Glutamate is an important modulator of cortical and subcortical dopamine function, and glutamate-dopamine interactions have been implicated in the actions of antipsychotic drugs (APDs) and, possibly the pathophysiology of schizophrenia. We have recently examined, by immunoblotting procedures, the effect of chronically-administered APDs on the levels of specific glutamate receptor subunits in the terminal fields of nigrostraiatal and mesocorticolimbic dopamine systems. One major findings was that halporeidol increased NMDAR1 subunit immunoreactivity in the striatum, while the atypical APD clozapine had no effect, consistent with the relatively weaker influence of this drug on nigrostriatal function. No effect was seen on levels of the AMPA receptor subunits, GluR1 or GluR2. Second, we found that chronic, but not acute, administration of haloperidol or clozapine increased GluR1 levels in the medial prefrontal cortex (PFC), with no influence on NMDAR1 or GluR2 levels. Third, we observed that clozapine, but not haloperiodol or several other treatments examined, increased GluR2 levels in the frontal/parietal cortex, nucleus accumbens, and hippocampus. The goal of the proposed studies is to further characterize regulation of glutamate receptor subunits by APDs. First, receptor regulation will be further characterized pharmacologically. This will include the analysis of additional drugs to establish the receptor mechanisms by which various APDs regulate receptor expression. This will also include studies of the time course and dose response of drug action, which is critical to compare the actions of multiple drug treatments. Second, the anatomical specificity of receptor regulation will be examined. This will be accomplished through the use of immunocytochemistry and in situ hybridization. Preliminary studies demonstrate the feasibility of these studies. Third, we will investigate possible molecular mechanisms by which APDs regulate glutamate receptor levels. We have found that several of the subunits are regulated at the mRNA level, consistent with the possibility that alterations in gene expression may be involved. As a result, we have recently begun to study APD regulation of transcription factors in the striatum, PFC, and Nac. The role played by CRED and Fos-like transcription factors in mediating APD regulation of glutamate receptors will be pursued by the use of an antisense oligonucleotide strategy and, to the extent possible, by heterologous recombinant mice. Preliminary data indicate the feasibility of using the antisense oligonucleotide strategy as a way of relating the regulation of specific transcription factors to the regulation of specific glutamate receptors in vivo. Fourth, APD regulation of glutamate receptor expression defines hypotheses concerning the functional changes in the striatum, PFC, and Nac. We propose to test these specific hypotheses by use of electrophysiological and in vivo microdialysis procedures. Together, the proposed studies represent a multidisciplinary and integrated investigation of the regulation of the glutamate system by APDs. Such regulation could be an important and novel mechanism through which these drugs exert some of their long- term effects on brain function.
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