Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol

Neurotensin (NT) is a neuropeptide neurotransmitter in the central nervous system. It has been implicated in the therapeutic and in the adverse effect s of neuroleptics. Activity of NT in brain can only be shown by direct inje ction of the peptide into that organ. However, we have developed a novel an alog of NT(8-13), NT69L, which is active upon intraperitoneal (i.p.) inject ion. Like atypical neuroleptics, NT69L blocked the climbing behavior in rat s, but not the licking and sniffing behaviors of a high close (600 mu g/kg) of the non-selective dopamine agonist apomorphine. Its blockade of climbin g was very potent with an ED50 (effective dose at 50% of maximum) of 16 mu g/kg. Both apomorphine and NT69L caused a long-lasting hypothermia, which w as greater with the peptide bur nor synergistic in combination with apomorp hine. The ED,, of NT69L for hypothermia was 390 mu g/kg. NT69L (up to 5 mg/ kg i.p.) did nut produce catalepsy. However, when given before haloperidol, NT69L, but not clozapine, completely prevented catalepsy. When given after haloperidol, NT69L, but not clozapine, reversed haloperidol's cataleptic e ffects with an ED50 of 260 mu g/kg. There was no significant difference bet ween the ED(50)s for hypothermia and anticataleptic effects of NT69L. Howev er, the ED50 for blocking the effects of apomorphine was significantly lowe r than the other two. These data suggest that NT69L may have neuroleptic pr operties in humans and may be useful in the treatment of extrapyramidal sid e effects caused by typical neuroleptics such as haloperidol. (C) 2000 Else vier Science B.V. All rights reserved.