Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: relevance to schizophrenia.

Abstract

Much evidence suggests that targeting the neurotensin (NT) system may provide a novel and promising treatment for schizophrenia. Our recent work shows that: NTS1 knockout (NTS1(-/-)) mice may provide a potential animal model for studying schizophrenia by investigating the effect of deletion NTS1 receptor on amphetamine-induced hyperactivity and neurochemical changes. The data indicate a hyper-dopaminergic state similar to the excessive striatal DA activity reported in schizophrenia. The present study was done to determine if NTS1(-/-) mice also have similar changes in behavior, in prefrontal neurotransmitters, and in protein expression, as observed in wild type (WT) mice treated with the psychotomimetic phencylclidine (PCP), an animal model for schizophrenia. Our results showed many similarities between untreated NTS1(-/-) mice and WT mice chronically treated with PCP (as compared with untreated WT mice): 1) lower PCP-induced locomotor activity; 2) similar avolition-like behavior in forced-swim test and tail suspension test; 3) lower prefrontal glutamate levels; 4) less PCP-induced dopamine release in medial prefrontal cortex (mPFC); and 5) down-regulation of mRNA and protein for DA D(1), DA D(2), and NMDAR2A in mPFC. Therefore, these data strengthen the hypothesis that the NTS1(-/-) mouse is an animal model of schizophrenia, particularly for the dysfunction of the prefrontal cortex. In addition, after chronic PCP administration, the DA D(1) receptor was up-regulated in NTS1(-/-) mice, results which suggest a possible interaction of NTS1/DA D(1) in mPFC contributing to chronic PCP-induced schizophrenia-like signs.

• Authors: Zhimin Li, Mona Boules, Katrina Williams, Andres Gordillo, Shuhua Li, Elliott Richelson
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 40 Issue 2 Pg. 467-77 (Nov 2010) ISSN: 1095-953X [Electronic] United States
• PMID: 20659557 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• RNA, Messenger
• Receptors, Neurotensin
• neurotensin type 1 receptor
• Glutamic Acid
• Phencyclidine
• Dopamine

Topics

• Animals
• Behavior, Animal (drug effects)
• Chromatography, High Pressure Liquid
• Disease Models, Animal
• Dopamine (genetics, metabolism)
• Down-Regulation (drug effects, genetics)
• Glutamic Acid (genetics, metabolism)
• Immobility Response, Tonic (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Motor Activity (drug effects, genetics)
• Phencyclidine
• Polymerase Chain Reaction
• Prefrontal Cortex (drug effects, metabolism)
• RNA, Messenger (drug effects, genetics)
• Receptors, Neurotensin (deficiency, genetics, metabolism)
• Schizophrenia (chemically induced, genetics, metabolism)
• Schizophrenic Psychology
• Swimming (psychology)
• Up-Regulation (drug effects, genetics)