The gerbil elevated plus-maze II: anxiolytic-like effects of selective neurokinin NK1 receptor antagonists.
Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity.
Varty
Geoffrey B
GB
CNS Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Geoffrey.Varty@SPCorp.com
Cohen-Williams
Mary E
ME
Morgan
Cynthia A
CA
Pylak
Ursula
U
Duffy
Ruth A
RA
Lachowicz
Jean E
JE
Carey
Galen J
GJ
Coffin
Vicki L
VL
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000077608:Aprepitant; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D005849:Gerbillinae; D018782:Maze Learning / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology
D014151:Anti-Anxiety Agents; D000900:Anti-Bacterial Agents; C089367:L 733560; C099406:L 742694; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D001569:Benzodiazepines; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D000077608:Aprepitant; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine