Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats.
Disruption of the Reelin and GABAergic signaling systems have been observed in psychiatric disorders including autism, schizophrenia, bipolar disorder, and major depression. Less is known of therapeutic interventions that may help ameliorate the effects of these disruptions. The current study investigated whether chronic administration of psychotropic medications (clozapine, fluoxetine, haloperidol, lithium, olanzapine, and valproic acid) used in the treatment of psychiatric disorders alters levels of Reelin, its receptor Vldlr, downstream molecules Gsk3 beta, Dab-1, and Gad65/67 in rat prefrontal cortex as measured by qRT-PCR and SDS-PAGE and western blotting. qRT-PCR revealed that mRNAs for Reelin, Vldlr, Dab-1, Gsk3 beta, and Gad65 were each significantly altered by at least one of the drugs tested, and in the case of Reelin, Dab-1, and Gsk3 beta, by multiple drugs. To verify our results, we also performed SDS-PAGE and western blotting experiments. Again, several of the protein products for Reelin, Vldlr, Dab-1, Gsk3 beta, Gad65, and Gad67 were also significantly altered by multiple drugs. The present results suggest that the Reelin signaling and GABAergic systems are affected by commonly used psychotropic medications. These changes may help explain the efficacy of these drugs and provide further support for the investigation of the Reelin and GABAergic signaling systems as therapeutic targets for the treatment of neuropsychiatric diseases.
Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, USA. fatem002@umn.edu
S Hossein
SH
Fatemi
Teri J
TJ
Reutiman
Timothy D
TD
Folsom
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D004334:Drug Administration Schedule; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; C499786:Dab1 protein, rat; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D011619:Psychotropic Drugs; D012333:RNA, Messenger; D011973:Receptors, LDL; D000091042:Reelin Protein; C000717129:Reln protein, rat; C036053:VLDL receptor; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2