Galanin GAL-R1 Receptor Null Mutant Mice Display Increased Anxiety-Like Behavior Specific to the Elevated Plus-Maze

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 À/À are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxietylike behavior, GAL-R1 À/À 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 À/À. 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.

GAL 3 receptor KO mice exhibit an anxiety-like phenotype

“…Studies in GAL 1 receptor-deficient (GAL 1 -KO) mice showed increased anxiety-like behavior in the EPM test, whereas anxietyrelated behavior under the less stressful test conditions of the L/ D box, emergence, and OF tests was normal (13). These observations support GAL's anxiolytic actions, which preferentially take place under stressful conditions, with GAL acting at the GAL 1 receptor subtype.…”

“…phenotype (12), whereas KO of this receptor in mice elicits increased anxiety-like behavior in the elevated plus maze (EPM) test but not in the light/dark (L/D) exploration, emergence, or open field (OF) tests (13). Consistent with an antidepressant-like effect of GAL 2 receptor signaling (14), Lu et al (15) observed a depressive-like phenotype in GAL 2 receptor-deficient (GAL 2 -KO) mice but found no GAL 2 receptor-mediated effects on anxiety-related behavior.…”

Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior

“…In addition, the expression of GalR1 mRNA is positively correlated with galanin level, but there is no such correlation with GalR2 or GalR3 expression in the hypothalamic nuclei of galanin transgenic mice [34] . Second, GalR1 knockout (GalR1-KO) mice show abnormal adaptation to dietary challenges under high-fat and high-glucose conditions, while showing normal regulation with chow diets [35][36][37] . In response to an acute 3-day high-fat challenge, GalR1-KO mice display impaired adaptation, leading to increased food intake and weight gain, compared with normal food intake and weight modulation in response to low-fat diets [35] .…”

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

“…The EPM was conducted as described previously (File, 2001;Holmes et al, 2003a;Lister, 1987). The apparatus comprised of two open arms (25 Â 8 cm 2 ) and two closed arms (25 Â 8 Â 12 cm 3 ) that extended from a common central platform (8 Â 8 cm 2 ).…”