title: Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.
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 these compounds may represent a novel class of anxiolytic agents.
authors.affiliation: Institute of Mental Health Research and Department of Psychiatry, School of Psychology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5. merali@uottawa.ca
authors.forename: Zul
authors.initials: Z
authors.lastname: Merali
authors.forename: Tania
authors.initials: T
authors.lastname: Bédard
authors.forename: Nick
authors.initials: N
authors.lastname: Andrews
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.forename: Alexander T
authors.initials: AT
authors.lastname: McKnight
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Gonzalez
authors.forename: Martyn
authors.initials: M
authors.lastname: Pritchard
authors.forename: Pam
authors.initials: P
authors.lastname: Kent
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000378:metabolism; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; D007211:Indoles; D018004:Receptors, Bombesin; D012701:Serotonin; C116774:PD 176252