine, serotonin, and their metabolites were assayed in the extracellular striatal fluid of the awake rat, obtained by microdialysis, by HPLC-EC. Spontaneous locomotor activity observed in rats given low-dose alprazolam and lorazepam evidenced a stimulatory effect only with alprazola m. The effect was maximum 90 min after administration of 0.0050 mg/kg alpra zolam. An anxiogenic-like action was evidenced with the elevated zero-maze for the two compounds. We observed a statistically significant increase in striatal dopamine concentrations only with alprazolam, during the period co rresponding to the behavioral stimulatory effects. We also showed a marked trend towards increased levels of serotonin with alprazolam but this modifi cation was not significant, in spite of statistically significant variation s of 5-HIAA. In the rat, behavioral stimulatory effects of low-dose benzodi azepines is evidenced with alprazolam but not lorazepam. This effect could be explained, at least in part, by increased extracellular dopamine concent rations in the striatum. Their different structures could explain the diffe rent pattern observed for the two benzodiazepines. (C) 2001 Published by El sevier Science B.V.