Clinical studies have demonstrated that NMDA receptor antagonists induce positive, negative and cognitive schizophrenic-like symptoms in healthy subjects and precipitate psychotic reactions in patients with schizophrenia. These data, and the resulting NMDA receptor hypofunction hypothesis of schizophrenia, provide a compelling rationale for characterizing neurobiological correlates in models of reduced NMDA receptor function. The present proposal will assess behavioral and brain metabolic phenotypes in a genetic model of reduced NMDA receptor function-the NMDA R1 (NR1) subunit deficient mouse. The NR1 subunit is a component of all NMDA receptors and reduced expression of this subunit will therefore result in a chronic state of NMDA receptor hypofunction. It is hypothesized that the behavioral and brain metabolic phenotypes associated with the NR1 deficient mouse model will mimic certain phenotypes observed in schizophrenic patients. Specifically, it is hypothesized that the NR1 deficient mice will exhibit reduced brain metabolism in prefrontal and limbic regions, and exhibit alterations in sensory processing (prepulse inhibition and startle habituation). If these hypotheses are correct, the mouse models could represent an approach to explore potential preventative strategies for schizophrenia. The proposed work also will test the hypothesis that administration of typical and atypical antipsychotic drugs will have different effects on the alterations in behavior and regional brain metabolic activity observed in the genetic model of reduced NMDA receptor function In addition to the heuristic value of the work for understanding differential effects of typical and atypical antipsychotic drugs, the proposed autoradiographic studies are analogous to human PET studies of brain metabolism and blood flow, and therefore offer an important potential translational opportunity to relate results found in rodents to humans. The proposed work will not only contribute to the understanding of neurobiological actions of atypical antipsychotic drugs, but also will provide paradigms in which novel pharmacological strategies could be explored for the treatment of schizophrenia. In addition, characterizing neurobiological actions of antipsychotic drugs in the genetic model of NMDA receptor hypofunction could help delineate neurochemical dysfunction in these models, and by inference, potential pathophysiological processes in schizophrenia. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063398-03
Application #
6879724
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Meinecke, Douglas L
Project Start
2003-04-10
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
3
Fiscal Year
2005
Total Cost
$254,625
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Duncan, Gary E; Inada, Ken; Farrington, Joseph S et al. (2009) Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress. Brain Res 1265:186-95
Duncan, Gary E; Inada, Ken; Farrington, Joseph S et al. (2008) Seizure responses and induction of Fos by the NMDA agonist (tetrazol-5-yl)glycine in a genetic model of NMDA receptor hypofunction. Brain Res 1221:41-8
Moy, Sheryl S; Nadler, Jessica J; Poe, Michele D et al. (2008) Development of a mouse test for repetitive, restricted behaviors: relevance to autism. Behav Brain Res 188:178-94
Moy, Sheryl S; Perez, Antonio; Koller, Beverly H et al. (2006) Amphetamine-induced disruption of prepulse inhibition in mice with reduced NMDA receptor function. Brain Res 1089:186-94
Duncan, Gary E; Moy, Sheryl S; Lieberman, Jeffrey A et al. (2006) Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction. Pharmacol Biochem Behav 85:481-91
Duncan, Gary E; Moy, Sheryl S; Lieberman, Jeffery A et al. (2006) Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function. Psychopharmacology (Berl) 184:190-200
Duncan, Gary E; Moy, Sheryl S; Perez, Antonio et al. (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507-19
Miyamoto, Seiya; Snouwaert, John N; Koller, Beverly H et al. (2004) Amphetamine-induced Fos is reduced in limbic cortical regions but not in the caudate or accumbens in a genetic model of NMDA receptor hypofunction. Neuropsychopharmacology 29:2180-8