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 i...
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| Veröffentlicht in: | Molecular psychiatry 2001-07, Vol.6 (4), p.380-386 |
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| creator | MELONE, M VITELLARO-ZUCCARELLO, L VALLEJO-ILLARRAMENDI, A PEREZ-SAMARTIN, A MATUTE, C COZZI, A PELLEGRINI-GIAMPIETRO, D. E ROTHSTEIN, J. D CONTI, F |
| description | 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. |
| doi_str_mv | 10.1038/sj.mp.4000880 |
| format | Article |
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E ; ROTHSTEIN, J. D ; CONTI, F</creator><creatorcontrib>MELONE, M ; VITELLARO-ZUCCARELLO, L ; VALLEJO-ILLARRAMENDI, A ; PEREZ-SAMARTIN, A ; MATUTE, C ; COZZI, A ; PELLEGRINI-GIAMPIETRO, D. E ; ROTHSTEIN, J. D ; CONTI, F</creatorcontrib><description>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.</description><identifier>ISSN: 1359-4184</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/sj.mp.4000880</identifier><identifier>PMID: 11443521</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing Group</publisher><subject>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</subject><ispartof>Molecular psychiatry, 2001-07, Vol.6 (4), p.380-386</ispartof><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2001 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2001</rights><rights>Macmillan Publishers Limited 2001.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c577t-199b40ee06cf1fd3d61c2792b1a3977867e1b7d89e2145f7c14e39014fc495a33</citedby><cites>FETCH-LOGICAL-c577t-199b40ee06cf1fd3d61c2792b1a3977867e1b7d89e2145f7c14e39014fc495a33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1022625$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11443521$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MELONE, M</creatorcontrib><creatorcontrib>VITELLARO-ZUCCARELLO, L</creatorcontrib><creatorcontrib>VALLEJO-ILLARRAMENDI, A</creatorcontrib><creatorcontrib>PEREZ-SAMARTIN, A</creatorcontrib><creatorcontrib>MATUTE, C</creatorcontrib><creatorcontrib>COZZI, A</creatorcontrib><creatorcontrib>PELLEGRINI-GIAMPIETRO, D. E</creatorcontrib><creatorcontrib>ROTHSTEIN, J. D</creatorcontrib><creatorcontrib>CONTI, F</creatorcontrib><title>The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><description>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.</description><subject>Amino Acid Transport System X-AG</subject><subject>Animals</subject><subject>Antipsychotic Agents - pharmacology</subject><subject>Antipsychotics</subject><subject>ATP-Binding Cassette Transporters - analysis</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>Biological and medical sciences</subject><subject>Cerebral cortex</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Clozapine</subject><subject>Clozapine - pharmacology</subject><subject>Cortex (frontal)</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Frontal Lobe - drug effects</subject><subject>Frontal Lobe - metabolism</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genetic aspects</subject><subject>Glutamate</subject><subject>Glutamatergic transmission</subject><subject>Glutamic Acid - metabolism</subject><subject>Glutamic acid transporter</subject><subject>Immunoreactivity</subject><subject>In Vitro Techniques</subject><subject>Medical sciences</subject><subject>Microdialysis</subject><subject>mRNA</subject><subject>Neuropharmacology</subject><subject>Oocytes</subject><subject>Oocytes - drug effects</subject><subject>Oocytes - physiology</subject><subject>Pharmacology. Drug treatments</subject><subject>Physiological aspects</subject><subject>Potassium chloride</subject><subject>Psycholeptics: tranquillizer, neuroleptic</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopharmacology</subject><subject>Psychotropic drugs</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recombinant Proteins - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>Schizophrenia</subject><subject>Synaptic transmission</subject><subject>Xenopus laevis</subject><issn>1359-4184</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1ks2P1CAYxhujcdfVo1dD1MRTRz5Le9xsdDWZxMt4JpS-zDJpoQLN7njwb5dxm6waDQcI_J6HF96nql4SvCGYte_TYTPNG44xblv8qDonXDa1ELJ9XNZMdDUnLT-rnqV0wPh0KJ5WZ4RwzgQl59WP3Q0guJsjpOSCR8Gi_bhkPekMKEft0xxihoiut7uaIOdRLoKoMzIQoY96ROYE3CGX0BBufR1hv4xFPaD--AvWPrs5Hc1NyM6gIS57ZMbwXc_Ow_PqidVjghfrfFF9_fhhd_Wp3n65_nx1ua2NkDLXpOt6jgFwYyyxAxsaYqjsaE8066RsGwmkl0PbASVcWGkIB9aV51rDO6EZu6je3fvOMXxbIGU1uWRgHLWHsCQlRceIEI0s5Ju_yENYoi_FKdpwIQXtWFuo1_-lKKGlHZI9WO31CMp5G8qHmtPF6pJiionkDS7U5h9UGQNMzgQP1pX9PwT1vcDEkFIEq-boJh2PimB1yoRKBzXNas1E4V-ttS79BMMDvYagAG9XQCejR1u6blz6zZXShgr2E1o3vPw</recordid><startdate>20010701</startdate><enddate>20010701</enddate><creator>MELONE, M</creator><creator>VITELLARO-ZUCCARELLO, L</creator><creator>VALLEJO-ILLARRAMENDI, A</creator><creator>PEREZ-SAMARTIN, A</creator><creator>MATUTE, C</creator><creator>COZZI, A</creator><creator>PELLEGRINI-GIAMPIETRO, D. 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E</au><au>ROTHSTEIN, J. D</au><au>CONTI, F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine</atitle><jtitle>Molecular psychiatry</jtitle><addtitle>Mol Psychiatry</addtitle><date>2001-07-01</date><risdate>2001</risdate><volume>6</volume><issue>4</issue><spage>380</spage><epage>386</epage><pages>380-386</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><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-[(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.</abstract><cop>Basingstoke</cop><pub>Nature Publishing Group</pub><pmid>11443521</pmid><doi>10.1038/sj.mp.4000880</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular psychiatry, 2001-07, Vol.6 (4), p.380-386 |
| issn | 1359-4184 1476-5578 |
| language | eng |
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| 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 |
| title | The expression of glutamate transporter GLT-1 in the rat cerebral cortex is down-regulated by the antipsychotic drug clozapine |
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