Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice

Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits i n spatial learning, and increased intermale aggression. Here. we report inc reased anxiety-like behavior of homozygous (NCAM(-/-)) and heterozygous (NC AM(+/-)) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety-like behavior was reduced in both NCAM(+/+) and NCAM(-/-) mice by systemic administration of the benzodiazepine agonis t diazepam and the 5-HT1A receptor agonists buspirone and 8-OH-DPAT. Howeve r, NCAM(-/-) mice showed anxiolytic-like effects at lower doses of buspiron e and 8-OH-DPAT than NCAM(+/+) mice. Such increased response to 5-HT1A rece ptor stimulation suggests a functional change in the serotonergic system of NCAM(-/-) mire, likely involved in the control of anxiety and aggression. However, 5-HT1A receptor binding and tissue content of serotonin and its me tabolite 5-hydroxy-indolacetic acid were found unaltered in every brain are a of NCAM(-/-) mice investigated, indicating that expression of 5-MT1A rece ptors as well as synthesis and release of serotonin are largely unchanged i n NCAM(-/-) mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5-MT1A receptors and inwardly rectifying K + channels as the respective effector systems, (C) 1999 John Wiley & Sons, Inc. J Neurobiol 40: 343-355, 1999.