Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L.
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 (10 mg kg(-1)) and dizocilpine (1 mg kg(-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 (1 mg kg(-1)) and NT69L (1 mg kg(-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.
Neuropsychopharmacology Laboratory, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
Alfredo
A
Oliveros
Michael G
MG
Heckman
Maria
M
Del Pilar Corena-McLeod
Katrina
K
Williams
Mona
M
Boules
Elliott
E
Richelson
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D017353:Gene Deletion; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000502:physiology; D009496:Neurotensin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics*; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics*
D014150:Antipsychotic Agents; C490984:Ntsr2 protein, mouse; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C407426:neurotensin 69L; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D016291:Dizocilpine Maleate; D003024:Clozapine; D003913:Dextroamphetamine