1. ¹Section on Behavioral Genomics, National Institute of Mental Health, NIH, Bethesda, MD, USA
2. ²Laboratory of Clinical Science, National Institute of Mental Health, NIH, Bethesda, MD, USA
3. ³Garvan Institute of Medical Research, Sydney, Australia

Correspondence: Dr A Holmes, Section on Behavioral Genomics, National Institute of Mental Health, Building 10, Room 4D11, Bethesda, MD 20892-1375, USA. Tel:+1 301 496 4838; Fax: 301-480-1164; E-mail: aholmes@intra.nimh.nih.gov

Received 16 October 2002; Revised 18 December 2002; Accepted 2 January 2003; Published online 9 April 2003.

Abstract

The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 -/- are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxiety-like behavior, GAL-R1 -/- showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 -/-. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.