Several clinical findings suggest that schizophrenia may involve improper functioning of the prefrontal cortex. Two basic assumptions are made in this application: (1) the proposed prefrontal cortex malfunction may alter the excitatory amino acid neurotransmission of prefrontal cortex efferents and (2) chronic antipsychotic drug treatment may exert some of its effects by acting on excitatory amino acid transmission through its interaction with midbrain dopamine systems. These assumptions are in part based on the clinical findings that have pointed to prefrontal cortical hypometabolism in schizophrenic patients during performance of frontal lobe tasks and our preliminary data indicating that the basal extracellular concentration of the putative excitatory amino acid transmitter, 1-glutamate, is significantly higher in animals that have been treated chronically with the antipsychotic drug haloperidol. The goals of the proposed experiments are to enhance our understanding of the basic biochemical characteristics of prefrontal cortex excitatory efferents and their interaction with subcortical dopamine systems, which are thought to be important sites for the action of antipsychotic drugs. Specifically, the following questions are addressed: (1) What are the basic release characteristics of excitatory amino acid. For example, do excitatory amino acid presynaptic receptors modulate their, own release? (2) How do excitatory amino acids and dopamine modulate each others function in subcortical areas. (3) How does treatment with antipsychotic drugs affect release characteristics of excitatory amino acids in the above regions and finally, (4) How does a decrease in prefrontal cortex neurotransmission alter the release characteristics of excitatory amino acids and dopamine in subcortical areas? The technique of in vivo microdialysis in conscious rats along with complementary in vivo and in vitro biochemical techniques will be utilized to perform the above experiments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH048404-04
Application #
2248128
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1992-09-15
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Park, Junchol; Wood, Jesse; Bondi, Corina et al. (2016) Anxiety Evokes Hypofrontality and Disrupts Rule-Relevant Encoding by Dorsomedial Prefrontal Cortex Neurons. J Neurosci 36:3322-35
Simon, Nicholas W; Moghaddam, Bita (2015) Neural processing of reward in adolescent rodents. Dev Cogn Neurosci 11:145-54
Totah, Nelson K B; Kim, Yunbok; Moghaddam, Bita (2013) Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection. J Neurophysiol 110:75-85
Sturman, David A; Mandell, Daniel R; Moghaddam, Bita (2010) Adolescents exhibit behavioral differences from adults during instrumental learning and extinction. Behav Neurosci 124:16-25
Pehrson, Alan L; Moghaddam, Bita (2010) Impact of metabotropic glutamate 2/3 receptor stimulation on activated dopamine release and locomotion. Psychopharmacology (Berl) 211:443-55