Potschka H, Fedrowitz M, Löscher W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1999 Jun 18;374(2):175-87. doi: 10.1016/s0014-2999(99)00311-8.
Electrical kindling in rats has previously been shown to cause a hypersensitivity to amphetamine-like behavioral effects of competitive NMDA receptor antagonists such as D,L-(E)-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), or 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate (SDZ EAA 494; D-CPPene). From this observation, it was concluded that kindling-induced epileptogenesis enhances the potential of competitive NMDA receptor antagonists to induce such unwanted adverse effects, predicting that such drugs may induce more severe side effects in epileptic patients than in healthy volunteers, which was confirmed in clinical trials. In the present study, we thought to examine the biochemical basis for the enhanced susceptibility of kindled rats to amphetamine-like behavioral effects of NMDA receptor antagonists by measuring extracellular levels of dopamine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin (5-hydroxytryptamine, 5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of awake, behaving rats, using in vivo microdialysis. When administered systemically, D-CPPene, 15 mg/kg i.p., caused more intense stereotyped behaviors in kindled than in non-kindled rats. While there was no significant alteration in extracellular dopamine, in both groups of rats HVA and 5-HIAA significantly increased. In kindled rats, basal levels of HVA and the increase in HVA in response to D-CPPene were higher compared to non-kindled animals. When administered intrastriatally via the microdialysis probe, D-CPPene, 10 microM, significantly increased dopamine, HVA and 5-HIAA, which was associated with stereotyped behaviors. Again, these behaviors were more intense in kindled rats. The data indicate that a competitive NMDA receptor antagonist at high, behaviorally active doses induces increases in striatal dopamine and presumably also 5-HT release, which most likely underlie the amphetamine-like behavioral effects of such a drug. Kindling enhances the sensitivity to these behavioral effects, which could be related to a more marked dopamine and 5-HT release. Thus, in order to avoid false predictions for the clinical situation, it is important to study the behavioral and biochemical effects of NMDA receptor antagonists not only in naive, healthy animals but also in animals that mimic the disease for which a drug is developed.
先前的研究表明，在大鼠中电刺激诱发点燃效应会导致其对竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂如D,L-(E)-氨基-4-甲基-5-膦酰基-3-戊烯酸（CGP 37849）、D-(E)-2-氨基-4-甲基-5-膦酰基-3-戊烯酸（CGP 40116）或3-(2-羧基哌嗪-4-基)丙烯基-1-膦酸酯（SDZ EAA 494；D-CPPene）的苯丙胺样行为效应产生超敏反应。基于这一观察结果，得出的结论是，点燃诱导的癫痫发生增强了竞争性NMDA受体拮抗剂诱发此类不良副作用的可能性，据此预测此类药物在癫痫患者中可能比在健康志愿者中诱发更严重的副作用，这在临床试验中得到了证实。在本研究中，我们试图通过测量清醒、行为活跃的大鼠纹状体中多巴胺、多巴胺代谢产物二羟基苯乙酸（DOPAC）和高香草酸（HVA）以及血清素（5-羟色胺，5-HT）代谢产物5-羟吲哚乙酸（5-HIAA）的细胞外水平，来研究点燃大鼠对NMDA受体拮抗剂苯丙胺样行为效应易感性增强的生化基础，采用体内微透析技术。腹腔注射15 mg/kg的D-CPPene后，与未点燃大鼠相比，点燃大鼠出现了更强烈的刻板行为。虽然两组大鼠的细胞外多巴胺水平没有显著变化，但HVA和5-HIAA均显著升高。与未点燃动物相比，点燃大鼠的HVA基础水平以及对D-CPPene反应时HVA的增加幅度更高。通过微透析探针纹状体内注射10 μM的D-CPPene后，多巴胺、HVA和5-HIAA显著增加，这与刻板行为相关。同样，这些行为在点燃大鼠中更为强烈。数据表明，高剂量、具有行为活性的竞争性NMDA受体拮抗剂会诱导纹状体多巴胺增加，推测也会诱导5-HT释放，这很可能是此类药物苯丙胺样行为效应的基础。点燃增强了对这些行为效应的敏感性，这可能与更显著的多巴胺和5-HT释放有关。因此，为了避免对临床情况做出错误预测重要的是不仅要在未接触过药物的健康动物中，还要在模拟药物所针对疾病的动物中研究NMDA受体拮抗剂的行为和生化效应。
