title: GABAergic mRNA expression is upregulated in the prefrontal cortex of rats sensitized to methamphetamine.
abstract: Inhibitory gamma-aminobutyric acid (GABA)-mediated neurotransmission plays an important role in the regulation of the prefrontal cortex (PFC), with increasing evidence suggesting that dysfunctional GABAergic processing of the PFC may underlie certain deficits reported across psychotic disorders. Methamphetamine (METH) is a psychostimulant that induces chronic psychosis in a subset of users, with repeat administration producing a progressively increased vulnerability to psychotic relapse following subsequent drug administration (sensitization). The aim here was to investigate changes to GABAergic mRNA expression in the PFC of rats sensitized to METH using quantitative polymerase chain reaction (qPCR). Male Sprague-Dawley rats (n=12) underwent repeated methamphetamine (intraperitoneal (i.p.) or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute methamphetamine (1mg/kg i.p.) and RNA was isolated from the PFC to compare the relative mRNA expression of a range of GABA enzymes, transporters and receptors subunits. METH challenge resulted in a significant sensitized behavioral (locomotor) response in METH pre-treated animals compared with saline pre-treated controls. The mRNAs of transporters (GAT1 and GAT3), ionotropic GABAA receptor subunits (α3 and β1), together with the metabotropic GABAB1 receptor, were upregulated in the PFC of sensitized rats compared with saline controls. These findings indicate that GABAergic mRNA expression is significantly altered at the pre and postsynaptic level following sensitization to METH, with sensitization resulting in the transcriptional upregulation of several inhibitory genes. These changes likely have significant consequences on GABA-mediated neurotransmission in the PFC and may underlie certain symptoms conserved across psychotic disorders, such as executive dysfunction.
authors.affiliation: Department of Psychology, Macquarie University, Sydney, NSW, Australia.
authors.forename: Travis A
authors.initials: TA
authors.lastname: Wearne
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Parker
authors.affiliation: Department of Psychology, Macquarie University, Sydney, NSW, Australia.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Franklin
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Goodchild
authors.affiliation: Department of Psychology, Macquarie University, Sydney, NSW, Australia. Electronic address: jennifer.cornish@mq.edu.au.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cornish
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D050485:GABA Plasma Membrane Transport Proteins; C546258:Gabra3 protein, mouse; C546266:Gabrb1 protein, mouse; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C493419:Slc6a13 protein, mouse; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid
keywords: GABA; Gene expression sensitization; Methamphetamine; Prefrontal cortex; Psychosis