Ciproxifan, a Histamine H Receptor Antagonist and Inverse Agonist, Presynaptically Inhibits Glutamate Release in Rat Hippocampus

Ciproxifan is an H receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca-dependent glutamate release and cytosolic Ca concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Ca2.2 (N-type) and Ca2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A (PLA) inhibitor OBAA, prostaglandin E (PGE), PGE2 subtype 2 (EP) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca entry by diminishing PLA/PGE/EP receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.