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Psychopharmacology

, Volume 217, Issue 1, pp 127–142 | Cite as

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

  • Nina Segnitz
  • Thomas Ferbert
  • Andrea Schmitt
  • Peter Gass
  • Peter J. Gebicke-Haerter
  • Mathias ZinkEmail author
Original Investigation

Abstract

Rationale

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.

Objectives

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 3H-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.

Keywords

Animal model Aripiprazole Antipsychotic Dopamine Glutamate NMDA Receptor Schizophrenia Serotonin 

Abbreviations

ACC

Anterior cingulate cortex

APZ

Aripiprazole

CA1

Hippocampal subregion cornu ammonis 1

CA3

Hippocampal subregion cornu ammonis 3

CPU

Caudate nucleus and putamen

DG

Dentate gyrus

EAAT

Excitatory amino acid transporter

FPC

Fronto-parietal cortex

GABA

γ-Amino butyric acid

HB

Habenula

ISH

In situ hybridization

mRNA

Messenger ribonucleic acid

NMDA

N-Methyl-d-aspartate

NMDA-R

NMDA receptor

NT

Nucleotides

OC

Occipital cortex

PC

Parietal cortex

PFC

Prefrontal cortex

RSG

Retrosplenial granular cortex

S.E.M.

Standard error of the mean

TC

Temporal cortex

TH

Thalamus

vGluT1

Vesicular glutamate transporter 1

Notes

Acknowledgements

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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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Nina Segnitz
    • 1
  • Thomas Ferbert
    • 1
  • Andrea Schmitt
    • 2
    • 3
  • Peter Gass
    • 1
  • Peter J. Gebicke-Haerter
    • 4
  • Mathias Zink
    • 1
    Email author
  1. 1.Department of Psychiatry and Psychotherapy, Central Institute of Mental HealthUniversity of HeidelbergMannheimGermany
  2. 2.Department of PsychiatryUniversity of GoettingenGoettingenGermany
  3. 3.Laboratory of Neuroscience (LIM27), Institute of PsychiatryUniversity of Sao PauloSão PauloBrazil
  4. 4.Department of Psychopharmacology, Central Institute of Mental HealthUniversity of HeidelbergMannheimGermany

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