In the present study, we examined the regulation of neurotensin receptor following a chronic pharmacological blockade of the neurotensin transmission with a nonpeptide neurotensin receptor antagonist, SR 48692. Our results showed that treatment of the rats for five days with SR 48692, at a dose of 1 mg/kg, i.p., induced an increase of both the number of binding sites for 125I-neurotensin to whole brain membrane homogenates and neurotensin receptor mRNA levels in the ventral mesencephalon. This study brings the first evidence for an in vivo up-regulation of neurotensin receptors following their pharmacological blockade, and suggests that endogenous neurotensin exerts a tonic inhibitory control on neurotensin receptor mRNA levels.