Histamine H3 receptor-mediated G-protein activation in postmortem human prefrontal cortical membranes

[Speaker] Yuji Odagaki:1
[Co-author] Masakazu Kinoshita:1, Toshio Ota:1, J. Javier Meana:2, Luis F. Callado:2, Jesus A. Garcia-Sevilla:3
1:Department of Pharmacology, Saitama Medical University, Faculty of Medicine, Japan, 2:Department of Pharmacology, University of the Basque Country, Spain, 3:Laboratory of Neuropharmacology, University of the Balearic Islands, Spain

Bacground: Histamine is a modulatory neurotransmitter, regulating multiple brain functions including cognition and emotions. Accumulating evidence indicates implications of histamine H3 receptor abnormalities in psychiatric disorders. In the present study, functional activation of G-proteins coupled to histamine H3 receptor was determined in postmortem human prefrontal cortex obtained from control subjects.

Methods: Conventional [35S]GTPγS binding assay using filtration techniques was performed in human prefrontal cortical membranes, and the stimulatory effects of histamine on the specific biding were determined.

Results: The specific [35S]GTPγS binding in human prefrontal cortical membranes was stimulated by histamine in a concentration-dependent manner. The concentration-response curve of histamine-stimulated [35S]GTPγS binding was shifted rightward in parallel by the addition of increasing concentrations of iodophenpropit, a potent and selective histamine H3 receptor antagonist, with a mean pA2 value of 8.31. On the other hand, the histamine H1 receptor antagonist doxepine was less potent, with a mean pA2 of 6.79. Neither clozapine nor asenapine showed significant antagonistic effects on this response. The concentration-response curves were determined in 30 individual subjects. The mean EC50 was 404 nM (pEC50 = 6.39 ± 0.10). When the subjects were divided into the two groups depending on any drug(s) detected by toxicological screening, the pEC50 value was 5.95 ± 0.16 for the subjects in whom any drug (mainly ethanol) had been detected (N = 9). This value was significantly different compared to the pEC50 (6.58 ± 0.11) for the remainder (N = 21) (P < 0.01). There was no difference in %Emax or slope factor between the two groups.

Conclusions: In postmortem human prefrontal cortical membranes, functional activation of G-proteins coupled to histamine H3 receptor can be determined. Alcohol abuse may affect histamine H3 receptor-mediated signaling in the brain. Since species differences in pharmacological characteristics of histamine H3 receptors between human and rodents have been reported, we are planning further experiments using a series of histamine receptor ligands in brain membranes prepared from rat as well as human.
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