Sensorimotor gating in NTS1 and NTS2 null mice: Effects of d-amphetamine, dizocilpine, clozapine and NT69L

Alfredo Oliveros, Michael G. Heckman, Maria Del Pilar Corena-McLeod, Katrina Williams, Mona Boules, Elliott Richelson

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Pre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10mgkg-1) and dizocilpine (1mgkg-1). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1-/-) and NTS2 (NTS2-/-) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2-/- mice but not in NTS1-/- mice. In WT mice, clozapine (1mgkg-1) and NT69L (1mgkg-1) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2-/- mice clozapine blocked d-amphetamine- but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.

Original languageEnglish (US)
Pages (from-to)4232-4239
Number of pages8
JournalJournal of Experimental Biology
Volume213
Issue number24
DOIs
StatePublished - Dec 2010

Keywords

  • Clozapine
  • D-amphetamine
  • Dopamine
  • NT69L
  • NTS1
  • NTS2
  • Neurotensin
  • Pre-pulse inhibition
  • Schizophrenia

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Physiology
  • Aquatic Science
  • Animal Science and Zoology
  • Molecular Biology
  • Insect Science

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