Neurotensin is one of the genes previously found up-regulated in mice striatum after acute injection of MDMA (9 mg/kg). In order to examine the pharmacological significance of this effect, the involvement of the neurotensinergic system in MDMA-induced behaviors was explored in mice using the neurotensin receptor antagonist SR142948A (1 mg/kg). We found that acute administration of the antagonist inhibited the MDMA-elicited locomotor activity. SR142948A pre-treatment had no effect on the acquisition of conditioned place preference (CPP) to MDMA but abolished the expression of this behavior. We also studied the effects of acute and repeated exposure to MDMA on the mRNA level of neurotensin in mice striatum. Kinetic analysis of the regulation 1, 2, 6 and 12 h after acute injection of MDMA showed that the drug transiently up-regulates neurotensin mRNA in this structure. The time course of the modulation suggests that the effects observed with SR142948A are attributable to the release of a preexisting endogenous pool rather than the newly synthesized peptide. Repeated exposure to MDMA following the same injection pattern used in the CPP paradigm revealed an increase in mRNA level of neurotensin in mice striatum. These results indicate that endogenous neurotensin plays a role in both the acute locomotor activity and the expression of CPP induced by MDMA.