Aripiprazole differentially regulates the expression of Gad67 and γ-aminobutyric acid transporters in rat brain

  • Nina Peselmann
  • Andrea Schmitt
  • Peter J. Gebicke-Haerter
  • Mathias Zink
Original Paper

Abstract

The molecular etiology of schizophrenia comprises abnormal neurotransmission of the amino acid GABA (γ-aminobutyric acid). Neuropathological studies convincingly revealed reduced expression of glutamic acid decarboxylase (Gad67) in GABAergic interneurons. Several antipsychotics influence the expression of GABAergic genes, but aripiprazole (APZ), a partial dopaminergic and serotonergic receptor agonist, has not been involved into these studies so far. We treated Sprague–Dawley rats for 4 weeks or 4 months with APZ suspended in drinking water and doses of 10 and 40 mg per kg body weight. Gene expression of Gad67, the vesicular GABA transporter Slc32a1 (solute carrier family, Vgat), the transmembrane transporters Slc6a1 (Gat1) and Slc6a11 (Gat3) was assessed by semiquantitative radioactive in situ hybridization. APZ treatment resulted in time- and dose-dependent effects with qualitative differences between brain regions. In the 10-mg group, Slc6a1 was strongly induced after 4 weeks in the hippocampus, amygdala, and cerebral cortex, followed by an induction of Gad67 in the same regions after 4 months, while frontocortical regions as well as basal ganglia showed dose-dependent reductions of Gad67 expression after 4 months. In several frontocortical and subcortical regions, we observed a decrease of Slc32a1 and an increase of Slc6a11 expression. In conclusion, APZ modulates gene expression of GABAergic marker genes involved into pathogenetic theories of schizophrenia. APZ only partially mirrors the effects of other antipsychotics with some important differences regarding brain regions. The findings might be explained by regulatory connections between serotonergic, GABAergic, and dopaminergic neurotransmission and should be validated in behavioral animal models of psychotic disorders.

Keywords

Animal model Aripiprazole Antipsychotic GABA Gene expression Schizophrenia 

Abbreviations

ACC

Anterior cingulate cortex

AM

Amygdala

APZ

Aripiprazole

CA1

Hippocampal subregion cornu ammonis 1

CA3

Hippocampal subregion cornu ammonis 3

CPU

Caudate nucleus and putamen

DG

Granular layer of dentate gyrus

EAAT

Excitatory amino acid transporter

FPC

Frontal part of parietal cortex

GABA

γ-Aminobutyric acid

GAT

GABA transporter

HB

Habenula

Hypoth

Hypothalamic nuclei

ISH

In situ hybridization

Limb

Nuclei of horizontal and vertical limbic diagonal band

mRNA

Messenger ribonucleic acid

NMDA

N-methyl-d-aspartate

NR

NMDA-receptor

NT

Nucleotides

OC

Occipital cortex

PC

Parietal cortex (dorsal part)

PFC

Prefrontal cortex

RSG

Retrosplenial granular cortex

SEM

Standard error of the mean

TC

Temporal cortex

TH

Thalamus

Slc32a1

Vesicular GABA transporter

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Nina Peselmann
    • 1
  • Andrea Schmitt
    • 2
    • 3
  • Peter J. Gebicke-Haerter
    • 4
  • Mathias Zink
    • 1
    • 5
  1. 1.Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  2. 2.Department of Psychiatry and PsychotherapyLudwig-Maximilians-UniversityMunichGermany
  3. 3.Laboratory of Neuroscience (LIM27), Institute of PsychiatryUniversity of Sao PauloSão PauloBrazil
  4. 4.Department of Psychopharmacology, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany
  5. 5.Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergMannheimGermany

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