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

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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.

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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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Acknowledgments

This work has been funded by an unrestricted grant by Bristol-Myers Squibb GmbH & CoKGaA and Otsuka Pharmaceuticals to M.Z. The funding source had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of Interest

M. Z. holds scientific and speaker grants of the European Research Advisory Board (ERAB), German Science Foundation, and Pfizer Pharma GmbH, Servier, Astra Zeneca and Janssen Cilag. N.P., A.S., and P.J. G.-H. have no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany

    Nina Peselmann & Mathias Zink

  2. Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany

    Andrea Schmitt

  3. Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovidio Pires de Campos 785, São Paulo, SP, 05453-010, Brazil

    Andrea Schmitt

  4. Department of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159, Mannheim, Germany

    Peter J. Gebicke-Haerter

  5. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, P.O. Box 12 21 20, 68072, Mannheim, Germany

    Mathias Zink

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  1. Nina Peselmann
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Peselmann, N., Schmitt, A., Gebicke-Haerter, P.J. et al. Aripiprazole differentially regulates the expression of Gad67 and γ-aminobutyric acid transporters in rat brain. Eur Arch Psychiatry Clin Neurosci 263, 285–297 (2013). https://doi.org/10.1007/s00406-012-0367-y

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