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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

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_Science_ 1998 281: 1349–1352 Article  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Istituto di Fisiologia Umana, Università di Ancona, Via Tronto 10/A, Torrette di Ancona, Ancona, 60020, Italy M Melone & F

Conti * Dipartimento di Fisiologia e Biochimica Generali, Università di Milano, Via Celoria 26, Milan, 20133, Italy L Vitellaro-Zuccarello * Departamento de Neurociencias, Universidad del

Pais Vasco, 48940-Leioa, Vizcaya, Spain A Vallejo-Illarramendi, A Pérez-Samartin & C Matute * Dipartimento di Farmacologia Preclinica e Clinica, Università degli Studi di Firenze, Viale

G Pieraccini 6, Firenze, 50139, Italy A Cozzi & D E Pellegrini-Giampietro * Department of Neurology, The Johns Hopkins University, Baltimore, 21287–7519, MD, USA J D Rothstein Authors *

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Correspondence to F Conti. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 11 October 2000 * Revised: 08 January 2001 * Accepted: 10 January 2001 * Published: 09 July 2001 * Issue Date: 01 July

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not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * glutamate * glutamate uptake * neuroleptics *

transporter regulation * synaptic transmission * schizophrenia