AbstractThe ability to respond to unexpected or novel stimuli is critical for survival. Determining that a stimulus is indeed novel requires memory to ascertain its lack of familiarity. As the long‐term synaptic changes involved in memory formation require the cAMP response element binding protein (CREB), we examined the extent to which CREB is involved in responses to novel environments. These environments typically trigger an endocrine stress response. Thus, we measured behavioural and stress hormone responses to three novel and one familiar environment in mice with a targeted disruption of the alpha and delta isoforms of the CREB gene (CREBαδ– deficient mice). We found CREBαδ– deficient mice to be less active and more inhibited in the elevated plus maze, open field, and light/dark box, without showing differences in anxiety‐like behaviour. This inhibition is unique to novel environments because these mice display a normal phenotype in the home cage, a familiar environment. Although CREBαδ– deficient mice exhibit altered behaviour in novel environments, they show normal reactivity to mild and moderate stress as both basal and stress levels of corticosterone are similar to those of wild‐type controls. This is the first report of CREBαδ– deficient mice to: (i) show altered behaviour, not related to learning and memory‐associated behaviours, upon initial exposure to environments and (ii) serve as an animal model that can dissociate locomotor activity from anxiety‐like behaviour in novel environments.