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 language | English |
|---|---|
| Pages (from-to) | 380-386 |
| Number of pages | 7 |
| Journal | Molecular Psychiatry |
| Volume | 6 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2001 |
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Keywords
- Glutamate
- Glutamate uptake
- Neuroleptics
- Schizophrenia
- Synaptic transmission
- Transporter regulation
ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
Cite this
The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine. / Melone, M.; Vitellaro-Zuccarello, L.; Vallejo-Illarramendi, A.; Pérez-Samartin, A.; Matute, C.; Cozzi, A.; Pellegrini-Giampietro, D. E.; Rothstein, J. D.; Conti, F.
In: Molecular Psychiatry, Vol. 6, No. 4, 2001, p. 380-386.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=0034972585&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034972585&partnerID=8YFLogxK
U2 - 10.1038/sj.mp.4000880
DO - 10.1038/sj.mp.4000880
M3 - Article
C2 - 11443521
AN - SCOPUS:0034972585
VL - 6
SP - 380
EP - 386
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 4
ER -