INVOLVEMENT OF CORTICAL NEUROTENSIN IN THE REGULATION OF RAT MESO-CORTICO-LIMBIC DOPAMINE NEURONS - EVIDENCE FROM CHANGES IN THE NUMBER OF SPONTANEOUSLY ACTIVE A10 CELLS AFTER NEUROTENSIN RECEPTOR BLOCKADE

In order to further assess the role of endogenous neurotensin on midbr ain dopaminergic neuronal function, the effects of the selective neuro tensin 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 media ted through neurotensin receptor blockade. Five-week treatment with SR 48692 (3 mg/kg/day) produced a significant decrease of the number of active A101 but not A9 cells, which was reversed by apomorphine, sugge sting that these cells were under depolarization block. Single co-admi nistration 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 h aloperidol (1 and 0.25 mg/kg, respectively) induced an apomorphine-sen sitive decrease of the number of A10 active cells. Finally, SR 48692 ( 10 mg/kg) modified neither accumbal nor cortical basal DA release. Loc al 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 su ggest that neurotensin receptor blockade counteracts 0 a tonic inhibit ory regulation by endogenous neurotensin of mesolimbic dopaminergic fu nction and indicate that the prefrontal cortex is critically involved in this regulation. (C) 1997 Wiley-Liss, Inc.