Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299

  1. Chad J. Swanson*,†,
  2. Thomas P. Blackburn*,‡,
  3. Xuexiang Zhang*,
  4. Kang Zheng§,
  5. Zhi-Qing David Xu§,
  6. Tomas Hökfelt§,,
  7. Toni D. Wolinsky*,
  8. Michael J. Konkel*,
  9. Heidi Chen*,
  10. Huailing Zhong*,
  11. Mary W. Walker*,
  12. Douglas A. Craig*,
  13. Christophe P. G. Gerald*, and
  14. Theresa A. Branchek*
  1. *Lundbeck Research USA, Inc., Paramus, NJ 07652-1431; and §Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden

  1. Contributed by Tomas Hökfelt, October 13, 2005

Abstract

The neuropeptide galanin mediates its effects through the receptor subtypes Gal1, Gal2, and Gal3 and has been implicated in anxiety- and depression-related behaviors. Nevertheless, the receptor subtypes relevant to these behaviors are not known because of the lack of available galanin-selective ligands. In this article, we use behavioral, neurochemical, and electrophysiological approaches to investigate the anxiolytic- and antidepressant-like effects of two potent small-molecule, Gal3-selective antagonists, SNAP 37889 and the more soluble analog SNAP 398299. Acute administration of SNAP 37889 or SNAP 398299 enhanced rat social interaction. Furthermore, acute SNAP 37889 was also shown to reduce guinea pig vocalizations after maternal separation, to attenuate stress-induced hyperthermia in mice, to increase punished drinking in rats, and to decrease immobility and increase swimming time during forced swim tests with rats. Moreover, SNAP 37889 increased the social interaction time after 14 days of treatment and maintained its antidepressant effects during forced swim tests with rats after 21 days of treatment. In microdialysis studies, SNAP 37889 partially antagonized the galanin-evoked reduction in hippocampal serotonin (5-hydroxytryptamine, 5-HT), as did the 5-HT1A receptor antagonist WAY100635. Their combination produced a complete reversal of the effect of galanin. SNAP 398299 partially reversed the galanin-evoked inhibition of dorsal raphe cell firing and galanin-evoked hyperpolarizing currents. These results indicate that Gal3-selective antagonists produce anxiolytic- and antidepressant-like effects, possibly by attenuating the inhibitory influence of galanin on 5-HT transmission at the level of the dorsal raphe nucleus.

Footnotes

  • ↵ † To whom correspondence may be addressed at: Target Discovery and Assessment, Department of Mechanistic Studies, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652. E-mail: chjs{at}lundbeck.com.

  • ↵ To whom correspondence may be addressed. E-mail: tomas.hokfelt{at}neuro.ki.se.

  • ↵ ‡ Present address: Helicon Therapeutics, Inc., Farmingdale, NY 11735.

  • Conflict of interest statement: No conflicts declared.

  • Abbreviations: DRN, dorsal raphe nucleus; SSRI, selective serotonin reuptake inhibitor; CDP, chlordiazepoxide; 5-HT, serotonin (5-hydroxytryptamine); FST, forced swim test; vHip, ventral hippocampus; p.o., oral(ly) (per os); i.c.v., intracerebroventricular(ly).

  • Freely available online through the PNAS open access option.

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  1. Published online before print November 15, 2005, doi: 10.1073/pnas.0508970102 PNAS November 29, 2005 vol. 102 no. 48 17489-17494
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