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Mepyramine, a classical H<jats:sub>1<\/jats:sub>\u2010receptor antagonist\/inverse agonist, increased the NMDA current by about 40% during the first minutes of recording. This effect was concentration\u2010dependent, maximal at 10\u2009nM, and mimicked by triprolidine, another antagonist\/inverse agonist. No endogenous histamine was detected in the cultures by a selective immunoassay; both compounds were acting as inverse agonists. Indicating a high constitutive activity of the H<jats:sub>1<\/jats:sub> receptor in this system, histamine did not affect the NMDA rundown, including its settlement, but significantly reversed the effect of mepyramine. A similar pattern was obtained with 2,3 bromophenyl histamine, a selective H<jats:sub>1<\/jats:sub>\u2010receptor agonist. The initial increase induced by the two inverse agonists was followed by the same rundown as in controls. H<jats:sub>1<\/jats:sub>\u2010 and NMDA receptors are colocalized in most cultured neuronal cells. Mepyramine and histamine did not affect the GABA rundown. Our findings suggest an interaction between H<jats:sub>1<\/jats:sub>\u2010 and NMDA receptors. Inactivation of the H<jats:sub>1<\/jats:sub>\u2010receptor by its inverse agonists delays the settlement of the NMDA rundown, which may underlie their proconvulsant effect reported in clinics. Therefore, H<jats:sub>1<\/jats:sub>\u2010receptor constitutive activity and the effect of histamine revealed in its absence, tend to facilitate the initiation of the rundown, which is consistent with the anticonvulsant properties of histamine via activation of H<jats:sub>1<\/jats:sub>\u2010receptors reported in many studies.<\/jats:p>","DOI":"10.1002\/prp2.1216","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T06:40:02Z","timestamp":1728369602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Histamine H<sub>1<\/sub>\u2010receptor\u2010mediated modulation of NMDA receptors signaling responses"],"prefix":"10.1002","volume":"12","author":[{"given":"J.\u2010M.","family":"Arrang","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris, SPPIN \u2010 Saints\u2010P\u00e8res Paris Institute for the Neurosciences, CNRS  Paris 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