Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences, Institut National de la Santé et de la Recherche Médicale, 2 ter Rue d'Alésia, 75014 Paris, France.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):945-54. doi: 10.1124/jpet.110.168633. Epub 2010 Jun 8.
We previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, we have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs. The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.
我们之前提出倍他司汀在前庭疾病中的治疗作用源于其对组胺 H（3）受体（H（3）R）的拮抗剂特性。然而，H（3）R 表现出组成型活性，并且大多数 H（3）R 拮抗剂作为反向激动剂。在这里，我们研究了倍他司汀在重组 H（3）R 同工型上的作用。在抑制 cAMP 形成和 [(3)H]花生四烯酸释放方面，倍他司汀表现为纳米摩尔反向激动剂和微摩尔激动剂。这两种作用均被百日咳毒素抑制，在所有测试的同工型中均发现，并且在模拟细胞中未检测到，证实了与 H（3）R 的相互作用。倍他司汀的反向激动剂效力及其对 [(125)I]碘普罗芬结合的亲和力在大鼠和人类中相似。然后，我们通过测量小鼠大脑中的 tele-methylhistamine（t-MeHA）水平来研究倍他司汀对组胺神经元活性的影响。其急性腹腔内给药以 0.4mg/kg 的 ED（50）增加 t-MeHA 水平，表明反向激动作用。在较高剂量下，t-MeHA 水平逐渐恢复到基础水平，这种情况可能是由于激动作用所致。急性口服给药后，倍他司汀以 2mg/kg 的 ED（50）增加 t-MeHA 水平，右移可能是由于几乎完全的首过代谢所致。在每种情况下，倍他司汀的最大作用均低于西普罗芬，表明部分反向激动作用。口服 8 天治疗后，倍他司汀的唯一有效剂量为 30mg/kg，表明已产生耐受性。这些数据强烈表明，倍他司汀的治疗作用源于 H（3）自受体的反向激动作用诱导的组胺神经元活性增强。
