The anxiolytic-like activity of GR159897, a non-peptide NK2 receptor antagonist, in rodent and primate models of anxiety.
The non-peptide NK2 receptor antagonist, GR159897, was evaluated in two putative models of anxiety, the mouse light-dark box and the marmoset human intruder response test. Effects were compared to the structurally dissimilar NK2 antagonist, (+/-) SR48968 and the benzodiazepines, diazepam and chlordiazepoxide. GR159897 (0.0005-50 micrograms/kg SC) caused significant and dose-dependent increases in the amount of time mice spent in the more aversive light compartment of the light-dark box, with no effect on locomotor activity. (+/-)SR48968 (0.0005-0.5 microgram/kg SC) and diazepam (1-1.75 mg/kg SC), also increased time spent in the light compartment, without effect on locomotor activity. In the marmoset human intruder response test, GR159897 (0.2-50 micrograms/kg SC) significantly increased the amount of time marmosets spent at the front of the cage during confrontation with a human observer ("threat"). Similar effects were produced by (+/-)SR48968 (10-50 micrograms/kg SC) and chlordiazepoxide (0.3-3.0 mg/kg SC). These results provide further evidence, in both rodent and primate species, for the ability of NK2 antagonists to restore behaviours which have been suppressed by novel aversive environments. Such effects indicate that NK2 antagonists may have anxiolytic activity.
Department of Pharmacology, Glaxo Research & Development Ltd, Stevenage, UK.
D M
DM
Walsh
S C
SC
Stratton
F J
FJ
Harvey
I J
IJ
Beresford
R M
RM
Hagan
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010880:Piperidines / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*
D014151:Anti-Anxiety Agents; C092990:GR 159897; D007211:Indoles; D010880:Piperidines; D018041:Receptors, Neurokinin-2