Actions of betahistine at histamine receptors in the brain.
The actions of betahistine (N alpha-methyl-2-pyridylethylamine) on brain histamine receptors were investigated in a series of biological models. [3H]Mepyramine binding to H1-receptors in membranes from guinea-pig cerebellum was inhibited by betahistine with a Ki value of 31 microM. The binding of [3H]mepyramine in brain of the living mouse was inhibited by betahistine in high dosages (150-300 mg/kg). In slices from mouse cerebral cortex, betahistine induced [3H]glycogen hydrolysis in a concentration-dependent manner with an EC50 value of 9.0 microM with a maximal effect 57% that of histamine. Mepyramine and triprolidine, two H1-receptor antagonists, inhibited the betahistine-induced glycogenolysis with Ki values of 28 nM and 7 nM respectively. In slices from guinea-pig hippocampus, betahistine stimulated the accumulation of cyclic AMP in the presence of 5 microM impromidine, a H2-receptor agonist. The maximal effect represented 22% of that elicited by histamine at the H1-receptor and the EC50 value was 32.4 microM. Mepyramine at 0.1 microM partially blocked the response to betahistine. Together these various observations indicate that betahistine is a partial agonist at cerebral H1-receptors. Finally, betahistine was not an agonist at histamine H3-autoreceptors but was a rather potent antagonist of the inhibitory effect of exogenous histamine on [3H]histamine release elicited by K+ depolarisation in slices from rat cerebral cortex (Ki = 6.9 microM).
Arrang
J M
JM
Garbarg
M
M
Quach
T T
TT
Dam Trung TuongM
Yeramian
E
E
Schwartz
J C
JC
D000818:Animals; D001621:Betahistine / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D011738:Pyrilamine / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects* / Q000378:metabolism
D011725:Pyridines; D011968:Receptors, Histamine; D006003:Glycogen; D000242:Cyclic AMP; D011738:Pyrilamine; D001621:Betahistine