Schizophrenia has been associated with at least two receptor complexes, namely, dopamine and GLU. Theories have been developed which invoke hypotheses supporting specific roles for these neurotransmitters in schizophrenia. The overall goal of this application is to investigate and characterize the cellular pharmacology of presynaptic and postsynaptic mGLURs at pharmacologically and electrically isolated native excitatory and inhibitory synapses, while determining their role in an animal model of the GLU-NMDA Receptor Hypofunction (NRF)-hypothesis of schizophrenia. Intracellular recordings from a brain slice preparation of the dorsolateral septal nucleus (DLSN) will be used to investigate the cellular actions of specific mGLUR agonists and antagonists for the three GROUPs of mGLURs (I, II, III).
The specific aims of this application will determine: (1) the mechanisms by which an endogenous excitatory transmitter, GLU, regulates its own release via specific presynaptic mGLURs (autoreceptors); (2) how activation of mGLURs on gamma-aminobutyric acid (GABA)ergic terminals regulates the release of GABA via other types of presynaptic mGLURs (heteroreceptors); and (3) how activation of a postsynaptic mGLUR may potentiate the NMDA component of an excitatory synaptic terminal, a component suggested to be depressed in the NRF hypothesis of schizophrenia. Finally, mGLUR mechanisms in control animals will be compared with brains of animal models of schizophrenia from rats treated chronically with PCP, a drug known to induce behavioral changes similar to those seen in patients with schizophrenia. The DLSN slice preparation has been chosen to study since DLSN contains the relevant neuronal circuitry implicated in the GLU-NRF-hypothesis of schizophrenia as proposed by Coyle (Fig. 3) and the DLSN expresses multiple types of mGLURs. Furthermore, no comparable circuitry is available in a more reduced preparation. These experiments will enhance our understanding of the mechanisms of normal synaptic transmission and transmission in an animal model of schizophrenia. Together these data may provide evidence for the use of a novel group of drugs in the treatment of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057875-02
Application #
2883456
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Program Officer
Brady, Linda S
Project Start
1998-03-01
Project End
2002-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555