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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >Dopamine D4 receptor deficiency in mice alters behavioral responses to anxiogenic stimuli and the psychostimulant methylphenidate
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Dopamine D4 receptor deficiency in mice alters behavioral responses to anxiogenic stimuli and the psychostimulant methylphenidate

机译：小鼠的多巴胺D4受体缺乏对小鼠改变了对焦虑刺激和精神胆致甲基酚的行为反应

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摘要

An allele of the human dopamine D4 receptor (D4R) gene (DRD4), containing seven tandem repeats of a 48-base nucleotide sequence (DRD4.7), has been reproducibly found in novelty seekers, substance abusers, and individuals with attention-deficit hyperactivity disorder. One hypothesis predicts the resultant protein product of the DRD4.7 polymorphism is deficient in G protein-coupled signaling. If attenuated D4R signaling contributes to these complex behaviors, then wild-type (WT) mice and mice completely lacking D4Rs (D4R KO) might be expected to display significantly different behavioral responses to stimuli known to affect dopamine signaling, such as novelty or psychostimulants. Adolescent male D4R KO mice exhibited greater locomotor activity and spent less time in the anxiogenic center of a novel open field environment than WT littermates. The presence of D4Rs had no effect on emergence into a novel environment from a sheltered space or exploration of a novel object. Low doses of acute methylphenidate (MP) had no effect on the exploration of a novel object, but dose-dependently increased the latency to emerge into a novel environment from a sheltered space. WT and D4R KO mice responded differently to high doses of acute MP, displaying significantly elevated locomotor activity and reduced stereotypy relative to WT mice. Chronic MP treatment produced enhanced locomotor sensitization in D4R KO mice, however this effect could not be fully recapitulated using the putative D4R antagonist L-745-870. These studies suggest that the roles of D4R signaling in novelty-seeking behaviors and the response to psychostimulants are not as clear as previously reported, and that some of these effects may be due to developmental compensatory effects as a consequence of lost D4R expression. If the DRD4.7 variant results in deficient D4R signaling in vivo, this may contribute to an elevated risk of sensitization to drugs of abuse including psychostimulants used to treat ADHD. ? 2012 Elsevier Inc.
机译：含有48个碱核苷酸序列（DRD4.7）的七次串联重复的人多巴胺D4受体（D4R）基因（DRD4）的等位基因已在新奇寻求者，物质滥用者和有关注赤字的个人中复制地发现多动障碍。一个假设预测了DRD4.7多态性的所得蛋白质产物缺乏G蛋白偶联信号。如果衰减的D4R信号传导有助于这些复杂的行为，则可能预期野生型（WT）小鼠和完全缺乏D4RS（D4R KO）的小鼠，以显示出对影响多巴胺信号传导的刺激的显着不同的行为反应，例如新奇或精神疗法。青春期男性D4R KO小鼠在新颖的开放场环境的焦虑中心表现出更大的运动活性，并且在比WT凋落物的焦虑中心少花费。 D4RS的存在对从庇护的空间或新型物体探索的新环境中的出现没有影响。低剂量的急性甲基苯胺（MP）对新物体的探索没有影响，但剂量依赖性增加了从遮挡空间中出现的新环境的潜伏期。 WT和D4R KO小鼠对高剂量的急性MP反应，显示出显着升高的运动活性和相对于WT小鼠的陈规定型型。慢性MP处理在D4R KO小鼠中产生了增强的运动致敏，但是使用推定的D4R拮抗剂L-745-870无法完全重新携带这种效果。这些研究表明，D4R信号传导在新颖的寻求行为中的作用以及对精神疗法的反应并不像先前报道那样清楚，并且一些这些效果可能是由于失去D4R表达的发育补偿效果导致的。如果DRD4.7变体导致体内D4R信号传导缺陷，这可能有助于对滥用药物敏感的升高风险，包括用于治疗ADHD的精神疗法。还2012年elsevier公司

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