Kegeles L S, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann J J, Van Heertum R L, Cooper T B, Carlsson A, Laruelle M
Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York, New York 10032, USA.
Biol Psychiatry. 2000 Oct 1;48(7):627-40. doi: 10.1016/s0006-3223(00)00976-8.
Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans.
In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM.
Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023).
The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.
近期的脑成像研究表明，精神分裂症与纹状体中苯丙胺诱导的多巴胺释放增加有关。长期以来，人们一直推测，精神分裂症患者皮层下多巴胺系统的失调可能是由于前额叶皮层（PFC）未能充分控制皮层下多巴胺能功能所致。中脑多巴胺能神经元的活动部分受来自PFC的谷氨酸能投射通过谷氨酸能N-甲基-D-天冬氨酸（NMDA）受体调节。本研究的目的是检验以下假设：药理学诱导的NMDA传递中断会导致人类苯丙胺诱导的多巴胺释放增加。
在8名健康志愿者中，我们比较了在对照条件下以及在通过输注非竞争性NMDA拮抗剂氯胺酮（0.2mg/kg静脉推注，随后以0.4mg/kg/小时静脉输注4小时）诱导的NMDA传递持续中断的情况下，纹状体中苯丙胺诱导的（0.25mg/kg）多巴胺释放。通过单光子发射计算机断层扫描测定苯丙胺诱导的多巴胺释放，即放射性标记的D（2）受体拮抗剂[（123）I]IBZM的结合潜能（BP）降低。
氯胺酮显著增强了苯丙胺诱导的[（123）I]IBZM BP降低，从对照条件下的-5.5%±3.5%增加到氯胺酮预处理后的-12.8%±8.8%（重复测量方差分析，p = 0.023）。
氯胺酮诱导的苯丙胺诱导的多巴胺释放增加（超过两倍）在幅度上与精神分裂症患者中观察到的过度反应相当。这些数据与以下假设一致：精神分裂症患者中苯丙胺激发所揭示的多巴胺释放改变是由调节多巴胺能细胞活动的谷氨酸能神经元系统破坏所致。
