The substance P (NK1) receptor antagonist L-760735 inhibits fear conditioning in gerbils

Neuropharmacology. 2003 Mar;44(4):516-23. doi: 10.1016/s0028-3908(03)00023-6.

Abstract

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.

MeSH terms

  • Amygdala / drug effects
  • Amygdala / physiology
  • Animals
  • Anti-Anxiety Agents / pharmacology*
  • Conditioning, Psychological / drug effects*
  • Fear / drug effects*
  • Fear / psychology
  • Female
  • Gerbillinae
  • Ibotenic Acid
  • Male
  • Morpholines / pharmacology*
  • Neurokinin-1 Receptor Antagonists*
  • Peptide Fragments / pharmacology
  • Substance P / analogs & derivatives*
  • Substance P / pharmacology

Substances

  • Anti-Anxiety Agents
  • L 760735
  • Morpholines
  • Neurokinin-1 Receptor Antagonists
  • Peptide Fragments
  • GR 73632
  • Ibotenic Acid
  • Substance P