NEUROTENSIN RECEPTOR INTERACTION WITH DOPAMINERGIC SYSTEMS IN THE GUINEA-PIG BRAIN SHOWN BY NEUROTENSIN RECEPTOR ANTAGONISTS

Neurotensin has been suggested to be involved in neurological and ment al disorders associated with altered dopaminergic transmission. The la ck of a potent neurotensin receptor antagonist had prevented us from s tudying the real physiological implication of this peptide in brain fu nction. We thus recently developed such a non-peptide neurotensin rece ptor antagonist, SR 48692, xphenyl)-1H-pyrazole-3-carbonyl)amino)-adam antane- acid), which appeared to be potent in various central and peri pheral preparations. In the present study, we tested the pharmacologic al properties of SR 48692 and of two optically synthetic analogs of th is compound on neurotensin binding to both adult guinea-pig brain memb rane homogenates and coronal brain sections, as well as on neurotensin stimulation of the K+-evoked release of [H-3]dopamine in guinea-pig s triatal slices. Our results demonstrated that (1) high-affinity neurot ensin binding sites are present in the guinea-pig brain in regions ric h in both dopamine cell bodies and terminals; (2) the binding of neuro tensin is inhibited by SR 48692 and its related S(+) active analog, SR 48527, with IC50 values in the nM range and (3) the non-peptide antag onist has no agonist effect but antagonizes neurotensin-induced [H-3]d opamine release from guinea-pig striatal nerve terminals.