Pharmacological characterisation of the histamine H3 receptor in the rat hippocampus.
The purpose of this report was to pharmacologically characterise the histamine H3 in the rat hippocampus using radioligand binding studies with the H3 receptor antagonist [125I]iodophenpropit and the H3 receptor mediated inhibition of [3H]noradrenaline release. A dissociation constant of 0.33 nM and a maximal number of binding sites of 125 fmol/mg protein were found for [125I]iodophenpropit. Competition studies showed stereoselectivity for the (R) and (S) enantiomers of alpha-methylhistamine and 10 microM of GTPgammaS shifted the curve of (R)-alpha-methylhistamine rightwards. Up to 1 microM, (R)-alpha-methylhistamine displaced only 30% whereas the tested H3-antagonists displaced 50-60% of the total [125I]iodophenpropit bound. This indicates the presence of an additional non-H3 receptor binding site(s) for [125I]iodophenpropit in the rat hippocampus. This secondary site shows low affinity for H3 agonists, but high affinity for the tested H3 antagonists. Electrically evoked [3H]acetylcholine release was shown in slices of rat hippocampus. No H3 receptor modulation of [3H]acetylcholine release from hippocampal slices was detectable. However, H3 receptor activation inhibited 42% of the electrically-evoked [3H]noradrenaline release in rat hippocampal slices. The inhibition of [3H]noradrenaline release was effectively antagonized by the H3 antagonists thioperamide and burimamide. We describe the pharmacological identification of the histamine H3 receptor in the rat hippocampus and its similarities and differences from the cortical H3 receptor. These studies enable us to investigate changes in density and functionality of the hippocampal H3 receptor under (patho)physiological conditions.
Alves-Rodrigues
A
A
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, Netherlands.
Timmerman
H
H
Willems
E
E
Lemstra
S
S
Zuiderveld
O P
OP
Leurs
R
R
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006633:Histamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism*; D066298:In Vitro Techniques; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D006633:Histamine Antagonists; D007093:Imidazoles; D018377:Neurotransmitter Agents; D018100:Receptors, Histamine H3; D007550:Isothiuronium; C077791:iodophenpropit; D000109:Acetylcholine; D009638:Norepinephrine