CLOZAPINE AND HALOPERIDOL DIFFERENTIALLY AFFECT AMPA AND KAINATE RECEPTOR SUBUNIT MESSENGER-RNA LEVELS IN RAT CORTEX AND STRIATUM

Dopamine is the neurotransmitter most often implicated in the pathogen esis of schizophrenia. However, glutamatergic antagonists can cause ps ychotic symptoms in otherwise normal humans, and exacerbate these symp toms in schizophrenics. These findings have led to a model of dopamine -glutamate interactions in limbic cortex and striatum as a potential s ubstrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotro pic glutamate receptors would be differentially regulated by antipsych otic treatment. To begin to address this question, we examined the reg ulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment fo r 2 weeks, Both clozapine and haloperidol caused region-specific alter ations in the mRNA levels of these subunits, but there was no differen tial regulation in the cortex vs, the striatum. Haloperidol caused a d ecrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapi ne treatment caused an increase in gluR7 mRNA expression, and a decrea se in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesti ng mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our underst anding of dopamine-glutamate interactions in schizophrenia.