Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits in spatial learning, and increased intermale aggression. Here, we report increased anxiety-like behavior of homozygous (NCAM Ψ/Ψ ) and heterozygous (NCAM Ψ/Ψ ) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety-like behavior was reduced in both NCAM Ψ/Ψ and NCAM Ψ/Ψ mice by systemic administration of the benzodiazepine agonist diazepam and the 5-HT 1A receptor agonists buspirone and 8-OH-DPAT. However, NCAM Ψ/Ψ mice showed anxiolytic-like effects at lower doses of buspirone and 8-OH-DPAT than NCAM Ψ/Ψ mice. Such increased response to 5-HT 1A receptor stimulation suggests a functional change in the serotonergic system of NCAM Ψ/Ψ mice, likely involved in the control of anxiety and aggression. However, 5-HT 1A receptor binding and tissue content of serotonin and its metabolite 5-hydroxyindolacetic acid were found unaltered in every brain area of NCAM Ψ/Ψ mice investigated, indicating that expression of 5-HT 1A receptors as well as synthesis and release of serotonin are largely unchanged in NCAM Ψ/Ψ mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5-HT 1A receptors and inwardly rectifying K Ψ channels as the respective effector systems.