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

Mona Boules, Beth McMahon, Lewis Warrington, Jennifer Stewart, Joshua Jackson, Abdul Fauq, Daniel McCormick, Elliott Richelson

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Neurotensin (NT) is a tridecapeptide neurotransmitter in the central nervous 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 degradation 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 behavior in rats induced by the dopamine agonist apomorphine (600 μg/kg) with an ED50 of 5.6 mg/kg (i.p.), without affecting the licking and the sniffing behaviors. By itself NT77L did not cause catalepsy, but it moderately reversed haloperidol-induced catalepsy with an ED50 of 6.0 mg/kg (i.p.). Haloperidol alone did not lower body temperature, but it potentiated the body temperature lowering effect of NT77L. In studies using in vivo microdialysis NT77L showed similar effects on dopamine turnover to those of clozapine, and significantly different from those of haloperidol in the striatum. In the prefrontal cortex, NT77L significantly increased serotonergic transmission as evidenced by increased 5-hydroxyindole acetic acid:5-hydroxytryptamine (5-HIAA:5-HT) ratio. Thus, NT77L selectively caused hypothermia, over antinociception, while exhibiting atypical neuroleptic-like effects.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalBrain Research
Volume919
Issue number1
DOIs
StatePublished - Nov 16 2001

Keywords

  • Atypical neuroleptic
  • Catalepsy
  • Microdialysis
  • Neurotensin receptor
  • Subtype

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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