N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate transmission, along with dopamine (DA) and 3-aminobutyric acid (GABA) systems, has long been linked to schizophrenia, but all commonly prescribed antipsychotic agents act on DA receptors. Recent studies indicate that metabotropic glutamate receptor (mGluR) agonists reverse the behavioral effects of the NMDAR antagonist phencyclidine (PCP) and dizocilpine (MK-801) in animal models and in patients with schizophrenia. These studies suggest that mGluR2/3 receptor agonists have antipsychotic properties and may provide a new treatment of schizophrenia. This finding is exciting, but it raises some fundamental questions: Why do mGluR2/3 agonists have the same therapeutic efficacy as D2 receptor antipsychotic agents and by what mechanisms do mGluR2/3 agonists ameliorate behavior? We hypothesize that mGluR2/3 agonists restore the disrupted NMDAR function induced by the MK- 801 blockade by directly regulating the expression and trafficking of NMDAR subunits in the prefrontal circuitry. An integrated approach of in vivo pharmacologic agents, in vitro patch clamp recording, and molecular techniques will be used to test our hypothesis in the MK-801 animal model of schizophrenia. The proposed experiments will provide insights into the underlying mechanisms of mGluR regulation of NMDAR-mediated transmission and will contribute to a better understanding of how mGluR agonists reverse behavioral effects of NMDAR antagonists in animal models and of the underlying molecular pathophysiological characteristics and treatment of schizophrenia.

Public Health Relevance

Recent studies indicate that mGluR agonists have antipsychotic properties and may provide a new treatment of schizophrenia. However, a fundamental question raised is what mechanisms the mGluR2/3 agonists use to ameliorate behaviors. This study will certainly provide insights into the cellular and molecular mechanisms involved in actions of mGluR agonists as potential antipsychotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085666-05
Application #
8425100
Study Section
Special Emphasis Panel (ZRG1-PMDA-A (01))
Program Officer
Nadler, Laurie S
Project Start
2009-07-10
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$367,092
Indirect Cost
$129,492
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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