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

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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
Issue number4
Publication statusPublished - 2001



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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

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.