Pharmacological characterization of senktide-induced tail whips.
The tachykinin NK(3) receptor shows promise as a novel target for antipsychotics, but knowledge of downstream activity following tachykinin NK(3) receptor activation is lacking. To determine the practical utility of senktide-induced tail whips in mice as a tool for determining and characterizing downstream activity following tachykinin NK(3) receptor activation, mice were injected with 0.05 nmol of senktide i.c.v. and the number of tail whip bouts was counted for 20 min. Strain differences were observed, with NMRI mice showing a stronger tail whip response than C57Bl/6J mice. Tachykinin NK(3) receptor specificity was confirmed by the absence of the senktide-induced tail whip response in tachykinin NK(3) receptor knockout mice. Effects of tachykinin receptor pharmacological agents were tested by pretreatment with tachykinin NK(3) receptor antagonists (SB222200, talnetant and osanetant), which attenuated senktide-induced tail whips, and the tachykinin NK(1) receptor antagonist MK869, which had no effect on senktide-induced tail whips. Pharmacological interactions with other neurotransmitter systems were determined by pretreatment with dopamine D(1), D(2), and D(3) receptor antagonists, atypical antipsychotics, serotonin 5HT(1a) receptor antagonists, serotonin 5HT(2a/c) receptor antagonists, benzodiazepine and putative anxiolytics, antidepressants, and an anticholinergic. Senktide-induced tail whips were attenuated by dopamine D(2) receptor antagonists, atypical antipsychotics, serotonin 5HT(2a/c) antagonists, and benzodiazepine anxiolytics, but unaffected by drugs from other classes. Thus, the senktide-induced tail whip response is easily quantifiable, specific to the tachykinin NK(3) receptor, and provides valuable information on the downstream pharmacology of tachykinin NK(3) receptor activation.
Nordquist
Rebecca E
RE
F. Hoffmann-La Roche Ltd, Pharma Research Basel Discovery, Neuroscience, Building 72-148, CH-4070 Basel, Switzerland. r.e.nordquist1@uu.nl
Ballard
Theresa M
TM
Algeyer
Brigitte
B
Pauly-Evers
Meike
M
Ozmen
Laurence
L
Spooren
Will
W
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D001526:Behavioral Symptoms / Q000139:chemically induced*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D018042:Receptors, Neurokinin-3 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000172:deficiency; D012702:Serotonin Antagonists / Q000494:pharmacology; D013045:Species Specificity; D018709:Statistics, Nonparametric; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology; D013623:Tail / Q000187:drug effects* / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D018042:Receptors, Neurokinin-3; D012702:Serotonin Antagonists; C054724:senktide; D013373:Substance P