Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain
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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.
This study aims to investigate the effects of APZ on NMDA-R subunit expression and binding.
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 3H-MK-801 receptor autoradiography.
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.
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.
KeywordsAnimal model Aripiprazole Antipsychotic Dopamine Glutamate NMDA Receptor Schizophrenia Serotonin
Anterior cingulate cortex
Hippocampal subregion cornu ammonis 1
Hippocampal subregion cornu ammonis 3
Caudate nucleus and putamen
Excitatory amino acid transporter
γ-Amino butyric acid
In situ hybridization
Messenger ribonucleic acid
Retrosplenial granular cortex
Standard error of the mean
Vesicular glutamate transporter 1
This work has been funded by an unrestricted grant to M. Z. by Bristol-Myers Squibb GmbH & CoKGaA and Otsuka Pharmaceuticals. M. Z. holds scientific and speaker grants of the European Research Advisory Board (ERAB), Pfizer Pharma GmbH and Bristol Myers Squibb Pharmaceuticals, AstraZeneca, and Janssen Cilag. P.G. has been speaker for Pfizer Pharma GmbH and AstraZeneca. N.S., T.F., A.S., and P.J. G.-H. have no conflicts of interest.
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