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

• Published in: Molecular psychiatry Vol. 6; no. 4; pp. 380 - 386
• Main Authors: MELONE, M, VITELLARO-ZUCCARELLO, L, VALLEJO-ILLARRAMENDI, A, PEREZ-SAMARTIN, A, MATUTE, C, COZZI, A, PELLEGRINI-GIAMPIETRO, D. E, ROTHSTEIN, J. D, CONTI, F
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-07-2001
• Subjects: Amino Acid Transport System X-AG; Animals; Antipsychotic Agents - pharmacology; Antipsychotics; ATP-Binding Cassette Transporters - analysis; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Cerebral cortex; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Clozapine; Clozapine - pharmacology; Cortex (frontal); Dosage and administration; Drug therapy; Female; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Gene Expression Regulation - drug effects; Genetic aspects; Glutamate; Glutamatergic transmission; Glutamic Acid - metabolism; Glutamic acid transporter; Immunoreactivity; In Vitro Techniques; Medical sciences; Microdialysis; mRNA; Neuropharmacology; Oocytes; Oocytes - drug effects; Oocytes - physiology; Pharmacology. Drug treatments; Physiological aspects; Potassium chloride; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychotropic drugs; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism; RNA, Messenger - genetics; Schizophrenia; Synaptic transmission; Xenopus laevis; Italy; Spain; Immunohistochemistry; Cerebral cortex; Rat; Neuroleptic; Psychotropic; Biological transport; Rodentia; Central nervous system; Clozapine; Gene expression; Glutamate; Pathology; Vertebrata; Chemotherapy; Mammalia; Synaptic transmission; Animal; Antipsychotic; Biological effect; Brain (vertebrata)
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4000880

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.