Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats

Abstract

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 Gsk3β, 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, Gsk3β, and Gad65 were each significantly altered by at least one of the drugs tested, and in the case of Reelin, Dab-1, and Gsk3β, 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, Gsk3β, 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.