title: Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain.
abstract: BACKGROUND
  The glutamatergic theory of schizophrenia proposes a dysfunction of ionotropic N-methyl-D: -aspartate receptors (NMDA-R). Several therapeutic strategies address NMDA-R function and the effects of antipsychotic agents on NMDA-R expression have been described. Within the second-generation antipsychotics, the partial dopaminergic and serotonergic agonist aripiprazole (APZ) was able to counteract the behavioral effects of NMDA-R antagonists.
  
  
  OBJECTIVE
  This study aims to investigate the effects of APZ on NMDA-R subunit expression and binding.
  
  
  METHODS
  We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ in daily oral doses of 10 and 40 mg per kilogram of body weight. Gene expression of the NMDA-R subunits NR1, NR2A, NR2B, NR2C, and NR2D, respectively, was assessed by semiquantitative radioactive in situ hybridization and in parallel receptor binding using (3)H-MK-801 receptor autoradiography.
  
  
  RESULTS
  Increased expression levels of NR1 (4 weeks), NR2A (4 weeks), NR2C (4 weeks and 4 months), and NR2D (4 months) were observed in several hippocampal and cortical brain regions. The parallel reduced expression of NR2B mRNAs (4 months) resulted in a relative increase of the NR2A/NR2B ratio. Marked differences between specific brain regions, the doses of APZ, and the time points of assessment became obvious. On the receptor level, increased MK-801-binding was found after 4 weeks in the 40-mg group and after 4 months in the 10-mg group.
  
  
  CONCLUSIONS
  The effects of APZ converge in enhanced NMDA receptor expression and a shift of subunit composition towards adult-type receptors. Our results confirm the regulatory connections between dopaminergic, serotonergic, and glutamatergic neurotransmissions with relevance for cognitive and negative symptoms of schizophrenia.
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, P.O. Box 122120, 68072 Mannheim, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Segnitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Ferbert
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmitt
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gebicke-Haerter
authors.forename: Mathias
authors.initials: M
authors.lastname: Zink
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000068180:Aripiprazole; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D017403:In Situ Hybridization; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D021122:Protein Subunits; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D000068180:Aripiprazole; D004298:Dopamine