In vitro study | Most putative 5-HT neurons increased their firing rate (100635 basal firing rate) in dorsal raphe nucleus (DRN) sections perfused with WAY 13% (10 nM). In addition, WAY 100635 completely prevented the drop in discharge rates produced by 5-HT (3-15 μm),8-OH-DPAT (10 nM),5-carboxamidotryptamine (20 nM) and lesopitron (100 nM). By increasing the concentration of 5-HT to 300 μm, the antagonism exhibited by WAY 100635 was completely overcome. In hippocampal slices, WAY 100635 (0.5 nM -10 nM) did not alter resting membrane potential or intracellularly recorded cell membrane input resistance of the CA1 vertebral bodies. However, not only does WAY 100635 completely block hyperpolarization with an IC50 of 1.3 nM, it also reduces the output resistance of the films produced by 5-HT and 5-boxamidotryptamine with an IC50 of 22.5 μm and 50 nM, respectively. WAY 100635 has an IC50 of 1.35 nM for the 5-HT1A site, which is more than 100-fold more selective for a range of other CNS receptors. [[In the isolated guinea pig ileum, high concentration of WAY 100635 is a potent, unovercome antagonist of 5-carboxamidotryptamine on 5-HT1A receptor agonism, apparent pA2 value (at 0.3 nM) 9.71. [Based on the recent discovery of dopaminergic activity, the conclusions drawn in the study suggest that the use of WAY 100635 as a selective 5-HT1A antagonist may need to be re-evaluated. |
In vivo study | [In anesthetized rats, WAY 100635 blocked the inhibitory effect of 8-OH-DPAT on the discharge of dorsal raphe nucleus at a dose that itself had no inhibitory effect. In behavioral models, WAY 100635 does not induce significant behavioral changes in rats and guinea pigs by itself, but effectively antagonizes the 8-OH-DPAT-induced behavioral syndrome (minimum acting dose = 0.003 mg/kg s.c.,ID50 = 0.01 mg/kg s.c.). In mice and rats, WAY 100635 also blocked 8-OH-DPAT-induced hypothermia with an ID50 value of 0.01 mg/kg s.c. |