State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China.
Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China.
Mol Neurobiol. 2018 Sep;55(9):7567-7578. doi: 10.1007/s12035-018-0877-3. Epub 2018 Feb 10.
Drug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicated N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such as GluN3A, GluN2B, and GluN2A with various addiction-related phenotypes. Of these genes, GluN3A has been the most studied, and it has been revealed to play crucial roles in the etiology of addictions. In this communication, we provide an updated view of the genetic effects of NMDA receptor subunit genes and their functions in the etiology of addictions based on the findings from investigation of both common and rare variants as well as SNP-SNP interactions. To better understand the molecular mechanisms underlying addiction-related behaviors and to promote the development of specific medicines for the prevention and treatment of addictions, current efforts aim not only to identify more causal variants in NMDA receptor subunits by using large independent samples but also to reveal the molecular functions of these variants in addictions.
药物依赖是一种慢性脑部疾病，对个体使用者和社会都有有害的后果。谷氨酸是大脑中的主要兴奋性神经递质，体内和体外实验都表明 N-甲基-D-天冬氨酸（NMDA）受体，一种谷氨酸受体，是各种类型成瘾的一个元素。基于遗传学方法的最新发现，如全基因组连锁、候选基因关联、全基因组关联（GWA）和下一代测序，已经证明 NMDA 受体亚基基因如 GluN3A、GluN2B 和 GluN2A 与各种与成瘾相关的表型有显著的关联。在这些基因中，GluN3A 是研究最多的，它被揭示在成瘾的病因中起着关键作用。在本通讯中，我们根据对常见和罕见变异以及 SNP-SNP 相互作用的研究结果，提供了 NMDA 受体亚基基因的遗传效应及其在成瘾病因学中的作用的最新观点。为了更好地理解与成瘾相关的行为的分子机制，并促进预防和治疗成瘾的特定药物的发展，目前的努力不仅旨在通过使用大的独立样本来识别 NMDA 受体亚基中的更多因果变异，还旨在揭示这些变异在成瘾中的分子功能。
