Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model.
The selective H(3) receptor agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]imidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model. Water intake increased over baseline in a dose-related manner following intraperitoneal administration of 80, 160 or 240 micromol/kg (R)-alpha-MeHA, but this effect was dependent on age (P30<P60<P80=P120). [3H]-N-alpha-methylhistamine binding studies showed no change in H(3) receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 micromol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 micromol/kg), thioperamide (0.01-10 micromol/kg), clobenpropit (0.1-30 micromol/kg) and GT-2331 (0.03-10 micromol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 micromol/kg) only partially attenuated drinking elicited by (R)-alpha-MeHA: coadministration of proxyfan and ciproxifan resulted in an attenuation of ciproxifan's effects. This new dipsogenia model provides the first in vivo behavioral evidence for possible pharmacological differences between three putative H(3) receptor inverse agonists, GT-2331 and proxyfan.
Fox
Gerard B
GB
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9A, R4N5, Abbott Park, IL 60064-6115, USA. gerard.b.fox@abbott.com
Pan
Jia Bao
JB
Esbenshade
Timothy A
TA
Bitner
R Scott
RS
Nikkel
Arthur L
AL
Miller
Tom
T
Kang
Chae Hee
CH
Bennani
Youssef L
YL
Black
Lawrence A
LA
Faghih
Ramin
R
Hancock
Arthur A
AA
Decker
Michael W
MW
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects* / Q000502:physiology; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000502:physiology*; D013894:Thirst / Q000187:drug effects / Q000502:physiology
D017442:Histamine Agonists; D006633:Histamine Antagonists; D008024:Ligands; D018100:Receptors, Histamine H3