S-100b is an astroglial-derived protein, which plays a role in brain development and maintenance, and is known to play a specific role in the regulation of growth of the serotonergic neuronal system. In humans, the gene for S-100b is found on chromosome 21, within the region that is considered important for the phenotype of Down syndrome (DS). Thus, we have been studying a model of DS, the S-100b transgenic mouse. In the current study, we have examined anxiety and responses to novelty in adolescent (60-90 days) animals, at a time when we have shown the animals to be relatively lacking in serotonin innervation, compared to their CD-1 nontransgenic controls. In a test for approach/avoidance, the light/dark test, the S-100b transgenic mice animals showed no differences from control CD-1 mice. However, in the hole-board test for exploratory behavior, the S-100b animals were found to be less responsive to the inhibiting effects of the serotonin receptor 5-HT1A agonist, buspirone. Three tests were used to measure response to novelty. In the open field, the S100b animals showed greater activity longer than the control animals, and in the Y-maze test, the S-100b animals spent more time in the novel arm. In a test for novelty-induced gnawing, the S-100b animals were also more active than control animals. All of these suggest that the S-100b transgenic mice are slower to habituate to novelty than control animals. Finally, we tested the animals in a new procedure that we are proposing as a test for harm avoidance. In this apparatus, the S-100b animals showed more approaches to a novel and potentially harmful object than the control mice did. These results are discussed in reference to the known lack of serotonin in the animals, and to the behavioral phenotype of DS.