Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model

The selective H-3 receptor agonist (R)-alpha-methylhistainine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H3 receptor in mediating this behavior in a new dipsogenia model using the CD-I mouse. In addition, the putative inverse agonists ciproxifian, 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 mumol/kg (R)-alpha-MeKA, but this effect was dependent on age (P30<P60<P80=P120). [H-3]-N-alpha-methylhistamine binding studies showed no change in H3 receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 mumol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 mumol/kg), thioperamide (0.01-10 mumol/kg), clobenpropit (0.1-30 mumol/kg) and GT-2331 (0.03-10 mumol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 mumol/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 H3 receptor inverse agonists, GT-2331 and proxyfan. (C) 2002 Elsevier Science Inc. All rights reserved.