The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine

M. Melone, L. Vitellaro-Zuccarello, A. Vallejo-Illarramendi, A. Pérez-Samartin, C. Matute, A. Cozzi, D. E. Pellegrini-Giampietro, J. D. Rothstein, F. Conti

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

We show here that clozapine, a beneficial antipsychotic, down-regulates the expression of the glutamate transporter GLT-1 in the rat cerebral cortex, thereby reducing glutamate transport and raising extracellular glutamate levels. Clozapine treatment (25-35 mg kg-1 day-1 orally) reduced GLT-1 immunoreactivity in several brain regions after 3 weeks; this effect was most prominent after 9 weeks and most evident in the frontal cortex. GLT-1 protein levels were reduced in the cerebral cortex of treated rats compared with controls and were more severely affected in the anterior (71.9 ± 4.5%) than in the posterior (53.2 ± 15.4%) cortex. L-[3H]-glutamate uptake in Xenopus laevis oocytes injected with mRNA extracted from the anterior cerebral cortex of rats treated for 9 weeks was remarkably reduced (to 30.6 ± 8.6%) as compared to controls. In addition, electrophysiological recordings from oocytes following application of glutamate revealed a strong reduction in glutamate uptake currents (46.3 ± 10.2%) as compared to controls. Finally, clozapine treatment led to increases in both the mean basal (8.1 ± 0.7 μM) and the KCl-evoked (28.7 ± 7.7 μM) output of glutamate that were 3.1 and 3.5, respectively, higher than in control rats. These findings indicate that clozapine may potentiate glutamatergic synaptic transmission by regulating glutamate transport.

Original languageEnglish
Pages (from-to)380-386
Number of pages7
JournalMolecular Psychiatry
Volume6
Issue number4
DOIs
Publication statusPublished - 2001

Fingerprint

Amino Acid Transport System X-AG
Clozapine
Cerebral Cortex
Antipsychotic Agents
Glutamic Acid
Oocytes
Xenopus laevis
Frontal Lobe
Synaptic Transmission
Down-Regulation
Messenger RNA
Brain

Keywords

  • Glutamate
  • Glutamate uptake
  • Neuroleptics
  • Schizophrenia
  • Synaptic transmission
  • Transporter regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

Cite this

The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. / Melone, M.; Vitellaro-Zuccarello, L.; Vallejo-Illarramendi, A.; Pérez-Samartin, A.; Matute, C.; Cozzi, A.; Pellegrini-Giampietro, D. E.; Rothstein, J. D.; Conti, F.

In: Molecular Psychiatry, Vol. 6, No. 4, 2001, p. 380-386.

Research output: Contribution to journalArticle

Melone, M, Vitellaro-Zuccarello, L, Vallejo-Illarramendi, A, Pérez-Samartin, A, Matute, C, Cozzi, A, Pellegrini-Giampietro, DE, Rothstein, JD & Conti, F 2001, 'The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine', Molecular Psychiatry, vol. 6, no. 4, pp. 380-386. https://doi.org/10.1038/sj.mp.4000880
Melone, M. ; Vitellaro-Zuccarello, L. ; Vallejo-Illarramendi, A. ; Pérez-Samartin, A. ; Matute, C. ; Cozzi, A. ; Pellegrini-Giampietro, D. E. ; Rothstein, J. D. ; Conti, F. / The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. In: Molecular Psychiatry. 2001 ; Vol. 6, No. 4. pp. 380-386.
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