DIFFERENTIAL-EFFECTS OF THE NONPEPTIDE NEUROTENSIN ANTAGONIST, SR-48692, ON THE PHARMACOLOGICAL EFFECTS OF NEUROTENSIN AGONISTS

In in vitro studies, SR 48692, a nonpeptide neurotensin receptor antagonist, inhibited the binding of [H-3] or [I-125]neurotensin to membrane preparations from 10-day-old mouse brains and from HT-29 cells with K-i values of 3.9 and 8.6 nM, respectively. SR 48692 also antagonized the neurotensin-induced mobilization of intracellular calcium in HT-29 cells, in agreement with previous findings. In rat cerebellar slices SR 48692 blocked the increase in cyclic GMP levels evoked by neurotensin in a dose-dependent manner. In vivo, SR 48692 antagonized the increase in rat brain mesolimbic dopamine turnover induced by the systemically active neurotensin peptide, EI[(N-Me)Arg-Lys-Pra-Trp-tert-Leu-Leu]. No effects on dopamine turnover of either EI or SR 48692 were observed in the striatum. SR 48692 did not antagonize the EI-induced decreases in mouse body temperature and spontaneous locomotor activity (LMA) or the decreases in LMA induced by ICV-administered neurotensin. Although other explanations are possible, these findings support the hypothesis that a subtype of the NT receptor may mediate the locomotor and hypothermic actions of this peptide and that it is different from the NT receptor that is involved in dopamine turnover.