Neurotensin analog selective for hypothermia over antinociception and exhibiting atypical neuroleptic-like properties

Neurotensin (NT) is a tridecapeptide neurotransmitter in the central nervou s system. It has been implicated in the therapeutic effects of neuroleptics . Central activity of NT can only be demonstrated by direct injection into the brain, since it is readily degraded by peptidases in the periphery. We have developed many NT(8-13) analogs that are resistant to peptidase degrad ation and can cross the blood-brain barrier (BBB). In this study, we report on one of these analogs, NT77L. NT77L induced hypothermia (ED50=6.5 mg/kg, i.p.) but induced analgesia only at the highest dose examined (20 mg/kg, i .p.). Like the atypical neuroleptic clozapine, NT77L blocked the climbing b ehavior in rats induced by the dopamine agonist apomorphine (600 mug/kg) wi th an ED50 of 5.6 mg/kg (i.p.), without affecting the licking and the sniff ing behaviors. By itself NT77L did not cause catalepsy, but it moderately r eversed haloperidol-induced catalepsy with an ED50 of 6.0 mg/kg (i.p.). Hal operidol alone did not lower body temperature, but it potentiated the body temperature lowering effect of NT77L, In studies using in vivo microdialysi s NT77L showed similar effects on dopamine turnover to those of clozapine, and significantly different from those of haloperidol in the striatum. In t he prefrontal. cortex, NT77L significantly increased serotonergic transmiss ion as evidenced by increased 5-hydroxyindole acetic acid:5-hydroxytryptami ne (5-HIAA:5-HT) ratio. Thus, NT77L selectively caused hypothermia, over an tinociception, while exhibiting atypical neuroleptic-like effects. (C) 2001 Elsevier Science B.V. All rights reserved.