Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia.
Schizophrenia is associated with a cerebral glutathione deficit, which may leave the brain susceptible to oxidants. To study the consequences of a glutathione deficit, we treated developing rats with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and later investigated their behaviour until adulthood. Since rodents may in some occasions compensate for a glutathione deficit by ascorbic acid (AA), we used Osteogenic Disorder Shionogi (ODS) mutant rats, which like humans, cannot synthetize ascorbic acid. Moreover, as hyperactivity of the dopaminergic system may be associated with schizophrenia, some rats were treated with the dopamine uptake inhibitor GBR 12909. Whereas ODS rats treated with either BSO or GBR 12909 alone had normal behaviour, rats treated with both BSO and GBR 12909 failed to discriminate between familiar and novel objects although other behaviours proved to be normal. In contrast, nonmutant rats were not affected by treatment with BSO and GBR 12909. Our results suggest that low brain glutathione and ascorbic acid levels associated with a perturbation of the dopaminergic system actively participate in the development of some cognitive deficits affecting schizophrenic patients.
Castagné
Vincent
V
Center for Research in Psychiatric Neuroscience, Department of Adult Psychiatry, Lausanne University-CHUV, CH-1008 Prilly, Lausanne, Switzerland. vincent.casagne@inst.hospvd.ch
Rougemont
Michaël
M
Cuenod
Michel
M
Do
Kim Q
KQ
D000818:Animals; D001206:Ascorbic Acid Deficiency / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000235:genetics*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D019328:Buthionine Sulfoximine; C043425:vanoxerine; D005978:Glutathione; D004298:Dopamine