title: Regulation of cortical and subcortical glutamate receptor subunit expression by antipsychotic drugs.
abstract: Because glutamate is an important modulator of subcortical dopamine (DA) function, and abnormal glutamate/DA interactions may be involved in the pathophysiology of schizophrenia, we examined the effect of chronically administered antipsychotic drugs (APDs) on the levels of specific glutamate receptor subunits in the terminal fields of nigrostriatal and mesocorticolimbic DA systems. By immunoblotting procedures using antibodies specific for the NMDAR1, GluR1, and GluR2 subunits, we found that haloperidol (predominantly a D2-like antagonist) increased NMDAR1 subunit immunoreactivity (and mRNA levels) in the striatum, while the D1-like antagonist SCH 23390 had the opposite effect. No effect was seen on GluR1 or GluR2 levels. The result that D1-like and D2-like receptor antagonism can reciprocally regulate NMDAR1 expression is consistent with our observation that complete unilateral destruction of the nigrostriatal DA pathway with 6-hydroxy-dopamine had no effect on striatal NMDAR1 subunit levels. Further examination of these striatal effects revealed that chronic treatment with the D2-like receptor antagonist raclopride significantly increased NMDAR1 levels in the striatum, while the 5-HT2a/2c antagonist mianserin tended to produce an increase that did not achieve statistical significance. These findings indicate that the dopaminergic antagonist properties of haloperidol are likely most responsible for its regulation of this subunit. In contrast, the atypical APD clozapine had no effect on striatal NMDAR1 levels, consistent with the relatively weaker influence of this drug on nigrostriatal DA function. The second major finding of the present study was the ability of haloperidol and clozapine to increase GluR1 levels in the medial prefrontal cortex (PFC), whereas chronic SCH 23390 treatment decreased GluR1 levels.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
authors.forename: L W
authors.initials: LW
authors.lastname: Fitzgerald
authors.forename: A Y
authors.initials: AY
authors.lastname: Deutch
authors.forename: G
authors.initials: G
authors.lastname: Gasic
authors.forename: S F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D008803:Mianserin / Q000494:pharmacology; D008959:Models, Neurological; D016627:Oxidopamine / Q000633:toxicity; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000235:genetics; D012457:Salicylamides / Q000494:pharmacology; D012559:Schizophrenia / Q000378:metabolism; D012701:Serotonin / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012457:Salicylamides; D008803:Mianserin; D012701:Serotonin; D020891:Raclopride; D016627:Oxidopamine; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine