SR-48692, A NONPEPTIDE NEUROTENSIN RECEPTOR ANTAGONIST DIFFERENTIALLYAFFECTS NEUROTENSIN-INDUCED BEHAVIOR AND CHANGES IN DOPAMINERGIC TRANSMISSION

Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 mu g/0.5 mu l) produced behavioural excitation illust rated by contralateral circling. Given orally, SR 48692, a selective a nd potent non-peptide neurotensin receptor antagonist, significantly r educed these rotations with a triphasic dose-effect relationship. Inhi bition occurred at 0.12mg/kg; further increases in dose up to 2.5 mg/k g produced no significant antagonism, then at doses greater than or eq ual to 5 mg/kg, a second phase of antagonism was observed. Bilateral i njection of neurotensin (0.5 mu g each side) into the nucleus accumben s antagonized the increase in locomotor activity following intraperito neal injection of amphetamine. Given orally, SR 48692 reduced dose-dep endently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Usin g high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the vent ral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between n eurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR, 48692 to affect neurotensin-evoked behavio ural versus biochemical changes supports the concept of neurotensin re ceptor heterogeneity.