Van Waes Vincent, Vandrevala Malcolm, Beverley Joel, Steiner Heinz
Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
Addict Biol. 2014 Nov;19(6):986-95. doi: 10.1111/adb.12067. Epub 2013 Jun 13.
There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.
精神兴奋药，如哌醋甲酯（利他林；多巴胺再摄取抑制剂），在医学治疗中以及作为健康人的认知增强剂的使用正在增加。已知哌醋甲酯会产生一些与成瘾相关的基因调控。动物模型的最新研究结果表明，包括氟西汀在内的选择性5-羟色胺再摄取抑制剂（SSRI）可增强哌醋甲酯对基因表达的急性诱导作用，从而表明5-羟色胺在多巴胺诱导的基因调控中具有急性促进作用。我们研究了在青春期大鼠中，反复给予氟西汀并联合哌醋甲酯，是否会促进对反复接触可卡因等非法精神兴奋药所确立的基因调控效应——使基因诱导性减弱（抑制）。我们通过原位杂交组织化学法，测量了用哌醋甲酯（5毫克/千克）、氟西汀（5毫克/千克）或两者联合进行为期5天的反复治疗，对纹状体中神经可塑性相关基因（Zif268、Homer1a）受可卡因诱导的诱导性的影响。单独反复给予哌醋甲酯产生的基因减弱作用极小，而单独给予氟西汀则无作用。相比之下，在哌醋甲酯中加入氟西汀可显著增强哌醋甲酯对这两种基因的诱导减弱作用。这种增强作用在整个纹状体中都有，但在外侧感觉运动纹状体中最为显著，从而模拟了可卡因的作用。对于非法精神兴奋药，基因表达减弱被认为是成瘾分子基础的一部分。因此，我们的研究结果表明，诸如氟西汀之类的SSRI可能会增加哌醋甲酯的成瘾倾向。
