Wlaź P, Ebert U, Potschka H, Löscher W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1998 Jul 24;353(2-3):177-89. doi: 10.1016/s0014-2999(98)00409-9.
We have previously reported that a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), produces stereotyped behaviors and hyperlocomotion in amygdala kindled rats at doses which do not induce such phencyclidine (PCP)-like behaviors in nonkindled rats, indicating that kindling predisposes rats to such adverse effects of competitive NMDA receptor antagonists. From these data we predicted that epileptic patients may exhibit a hypersensitivity to PCP-like adverse effects of competitive NMDA receptor antagonists, which was subsequently confirmed in a clinical trial with D-CPPene (SDZ EAA-494; 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate). For further exploration of the functional alterations in NMDA receptor responsiveness produced by kindling, we studied whether the enhanced susceptibility of amygdala-kindled rats to PCP-like adverse effects of CGP 37849 is also observed with D-CPPene. Furthermore, we determined whether the enhanced susceptibility of kindled rats to such adverse effects occurs only after relatively short intervals following the last seizure, as used in our previous study, or is a more permanent phenomenon. For this purpose, we compared adverse effects in kindled rats not only with naive (non-implanted) controls, as done in our previous study, but used electrode-implanted nonkindled rats as an additional control to assess the possible bias of mere electrode-implantation. In addition, we studied whether the enhanced susceptibility to NMDA receptor antagonists of electrically kindled rats is also present in chemically kindled animals. In some experiments, the PCP-like uncompetitive NMDA receptor antagonist MK-801 (dizocilpine) was included for comparison. In amygdala kindled rats, D-CPPene produced significantly more stereotyped behaviors than in electrode-implanted or naive nonkindled controls. The enhanced sensitivity of electrically kindled rats to PCP-like stereotypies induced by D-CPPene was observed both 7 and 180 days after the last kindled seizure, indicating a long-lasting if not permanent hypersensitivity to these adverse effects. In addition, more intense circling was observed in amygdala kindled rats, whereas hyperlocomotion only tended to be more intense after D-CPPene in kindled rats. These alterations in D-CPPene-induced behaviors were not observed after chemical kindling with pentylenetetrazole, but D-CPPene induced significantly less hypothermia in chemically kindled rats both 7 and 70 days after the last seizure. The data demonstrate that kindling produces long-lasting alterations in some adverse effects of D-CPPene, substantiating that epileptogenesis as initiated by kindling renders the brain more susceptible to PCP-like behavioral side effects of competitive NMDA receptor antagonists.
我们之前曾报道，一种竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，DL-[E]-2-氨基-4-甲基-5-膦酰基-3-戊烯酸（CGP 37849），在杏仁核点燃大鼠中产生刻板行为和运动亢进，而在未点燃大鼠中，相同剂量不会诱导出类似苯环己哌啶（PCP）的行为，这表明点燃使大鼠对竞争性NMDA受体拮抗剂的此类不良反应更敏感。基于这些数据，我们预测癫痫患者可能对竞争性NMDA受体拮抗剂的类似PCP的不良反应表现出超敏反应，随后在一项使用D-CPPene（SDZ EAA-494；3-(2-羧基哌嗪-4-基)丙烯基-1-膦酸酯）的临床试验中得到证实。为了进一步探究点燃引起的NMDA受体反应性的功能改变，我们研究了杏仁核点燃大鼠对CGP 37849类似PCP不良反应的易感性增强是否也见于D-CPPene。此外，我们确定点燃大鼠对这种不良反应的易感性增强是否仅在如我们之前研究中那样的最后一次癫痫发作后的相对短时间内出现，还是一种更持久的现象。为此，我们不仅像之前研究那样将点燃大鼠的不良反应与未处理（未植入电极）的对照进行比较，还使用植入电极的未点燃大鼠作为额外对照，以评估单纯电极植入可能产生的偏差。此外，我们研究了电点燃大鼠对NMDA受体拮抗剂的易感性增强在化学点燃动物中是否也存在。在一些实验中，还纳入了类似PCP的非竞争性NMDA受体拮抗剂MK-801（地佐环平）进行比较。在杏仁核点燃大鼠中，D-CPPene产生的刻板行为明显多于植入电极或未处理的未点燃对照。在最后一次点燃发作后的7天和180天，均观察到电点燃大鼠对D-CPPene诱导的类似PCP刻板行为的敏感性增强，表明对这些不良反应存在持久（即便不是永久性）的超敏反应。此外，在杏仁核点燃大鼠中观察到更剧烈的转圈行为，而点燃大鼠在给予D-CPPene后仅运动亢进倾向更明显。在用戊四氮进行化学点燃后，未观察到D-CPPene诱导行为的这些改变，但在最后一次癫痫发作后的7天和70天，D-CPPene在化学点燃大鼠中诱导的体温过低明显减轻。数据表明，点燃使D-CPPene的某些不良反应产生持久改变，证实由点燃引发的癫痫发生使大脑更容易受到竞争性NMDA受体拮抗剂类似PCP的行为副作用影响。
