THE CONSTITUTIVE ACTIVITY OF THE HISTAMINE H1 RECEPTOR INTERACTION WITH THE NMDA RECEPTOR : CONSEQUENCES IN EPILEPSY

Abstract

SummaryObjectivesTo explore the epileptogenic effects of several drugs specific to the antihistaminic H1 receptor on NMDA and GABA responses.MethodsWith patch-clamp whole-cell recordings of hippocampal neurons of rats, we observe the effects of several histaminergic agonists and antagonists on the NMDA and GABA currents. During the NMDA rundown and GABA rundown, we applied the drugs and observe the effect on the responses, and compare them to control conditions.ResultsMepyramine with nanomolar concentrations increases significantly the NMDA responses about 35 %, this effect is mimicked by another Anti H1 drug Triprolidine. Histamine alone has no effect on NMDA rundown but 100 μM Histamine can reduce partially the effect of Mepyramine. An H1 receptor agonist 2,3 Bromophenyl Histamine also shows the same properties as Histamine. The H1 receptor of Histamine seems to be crucial during these experiments, blockade of its constitutive activity by Mepyramine induces a significant increase of the NMDA responses. On the GABA response, the same nanomolar dose of Mepyramine has no effect on the rundown and we also observed no effect of Histamine on the GABA rundown.SignificanceAn interaction between Histamine H1 receptor and the NMDA is revelated by using Mepyramine in nanomolar concentration, Histamine has no effect on these responses also in these experiments Mepyramine acts as an inverse agonist blocking the constitutive activity of the H1 receptor. The constitutive activity of the H1 receptor seems to be crucial in the regulation of NMDA receptor activities.Keys Pointsͦ The use of antihistaminic H1 drugs can facilitate the apparition of epileptic seizures,ͦ During rundown experiments, Mepyramine, a high potent H1 antagonist increased the NMDA responses, while Histamine as no effect.ͦ On GABA rundown both Mepyramine and Histamine show no effect.ͦ Constitutive activity of the Histamine H1 receptor seems to be crucial for the NMDA receptor activity.