In order to further assess the role of endogenous neurotensin on midbrain dopaminergic neuronal function, the effects of the selective neurotensin receptor antagonists SR 48692 and SR 48527 were investigated on the number of spontaneously active A9 and A10 dopaminergic neurons in rats. Single intraperitoneal administration of SR 48692 (0.1-3 mg/kg) dose-dependently increased the number of active A10, but not A9 cells. SR 48527 (1 mg/kg) had a similar profile, but not SR 49711, its low affinity R-enantiomer, indicating that the effects observed were mediated through neurotensin receptor blockade. Five-week treatment with SR 48692 (3 mg/kg/day) produced a significant decrease of the number of active A10, but not A9 cells, which was reversed by apomorphine, suggesting that these cells were under depolarization block. Single co-administration of inactive doses of SR 48692 (0.1 mg/kg) and haloperidol (0.0625 mg/kg) significantly increased the number of active A10 cells. Conversely, co-administered active doses of SR 48692 or SR 48527 and haloperidol (1 and 0.25 mg/kg, respectively) induced an apomorphine-sensitive decrease of the number of A10 active cells. Finally, SR 48692 (10 mg/kg) modified neither accumbal nor cortical basal DA release. Local micro-injection of SR 48692 (10[-11]-10[-9] M), but not that of SR 49711 (10[-9] M), into the prefrontal cortex, increased the number of active A10 cells in a concentration-dependent manner. These results suggest that neurotensin receptor blockade counteracts a tonic inhibitory regulation by endogenous neurotensin of mesolimbic dopaminergic function and indicate that the prefrontal cortex is critically involved in this regulation.