Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum.
Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine-glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation 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 for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease 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 interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine-glutamate interactions in schizophrenia.
Healy
D J
DJ
Department of Psychiatry and Mental Health Research Institute, University of Michigan, Ann Arbor 48109-0720, USA. drdan@umich.edu
Meador-Woodruff
J H
JH
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism
D003024:Clozapine; D006220:Haloperidol; D012333:RNA, Messenger; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2