Iravani M M, Muscat R, Kruk Z L
Neurodegenerative Disease Research Centre, Pharmacology Group, Kings College London, UK.
Synapse. 1999 Jun 1;32(3):212-24. doi: 10.1002/(SICI)1098-2396(19990601)32:3<212::AID-SYN7>3.0.CO;2-M.
The effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) and a competitive NMDA antagonist, (+/-)-3-2-carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) were compared in electrically evoked 5-HT release in the brain slices incorporating the substantia nigra pars reticulata (SNr) or the dorsal raphé nucleus (DRN) using fast cyclic voltammetry (FCV). Electrical stimulation of either the SNr or the DRN with 50 pulses at frequencies greater than 10 Hz generated signals that were indistinguishable from 5-HT. In the SNr, 0.6-60 microM MK-801 concentration dependently potentiated stimulated 5-HT release. CPP 20 microM or NMDA 100 microM had no effect on 5-HT release evoked by electrical stimulation. In the SNr, 1 microM fluvoxamine or 0.6-60 microM MK-801 potentiated electrically evoked release of 5-HT. Pre-exposure to 20 microM MK-801 inhibited the enhancing effects of 1 microM fluvoxamine on electrically evoked 5-HT release in the SNr. In the DRN, the presence of 1 microM fluvoxamine or 20 microM MK-801 weakly potentiated 5-HT release. In the presence of 1 microM methiothepin (a nonselective 5-HT1-2 antagonist), 1 microM fluvoxamine or 20 microM MK-801 were equipotent in potentiating the concentration of 5-HT released in response to electrical stimulation. The T1/2 values for 5-HT release following MK-801 or fluvoxamine administration were significantly increased. Potentiation of 5-HT release by MK-801 in the SNr and the DRN and lack of effect of either CPP or NMDA on 5-HT release or uptake argues against a role for NMDA receptors in modulation of 5-HT release. Inhibition of fluvoxamine induced potentiation of 5-HT signal in the presence of MK-801 suggests that MK-801 and fluvoxamine may interact at the level of the 5-HT transporter.
使用快速循环伏安法（FCV），在包含黑质网状部（SNr）或中缝背核（DRN）的脑片中，比较了非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐环平（（+）-MK-801）和竞争性NMDA拮抗剂（+/-）-3-（2-羧基哌嗪-4-基）-丙基-1-膦酸（CPP）对电诱发5-羟色胺（5-HT）释放的影响。以大于10Hz的频率对SNr或DRN进行50次脉冲的电刺激所产生的信号与5-HT无法区分。在SNr中，0.6 - 60μM的MK-801浓度依赖性地增强了刺激引起的5-HT释放。20μM的CPP或100μM的NMDA对电刺激诱发的5-HT释放没有影响。在SNr中，1μM氟伏沙明或0.6 - 60μM的MK-801增强了电诱发的5-HT释放。预先暴露于20μM的MK-801会抑制1μM氟伏沙明对SNr中电诱发的5-HT释放的增强作用。在DRN中，1μM氟伏沙明或20μM的MK-801的存在微弱地增强了5-HT释放。在1μM甲硫噻平（一种非选择性5-HT1-2拮抗剂）存在的情况下，1μM氟伏沙明或20μM的MK-801在增强电刺激后释放的5-HT浓度方面具有同等效力。给予MK-801或氟伏沙明后5-HT释放的半衰期值显著增加。MK-801在SNr和DRN中对5-HT释放的增强作用以及CPP或NMDA对5-HT释放或摄取均无影响，这表明NMDA受体在调节5-HT释放中不起作用。在MK-801存在的情况下，氟伏沙明诱导的5-HT信号增强受到抑制，这表明MK-801和氟伏沙明可能在5-HT转运体水平相互作用。
