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

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.

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Acknowledgements

This paper is dedicated to GianFranco Marchesi (1940–1998), Professor of Psychiatry at the University of Ancona, who stimulated this study. This work was supported by a Theodore and Vana Stanley Foundation Research Award (to FC) and by grants from Telethon (962/97 to FC) and University del Pais Vasco (CM). We are grateful to Marco Catalano, Aldo Rustioni, and Giulio Tononi for critical comments on an earlier version of this paper and Andrea Minelli for helpful discussions.

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Melone, M., Vitellaro-Zuccarello, L., Vallejo-Illarramendi, A. et al. The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. Mol Psychiatry 6, 380–386 (2001). https://doi.org/10.1038/sj.mp.4000880

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Keywords

  • glutamate
  • glutamate uptake
  • neuroleptics
  • transporter regulation
  • synaptic transmission
  • schizophrenia

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