Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK1 receptor antagonist.
The selective tachykinin NK1 receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine (MK-869), has been recently described as a novel therapeutic approach for anxiety/depression. A frequently used model to establish the central nervous system (CNS) activity of tachykinin NK1 receptor antagonists is the inhibition of NK1 agonist-induced foot tapping in gerbils. In the present study, we demonstrate that foot tapping can also be induced in most, but not all, gerbils by footshock and associated cues. MK-869 (0.3-3 mg/kg, i.p.) dose-dependently blocked this foot tapping response. This effect was further shown to be due to selective NK1 receptor blockade, since (2S,3S)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 3 mg/kg, i.p.) inhibited foot tapping, whereas its less active enantiomer (2R,3R)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-100,263; 3 mg/kg, i.p.) had no effect. Diazepam (1-10 mg/kg, i.p.) also inhibited foot tapping, whereas fluoxetine (10-30 mg/kg, i.p.) markedly increased this behaviour. The present data support the view that foot tapping in the gerbil is a behavioural response to an aversive stimulus, and is robustly inhibited by two NK1 receptor antagonists. The data support a role for tachykinin NK1 receptor antagonists as novel anxiolytic/antidepressants.
Ballard
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Preclinical CNS Research, PRBN-B, Bau 72/149, F. Hoffmann-La Roche AG, CH-4070, Basel, Switzerland. THERESA_M.BALLARD@Roche.com
Sänger
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S
Higgins
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GA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D000077608:Aprepitant; D003216:Conditioning, Operant; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D005849:Gerbillinae; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism
D014151:Anti-Anxiety Agents; D018687:Antidepressive Agents, Second-Generation; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D005473:Fluoxetine; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D000077608:Aprepitant; D003975:Diazepam