The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils.
The ability of the substance P (NK(1) receptor) antagonist (SPA) L-760735 to inhibit conditioned fear was assessed in gerbils using a four plate apparatus. Animals that had been treated with diazepam (3 mg/kg) or L-760735 (3 mg/kg) 30 min before a 3 min conditioning session in the apparatus exhibited a release of plate crossings during the retest session approximately 3 h later. Plate crossings were also increased when animals received diazepam or L-760735 30 min before the retest session. In contrast, fluoxetine and venlafaxine (30 mg/kg) did not exhibit anxiolytic-like effects. During the retest session, gerbils drummed their hind feet on the floor; this behaviour was not observed spontaneously in gerbils that were naïve to the apparatus. Foot drumming was abolished by pretreatment with L-760735 or diazepam (3 mg/kg) but was markedly increased following administration of fluoxetine or venlafaxine (30 mg/kg). Foot drumming elicited by aversive conditioning alone or in combination with fluoxetine was abolished by administration of L-760735 and by amygdala lesions involving the basolateral and lateral nuclei, indicating that this behaviour is an alarm signal or fear response mediated via release of substance P in brain circuits involving the amygdala. The observations provide further evidence for an anxiolytic-like profile of SPAs in preclinical assays and demonstrate a clear difference between the actions of SPAs and established antidepressant drugs.
Rupniak
N M J
NM
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. nadia_rupniak@merck.com
Webb
J K
JK
Fisher
A
A
Smith
D
D
Boyce
S
S
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects* / Q000523:psychology; D005260:Female; D005849:Gerbillinae; D007051:Ibotenic Acid; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
D014151:Anti-Anxiety Agents; C114226:L 760735; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; C068032:GR 73632; D007051:Ibotenic Acid; D013373:Substance P