GABAergic mRNA expression is differentially expressed across the prelimbic and orbitofrontal cortices of rats sensitized to methamphetamine: Relevance to psychosis

摘要

Psychotic disorders, such as schizophrenia, are characterized by prevalent and persistent executive deficits that are believed to be the result of dysfunctional inhibitory gamma-aminobutyric acid (GABA) processing of the prefrontal cortex (PFC). Methamphetamine (METH) is a commonly used psychostimulant that can induce psychotic and cognitive symptoms that are indistinguishable to schizophrenia, suggesting that METH-induced psychosis may have a similar GABAergic profile of the PFC. As the PFC consists of multiple subregions, the aim of the current study was to investigate changes to GABAergic mRNA expression in the prelimbic (PRL) and orbitofrontal (OFC) cortices of the PFC in rats sensitized to repeated METH administration. Male Sprague Dawley rats underwent daily METH or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute METH administration, RNA was isolated from the PRL and OFC and quantitative PCR was used to compare the relative expression of GABA enzymes, transporters, metabolites and receptor subunits. GAD(67), GAD(65), GAT(1), GAT(3), VGAT and GABA(T) mRNA expression were upregulated in the PRL. Ionotropic GABAA receptor subunits alpha 1, alpha 3, alpha 5 and beta 2 were specifically upregulated in the OFC. These findings suggest that alterations to GABAergic mRNA expression following sensitization to METH are biologically dissociated between the OFC and PRL, suggesting that GABAergic gene expression is significantly altered following chronic METH exposure in a brain-region and GABA-specific manner. These changes may lead to profound consequences on central inhibitory mechanisms of localized regions of the PFC and may underpin common behavioral phenotypes seen across psychotic disorders. (C) 2016 Elsevier Ltd. All rights reserved.