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.
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