Wearne Travis A, Parker Lindsay M, Franklin Jane L, Goodchild Ann K, Cornish Jennifer L
Department of Psychology, Macquarie University, Sydney, NSW, Australia.
Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.
Behav Brain Res. 2016 Jan 15;297:224-30. doi: 10.1016/j.bbr.2015.10.026. Epub 2015 Oct 22.
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.
抑制性γ-氨基丁酸（GABA）介导的神经传递在额叶前皮质（PFC）的调节中起重要作用，越来越多的证据表明，PFC的GABA能处理功能失调可能是各种精神障碍中所报告的某些缺陷的基础。甲基苯丙胺（METH）是一种精神兴奋剂，在一部分使用者中会诱发慢性精神病，重复给药会使随后再次给药后出现精神病复发的易感性逐渐增加（致敏作用）。本研究的目的是使用定量聚合酶链反应（qPCR）研究对METH致敏的大鼠PFC中GABA能mRNA表达的变化。雄性Sprague-Dawley大鼠（n = 12）接受重复的甲基苯丙胺（腹腔注射（i.p.））或生理盐水注射，持续7天。停药14天后，用急性甲基苯丙胺（1mg/kg i.p.）对大鼠进行激发，然后从PFC中分离RNA，以比较一系列GABA酶、转运体和受体亚基的相对mRNA表达。与生理盐水预处理的对照组相比，METH激发导致METH预处理动物出现明显的致敏行为（运动）反应。与生理盐水对照组相比，致敏大鼠PFC中转运体（GAT1和GAT3）、离子型GABAA受体亚基（α3和β1）以及代谢型GABAB1受体的mRNA上调。这些发现表明，对METH致敏后，GABA能mRNA表达在突触前和突触后水平均发生了显著改变，致敏导致多个抑制性基因的转录上调。这些变化可能对PFC中GABA介导的神经传递产生重大影响，并可能是各种精神障碍中某些共同症状（如执行功能障碍）的基础。
