COMPARATIVE ANTIPSYCHOTIC PROFILES OF NEUROTENSIN AND A RELATED SYSTEMICALLY ACTIVE PEPTIDE AGONIST

Several lines of evidence have shown that neurotensin can modulate dop amine neurotransmission. It has been suggested that neurotensin has po tential antipsychotic activity because it reduces dopaminergic activit y preferentially in the nucleus accumbens. In the present study, the e ffects of neurotensin and NT1 ((NMe)-Me-alpha-Arg-Lys-Pro-Trp-Tle-Leu or Eisai hexapeptide), a metabolically stable and systemically active neurotensin agonist, were examined in several models of antipsychotic activity and side effect liability in mice; analgesic and hypothermic effects of both compounds also were determined. Up to high doses, neur otensin (5.0 and 10.1 mu g, ICV) and NT1 (10.0 and 20.0 mg/kg, IP) did not produce catalepsy. A much lower dose of neurotensin (0.03 mu g, I CV) significantly reduced amphetamine-and phencyclidine-stimulated loc omotor activity; NTI also diminished amphetamine-and phencyclidine-sti mulated locomotion with ED50 values of 0.3 and 0.4 mg/kg, IP, respecti vely. Neurotensin (0.01-0.3 mu g, ICV) and NTI (0.1-1.0 mg/kg, SC) als o produced dose-dependent analgesia in the paw pressure test and decre ased body temperature; these effects were insensitive to pretreatment with naloxone (10.0 mg/kg, IF). Together, the results support the hypo thesis that neurotensin agonists have antipsychotic and analgesic acti vity. Moreover, the data suggest that such compounds may not produce e xtrapyramidal side effects. (C) 1997 Elsevier Science Inc.