European Neuropsychopharmacology 11 (2001) 41–50 www.elsevier.com / locate / euroneuro Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam a, a a a c b * ´ D. Bentue-Ferrer , J.M. Reymann , O. Tribut , H. Allain , E. Vasar , M. Bourin a ´ ´ ´ ´ Laboratoire de Pharmacologie Experimentale et Clinique, Faculte de Medecine,2 avenue du Pr Leon Bernard, 35043 Rennes Cedex, France b ´ ´ ´ Laboratoire de Pharmacologie, Faculte de Medecine, GIS Medicament,1 rue Gaston Veil, 44035 Nantes Cedex, France c Department of Physiology, University of Tartu, 18 Ravila Street, 50411 Tartu, Estonia Received 25 February 2000; received in revised form 8 September 2000; accepted 14 November 2000 Abstract Several recent studies have demonstrated that alprazolam and lorazepam, administered at low doses to healthy volunteers, improve cognitive functions and psychomotor performances. Paradoxical effects of low-dose benzodiazepines 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 benzodiazepines on spontaneous locomotor activity and performance in the elevated zero-maze, and to investigate the underlying neurobiological mechanisms. The dose-effect and the time-course of the action were studied for both compounds. Spontaneous locomotor activity was measured using a photoelectric actimeter. The level of anxiety of the animals was assessed in the elevated 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 alprazolam. The effect was maximum 90 min after administration of 0.0050 mg / kg alprazolam. 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 corresponding to the behavioral stimulatory effects. We also showed a marked trend towards increased levels of serotonin with alprazolam but this modification was not significant, in spite of statistically significant variations of 5-HIAA. In the rat, behavioral stimulatory effects of low-dose benzodiazepines is evidenced with alprazolam but not lorazepam. This effect could be explained, at least in part, by increased extracellular dopamine concentrations in the striatum. Their different structures could explain the different pattern observed for the two benzodiazepines.  2001 Published by Elsevier Science B.V. Keywords: Alprazolam; Lorazepam; Locomotor activity; Dopamine; Serotonin; Elevated zero-maze 1. Introduction metazepam (Deijen et al., 1991) or temazepam (Bourin et al., 1987) on motor control or memory and vigilance in Therapeutic doses of benzodiazepines induce well- healthy volunteers have also been described. known effects in humans: anxiolysis, sedation, myorelaxa- Paradoxical effects of low-dose benzodiazepines have tion, psychomotor impairment and anterograde amnesia. It been observed in experimental pharmacology models; in has also been demonstrated that acute or chronic adminis- the mouse, low-dose alprazolam increased spontaneous tration of low-dose alprazolam or lorazepam in healthy motor activity (Bourin et al., 1992) and locomotion in the ¨ volunteers produces significant improvement in cognitive open-field test (Lopez et al., 1988). According to Soder- functions and psychomotor performances (Bourin et al., palm et al. (1991), diazepam produces a biphasic dose 1994, 1995, 1998). Positive residual effects of lor- response with respect to locomotor activity with low doses increasing activity but higher doses producing a decrease. Similarly, with chlordiazepoxide, repeated doses have been *Corresponding author. Tel.: 133-299-33-6870; fax: 133-299-33- reported to enhance the stimulatory action of lower doses 6890. of the drug (Sansone, 1979). ´ ´ E-mail address: Daniele.Bentue-Ferrer@univ-rennes1.fr (D. Bentue- Ferrer). Different mechanisms of action have been put forward 0924-977X / 01 / $ – see front matter  2001 Published by Elsevier Science B.V. PII: S0924-977X(00)00137-1