Altered prefrontal dopaminergic function in chronic recreational ketamine users
Altered prefrontal dopaminergic function in chronic recreational ketamine users
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DOI：
10.1176/appi.ajp.162.12.2352
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发表时间：
2005-12-01
影响因子：
17.7
通讯作者：
Abi-Dargham, A
中科院分区：
文献类型：
--
作者：
Narendran, R;Frankle, WG;Abi-Dargham, A
目的：氯胺酮是一种非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，在人类和动物医学中用作注射麻醉剂。非法使用氯胺酮作为娱乐性药物的情况正在迅速增加。目前对人类大脑中反复接触氯胺酮的后果知之甚少。动物研究表明，前额叶多巴胺能系统是特别容易受到重复给药的NMDA拮抗剂的毒性作用。在这项研究中，多巴胺D-1受体的可用性进行了评估，通过使用正电子发射断层扫描和选择性D-1受体放射性配体[C-11] NNC 112在一组14个娱乐性慢性氯胺酮用户和匹配的健康subjects.Method：氯胺酮滥用的历史被证实在受试者的头发分析。[C-11] NNC 112结合电位采用动脉输入函数进行动力学分析测定。结果：与对照受试者（平均值= 1.35 ml/g，SD = 0.35）相比，长期氯胺酮使用者（[C-11] NNC 112结合电位：平均值= 1.68 ml/g，SD = 0.40）的背外侧前额叶皮层D-1受体可用性显著上调。在其他皮质、边缘系统或纹状体区域没有发现显著差异。在长期氯胺酮使用者组中，背外侧前额叶皮层[C-11] NNC 112结合电位上调与氯胺酮小瓶数量显著相关（一小瓶约200-300 mg氯胺酮）。结论：长期氯胺酮使用者表现出背外侧前额叶皮层D-1受体可用性的区域选择性上调，这是在动物研究中观察到的慢性多巴胺耗竭后的现象。这些数据表明，重复使用氯胺酮用于娱乐目的影响前额多巴胺能传递，这是一个与工作记忆和执行功能密切相关的系统。
Objective: Ketamine is a noncompetitive antagonist at the glutamatergic N- methyl-D-aspartate (NMDA) receptor that is used in human and animal medicine as an injectable anesthetic. The illegal use of ketamine as a recreational drug is rapidly growing. Very little is currently known about the consequences of repeated ketamine exposure in the human brain. Animal studies indicate that the prefrontal dopa-minergic system is particularly vulnerable to the toxic effects of repeated administration of NMDA antagonists. In this study, dopamine D-1 receptor availability was assessed by using positron emission tomography and the selective D-1 receptor radio-ligand [C-11] NNC 112 in a group of 14 recreational chronic ketamine users and matched healthy subjects.Method: History of ketamine abuse was confirmed in subjects by hair analysis. [C-11] NNC 112 binding potential was measured with kinetic analysis using the arterial input function.Results: Dorsolateral prefrontal cortex D-1 receptor availability was significantly up-regulated in chronic ketamine users ([C-11] NNC 112 binding potential: mean = 1.68 ml/g, SD = 0.40) relative to comparison subjects (mean = 1.35 ml/g, SD = 0.35). No significant differences were noted in other cortical, limbic, or striatal regions. In the chronic ketamine user group, dorsolateral prefrontal cortex [C-11] NNC 112 binding potential up-regulation was significantly correlated with the number of vials of ketamine (with a vial representing approximately 200-300 mg of ketamine) used per week.Conclusions: Chronic ketamine users exhibited a regionally selective up-regulation of D-1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies. These data suggest that the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function.