Bourson A, Kapps V, Zwingelstein C, Rudler A, Boess F G, Sleight A J
Pharma Division, Preclinical Research, F. Hoffmann-La Roche, Basel, Switzerland.
Naunyn Schmiedebergs Arch Pharmacol. 1997 Dec;356(6):820-6. doi: 10.1007/pl00005123.
Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affinity and doses for half-maximal response (ED50) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that interactions between the 5-ht5 receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht5 receptor. There are similarities between the pharmacology of the 5-HT7 receptor and that of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significant. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT7 antagonists.
高强度听觉刺激可诱发DBA/2J小鼠出现听源性癫痫发作。包括5-羟色胺（5-HT）在内的多种神经递质被认为参与介导了这一效应，因为先前的研究表明，5-HT耗竭或5-HT受体阻断可保护DBA/2J小鼠免受这些听源性癫痫发作的影响。本研究旨在通过尝试将化合物的体内效价与其对5-HT7受体的亲和力相关联，来确定新发现的5-HT7受体拮抗剂是否可保护DBA/2J小鼠免受听源性癫痫发作。相关性研究中使用的所有化合物均显示为5-HT7受体拮抗剂，并且在5-HT7亲和力与保护DBA/2J小鼠免受声音诱发癫痫发作的半数最大效应剂量（ED50）之间观察到统计学上的显著相关性（r = 0.80；P < 0.05）。在5-HT1A、5-HT2A或5-HT2C受体处，未观察到体内活性与亲和力之间的显著相关性。5-HT5受体之间的相互作用也不太可能保护DBA/2J小鼠免受听源性癫痫发作，因为在该体内模型中均有活性的麦角新碱和甲磺麦角林对5-HT5受体没有亲和力。5-HT7受体的药理学与5-HT1A受体的药理学之间存在相似性，然而，DBA/2J小鼠体内效价与5-HT1A亲和力之间的相关性并不显著。此外，5-HT1A受体拮抗剂WAY 100l35在拮抗小鼠5-HT1A受体介导效应的剂量下，不能保护DBA/2J小鼠免受听源性癫痫发作。这些数据表明，5-HT7受体拮抗剂可能预防DBA/2J小鼠的听源性癫痫发作，但确切结论尚需等待对选择性5-HT7拮抗剂的研究。
