TY - JOUR
T1 - Effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits
AU - Schmitt, Andrea
AU - Zink, Mathias
AU - Müller, Bettina
AU - May, Brigitte
AU - Herb, Anne
AU - Jatzko, Alexander
AU - Braus, Dieter F.
AU - Henn, Fritz A.
N1 - Funding Information:
Materials and Medication. [3H]-MK-801 was obtained from NEN (Life Science Products, Germany). Unlabeled MK-801 was purchased from Sigma (Germany). Haloperidol (Janssen Research Foundation) and clozapine (Novartis, Basel, Switzerland) were supplied free of charge by the respective companies. All other chemicals were purchased from Sigma Chemicals (Taufkirchen, Germany).
PY - 2003/2/1
Y1 - 2003/2/1
N2 - Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1,5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [3H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [3H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.
AB - Postmortem studies in schizophrenic patients revealed alterations in NMDA receptor binding and gene expression of specific subunits. Because most of the patients had been treated with antipsychotics over long periods, medication effects might have influenced those findings. We treated animals with haloperidol and clozapine in clinical doses to investigate the effects of long-term antipsychotic treatment on NMDA receptor binding and gene expression of subunits. Rats were treated with either haloperidol (1,5 mg/kg/day) or clozapine (45 mg/kg/day) given in drinking water over a period of 6 months. Quantitative receptor autoradiography with [3H]-MK-801 was used to examine NMDA receptor binding. In situ hybridization was performed for additional gene expression studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [3H]-MK-801 binding was found to be increased after haloperidol treatment in the striatum and nucleus accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the nucleus accumbens. There were no alterations in gene expression of NMDA subunits in any of the three regions. However, the NR2A subunit was down-regulated in the hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D subunits did not differ between treatment groups and controls. Both altered NMDA receptor binding and subunit expression strengthen a hyperglutamatergic function after haloperidol treatment and may contribute to some of our postmortem findings in antipsychotically treated schizophrenic patients. Because the effects seen in different brain areas clearly vary between haloperidol and clozapine, they may also be responsible for some of the differences in efficacy and side effects.
KW - Clozapine
KW - Gene expression
KW - Haloperidol
KW - NMDA receptor
KW - NMDA subunits
KW - Receptor autoradiography
UR - http://www.scopus.com/inward/record.url?scp=0037321715&partnerID=8YFLogxK
U2 - 10.1023/A:1022325116309
DO - 10.1023/A:1022325116309
M3 - Article
C2 - 12608697
AN - SCOPUS:0037321715
SN - 0364-3190
VL - 28
SP - 235
EP - 241
JO - Neurochemical Research
JF - Neurochemical Research
IS - 2
ER -