Department of Physiology and Pharmacology, Oregon Health & Science University School of Medicine, Portland, OR, United States.
Pharmacol Biochem Behav. 2013 Feb;103(4):831-41. doi: 10.1016/j.pbb.2012.12.006. Epub 2012 Dec 19.
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.
人类多巴胺 D4 受体 (D4R) 基因的一个等位基因（DRD4），包含一个 48 个碱基核苷酸序列（DRD4.7）的七个串联重复，在寻求新奇的人、滥用药物者和注意力缺陷多动障碍患者中反复被发现。一种假设预测，DRD4.7 多态性的结果蛋白产物在 G 蛋白偶联信号传导中是不足的。如果减弱的 D4R 信号传导导致这些复杂行为，那么野生型（WT）小鼠和完全缺乏 D4R（D4R KO）的小鼠可能会对已知影响多巴胺信号传导的刺激（如新奇事物或精神兴奋剂）表现出明显不同的行为反应。青春期雄性 D4R KO 小鼠表现出更大的运动活性，并且在新奇开阔场环境的焦虑中心花费的时间少于 WT 同窝仔鼠。D4R 的存在对从遮蔽空间进入新环境或探索新物体没有影响。急性哌甲酯（MP）的低剂量对探索新物体没有影响，但剂量依赖性地增加了从遮蔽空间进入新环境的潜伏期。WT 和 D4R KO 小鼠对急性 MP 的高剂量反应不同，与 WT 小鼠相比，它们表现出显著升高的运动活性和减少刻板行为。慢性 MP 治疗在 D4R KO 小鼠中产生增强的运动敏化，但使用假定的 D4R 拮抗剂 L-745-870 不能完全再现这种效应。这些研究表明，D4R 信号传导在寻求新奇行为和对精神兴奋剂的反应中的作用并不像以前报道的那样明确，并且这些作用中的一些可能是由于失去 D4R 表达而导致的发育代偿效应。如果 DRD4.7 变体导致体内 D4R 信号传导不足，这可能会导致对包括用于治疗 ADHD 的精神兴奋剂在内的滥用药物的敏感性升高。
