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

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 (US)
Pages (from-to)380-386
Number of pages7
JournalMolecular psychiatry
Volume6
Issue number4
DOIs
StatePublished - Jul 4 2001

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine'. Together they form a unique fingerprint.

  • Cite this

    Melone, M., Vitellaro-Zuccarello, L., Vallejo-Illarramendi, A., Pérez-Samartin, A., Matute, C., Cozzi, A., Pellegrini-Giampietro, D. E., Rothstein, J. D., & 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, 6(4), 380-386. https://doi.org/10.1038/sj.mp.4000880