TY - JOUR
T1 - The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine
AU - Melone, M.
AU - Vitellaro-Zuccarello, L.
AU - Vallejo-Illarramendi, A.
AU - Pérez-Samartin, A.
AU - Matute, C.
AU - Cozzi, A.
AU - Pellegrini-Giampietro, D. E.
AU - Rothstein, J. D.
AU - Conti, F.
N1 - Funding Information:
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.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Glutamate
KW - Glutamate uptake
KW - Neuroleptics
KW - Schizophrenia
KW - Synaptic transmission
KW - Transporter regulation
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U2 - 10.1038/sj.mp.4000880
DO - 10.1038/sj.mp.4000880
M3 - Article
C2 - 11443521
AN - SCOPUS:0034972585
SN - 1359-4184
VL - 6
SP - 380
EP - 386
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 4
ER -