Several recent studies have suggested that gamma-aminobutyric acid (GABA) function in the frontal cortices is altered in schizophrenia. Post-mortem studies have reported decreased numbers of presumptive interneurons in the anterior cingulate cortex, the loss of NADPH diaphorase-containing interneurons in the prefrontal cortex (PFC), and a decrease in the number of neurons expressing GAD67 mRNA in the PFC. Since a current hypothesis of the pathophysiology of schizophrenia posits a decrease in functional dopaminergic activity in the PFC (coupled with a resultant increase in dopamine tone subcortically), it is possible that a decrease in local dopamine (DA) function results in decreased GABA function in the PFC. Consistent with this speculation are in vitro pharmacological and physiological studies suggesting that DA activates cortical GABA interneurons. We propose to characterize pharmacologically the regulation of GABA neurons in the PFC of the rat by DA and serotonin (5-HT). In vivo microdialysis in the awake, freely-moving rat will be used to monitor extracellular GABA levels in the PFC in response to administration of DA and 5-HT agonists. We will also use Fos immunohistochemistry to determine if DA and 5-HT impact specific subsets of GABA neurons by examining monoamine agonist-elicited increases in Fos expression in histochemically- defined subsets of interneurons.
In specific aim 2 we will determine the effects of acute and chronic administration of antipsychotic drugs (APDs) that are DA or 5-HT antagonists or mixed DA/5-HT antagonists on extracellular GABA levels in the PFC. In order to assess adaptive changes in GABAergic neurons in response to chronic APD treatment, studies in specific aim 3 will use in situ hybridization histochemistry (ISHH) to determine levels of the mRNAs encoding for the glutamic acid decarboxylases GAD67 or GAD65, and use immunoblots to measure levels of the respective GAD proteins and calcium binding proteins. These studies aim to characterize the monoaminergic regulation of cortical interneurons using neurochemical, pharmacological, and anatomical methods, and may help elucidate the pathophysiology of schizophrenia and the mechanisms of action of antipsychotic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057995-03
Application #
2891063
Study Section
Special Emphasis Panel (ZMH1-NRB-A (01))
Program Officer
Brady, Linda S
Project Start
1997-04-05
Project End
2000-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Bubser, Michael; Fadel, Jim R; Jackson, Lela L et al. (2005) Dopaminergic regulation of orexin neurons. Eur J Neurosci 21:2993-3001
Wang, Hui-Dong; Dunnavant, Floyd D; Jarman, Tabitha et al. (2004) Effects of antipsychotic drugs on neurogenesis in the forebrain of the adult rat. Neuropsychopharmacology 29:1230-8
Petrie, Kimberly A; Bubser, Michael; Casey, Cheryl D et al. (2004) The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat. Neuropsychopharmacology 29:1878-88
Rieck, Richard W; Ansari, M S; Whetsell Jr, William O et al. (2004) Distribution of dopamine D2-like receptors in the human thalamus: autoradiographic and PET studies. Neuropsychopharmacology 29:362-72
Scruggs, Jennifer L; Schmidt, Dennis; Deutch, Ariel Y (2003) The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci Lett 346:137-40
Fadel, J; Deutch, A Y (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379-87
Woo, Nam-Sik; Lu, Jianming; England, Roger et al. (2002) Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus 12:258-68
Fadel, Jim; Bubser, Michael; Deutch, Ariel Y (2002) Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22:6742-6
Bubser, Michael; Deutch, Ariel Y (2002) Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum. Eur J Neurosci 15:713-20
Bubser, M; Backstrom, J R; Sanders-Bush, E et al. (2001) Distribution of serotonin 5-HT(2A) receptors in afferents of the rat striatum. Synapse 39:297-304

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