RESUMO
The regulation of the dopamine (DA) receptors is of considerable interest, in part because treatment with antipsychotic drugs is known to upregulate striatal D2-like receptors. While previous studies have focused on the regulation of striatal DA receptors, less is known about the pharmacological regulation of cortical DA receptors. The purpose of this study was to examine the regulation of DA mRNA receptor expression in the cortex compared to the striatum following treatment with antipsychotic agents. Adult male Sprague-Dawley rats were injected daily with haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day) or a control vehicle for a period of 14 days. Following treatment, brains were subjected to in situ hybridization for the mRNAs encoding the five dopamine receptors; only D1, D2, and D3 receptor mRNAs were detected in these regions. Haloperidol tended to either modestly upregulate or have no effect on dopamine receptor mRNAs detected in striatal structures, while clozapine generally downregulated these mRNAs. On the other hand, in the cortex, both drugs had striking effects on D1 and D2 mRNA levels. Cortical D1 mRNA was upregulated by haloperidol, but this effect was primarily restricted to cingulate cortex; clozapine also upregulated D1 mRNA, but primarily in parietal regions. Haloperidol downregulated D2 mRNA in the majority of cortical regions, but most dramatically in frontal and cingulate regions; clozapine typically upregulated this mRNA, but primarily in regions other than frontal and cingulate cortex. These results indicate that clozapine and haloperidol each have regionally-specific effects, and differentially regulate dopamine receptor mRNA expression in striatal and cortical regions of the rat brain.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Clozapina/farmacologia , Corpo Estriado/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Haloperidol/farmacologia , Proteínas do Tecido Nervoso/biossíntese , RNA Mensageiro/biossíntese , Receptores de Dopamina D1/biossíntese , Receptores de Dopamina D2/biossíntese , Animais , Antipsicóticos/farmacologia , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Hibridização In Situ , Masculino , Proteínas do Tecido Nervoso/genética , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Receptores de Dopamina D3 , Esquizofrenia/metabolismoRESUMO
Dopamine-glutamate interactions within discrete neural circuits are increasingly recognized as potential substrates for dysregulation in schizophrenia, and as a result, potential targets for pharmacological intervention in this illness. We examined the regulation, by haloperidol (2 mg kg-1 day-1) and clozapine (20 mg kg-1 day-1), of the mRNAs encoding the four AMPA receptor subunits (gluR1-gluR4), three low-affinity kainate receptor subunits (gluR5-gluR7), and two high-affinity kainate subunits (KA1 and KA2) in the rat hippocampal formation and associated entorhinal cortex. A complex and differential pattern of AMPA and kainate subunit mRNA regulation by clozapine and haloperidol was observed in this study. Both drugs caused significant alterations of most of these mRNAs, but in a heterogeneous and region-specific fashion. These data suggest that these antipsychotic drugs alter the expression of the genes encoding the subunits that express ionotropic glutamate receptors. Given the importance of glutamatergic mechanisms and the hippocampal formation in schizophrenia, these data suggest a potential substrate for neurotransmitter dysregulation in this illness, as well as a potential target for therapeutic intervention.
