The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine.
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-[(3)H]-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 microM) and the KCl-evoked (28.7 +/- 7.7 microM) 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.
Melone
M
M
Istituto di Fisiologia Umana, Università di Ancona, Via Tronto 10/A, Torrette di Ancona, 60020 Ancona, Italy.
Vitellaro-Zuccarello
L
L
Vallejo-Illarramendi
A
A
Pérez-Samartin
A
A
Matute
C
C
Cozzi
A
A
Pellegrini-Giampietro
D E
DE
Rothstein
J D
JD
Conti
F
F
D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000235:genetics*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D017551:Microdialysis; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D014982:Xenopus laevis
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D014150:Antipsychotic Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018698:Glutamic Acid; D003024:Clozapine