Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, J5, 68159 Mannheim, Germany.
Eur Arch Psychiatry Clin Neurosci. 2013 Jun;263(4):285-97. doi: 10.1007/s00406-012-0367-y. Epub 2012 Sep 12.
The molecular etiology of schizophrenia comprises abnormal neurotransmission of the amino acid GABA (γ-aminobutyric acid). Neuropathological studies convincingly revealed reduced expression of glutamic acid decarboxylase (Gad67) in GABAergic interneurons. Several antipsychotics influence the expression of GABAergic genes, but aripiprazole (APZ), a partial dopaminergic and serotonergic receptor agonist, has not been involved into these studies so far. We treated Sprague-Dawley rats for 4 weeks or 4 months with APZ suspended in drinking water and doses of 10 and 40 mg per kg body weight. Gene expression of Gad67, the vesicular GABA transporter Slc32a1 (solute carrier family, Vgat), the transmembrane transporters Slc6a1 (Gat1) and Slc6a11 (Gat3) was assessed by semiquantitative radioactive in situ hybridization. APZ treatment resulted in time- and dose-dependent effects with qualitative differences between brain regions. In the 10-mg group, Slc6a1 was strongly induced after 4 weeks in the hippocampus, amygdala, and cerebral cortex, followed by an induction of Gad67 in the same regions after 4 months, while frontocortical regions as well as basal ganglia showed dose-dependent reductions of Gad67 expression after 4 months. In several frontocortical and subcortical regions, we observed a decrease of Slc32a1 and an increase of Slc6a11 expression. In conclusion, APZ modulates gene expression of GABAergic marker genes involved into pathogenetic theories of schizophrenia. APZ only partially mirrors the effects of other antipsychotics with some important differences regarding brain regions. The findings might be explained by regulatory connections between serotonergic, GABAergic, and dopaminergic neurotransmission and should be validated in behavioral animal models of psychotic disorders.
精神分裂症的分子病因包括氨基酸 GABA（γ-氨基丁酸）的神经递质传递异常。神经病理学研究令人信服地表明 GABA 能中间神经元中谷氨酸脱羧酶（Gad67）的表达减少。几种抗精神病药物会影响 GABA 能基因的表达，但阿立哌唑（APZ），一种部分多巴胺和 5-羟色胺受体激动剂，迄今为止尚未参与这些研究。我们用 APZ 悬浮在饮用水中治疗 Sprague-Dawley 大鼠 4 周或 4 个月，剂量为 10 和 40mg/kg 体重。通过半定量放射性原位杂交评估 Gad67、囊泡 GABA 转运体 Slc32a1（溶质载体家族，Vgat）、跨膜转运体 Slc6a1（Gat1）和 Slc6a11（Gat3）的基因表达。APZ 治疗具有时间和剂量依赖性效应，并且脑区之间存在定性差异。在 10mg 组中，海马体、杏仁核和大脑皮层中的 Slc6a1 在 4 周后强烈诱导，随后在 4 个月后在相同区域诱导 Gad67，而额皮质区域和基底神经节在 4 个月后表现出剂量依赖性的 Gad67 表达减少。在几个额皮质和皮质下区域，我们观察到 Slc32a1 表达减少和 Slc6a11 表达增加。总之，APZ 调节参与精神分裂症发病机制理论的 GABA 能标记基因的基因表达。APZ 仅部分反映了其他抗精神病药物的作用，并且在脑区方面存在一些重要差异。这些发现可以通过 5-羟色胺能、GABA 能和多巴胺能神经传递之间的调节关系来解释，并且应该在精神障碍的行为动物模型中得到验证。
