Bombesin receptors as a novel anti-anxiety therapeutic target: BB 1 receptor actions on anxiety through alterations of serotonin activity

Zul Merali, Tania Bédard, Nick Andrews, Ben Davis, Alexander T. McKnight, M. Isabel Gonzalez, Martyn Pritchard, Pam Kent, Hymie Anisman

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

Abstract

The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)- cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido] propionamide], a nonpeptide bombesin (BB)BB1/BB2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction (3.75 and 7.5 mg/kg, i.p.), dose-dependently attenuated the number of vocalizations emitted by guinea pig pups separated from their mother (1-30 mg/kg, i.p.), reduced latency to approach a palatable snack in an anxiogenic (unfamiliar) environment, and reduced the fear-potentiated startle response (5 and 10 mg/kg, i.p., and 100-200 ng per rat, i.c.v.). When administered directly to the dorsal raphé nucleus (DRN), PD 176252 (20-500 ng) increased social interaction under aversive conditions, as did the 5-HT1A receptor agonist 8-hydroxy-2(di-n- propylamino)tetralin (50 ng). Furthermore, intra-DRN microinfusion of the peptide antagonist (PD 176252) suppressed, whereas its agonist [neuromedin B (NMB)-30] promoted, the in vivo release of 5-HT in the ventral hippocampus. In parallel, the suppressed social interaction elicited by intra-DRN administration of NMB was attenuated by a systemically administered 5-HT2C (but not 5-HT1A) receptor antagonist. Together, these findings suggest that endogenous BB-like peptides at the DRN evoke the release of 5-HT from the limbic nerve terminals originating from the raphé, specifically at the ventral hippocampus, resulting in anxiogenesis. The finding that this action was attenuated by BB receptor (BB1 and/or BB2) antagonists suggests that thesecompoundsmayrepresent a novel class of anxiolytic agents.

Original languageEnglish
Pages (from-to)10387-10396
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number41
DOIs
Publication statusPublished - 11 Oct 2006
Externally publishedYes

Keywords

  • 5-hydroxytryptamine
  • Anxiety
  • Dorsal raphé nucleus
  • Fear potentiated startle
  • Guinea pig pup vocalizations
  • Neuromedin B
  • Social interaction

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