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The Journal of Neuroscience, October 11, 2006, 26(41):10387-10396; doi:10.1523/JNEUROSCI.1219-06.2006

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Behavioral/Systems/Cognitive
Bombesin Receptors as a Novel Anti-Anxiety Therapeutic Target: BB₁ Receptor Actions on Anxiety through Alterations of Serotonin Activity

Zul Merali,^1,2 Tania Bédard,² Nick Andrews,³ Ben Davis,⁴ Alexander T. McKnight,⁵ M. Isabel Gonzalez,⁶ Martyn Pritchard,⁷ Pam Kent,² and Hymie Anisman⁸

¹Institute of Mental Health Research and Departments of Psychiatry and Cellular and Molecular Medicine, ²School of Psychology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5, ³Organon Laboratories, Newhouse Industrial Estate, Lanarkshire ML1 5SH, United Kingdom, ⁴Biowisdom, Harston Mill, Harston, Cambridge CB2 5GG, United Kingdom, ⁵ATMcK Consulting, Ely, Cambridgeshire CB6 3DL, United Kingdom, ⁶Neurology and Centres of Excellence for Drug Discovery, GlaxoSmithKline Research and Development, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom, ⁷Cambridge BioTechnology, Cambridge CB2 1XJ, United Kingdom, and ⁸Carleton University, Institute of Neuroscience, Ottawa, Ontario, Canada K1S 5B6

Correspondence should be addressed to Dr. Zul Merali, University of Ottawa Institute of Mental Health Research, Lady Grey Building, Room 2054, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4. Email: merali{at}uottawa.ca

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-HT_1A 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-HT_2C (but not 5-HT_1A) 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.

Key words: anxiety; 5-hydroxytryptamine; neuromedin B; dorsal raphé nucleus; social interaction; fear potentiated startle; guinea pig pup vocalizations

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Received March 21, 2006; revised July 27, 2006; accepted Aug. 7, 2006.

Correspondence should be addressed to Dr. Zul Merali, University of Ottawa Institute of Mental Health Research, Lady Grey Building, Room 2054, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4. Email: merali{at}uottawa.ca

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