To determine the cell groups which are activated by novelty stress, we examined the induction of c-fos mRNA in brain tissues following introduction of male rats to a novel open field. Male Fischer 344 rats were placed in a brightly lit open field and allowed to roam free for 20 min. Control animals were sacrificed upon removal from their home cage. Northern blot analysis revealed a 2.2 kb hybridization signal which increased in density following novelty. In situ hybridization analysis showed that c-fos mRNA was induced in a specific pattern consistent with the behavior. The regions of induction included the medial prefrontal and orbital cortex, cingulate and parietal cortex, hippocampal CA1 and CA3 pyramidal cell regions, dorsal and ventral anterior thalamic n. and paraventricular n. of the hypothalamus. C-fos mRNA also increased in the anterior pituitary gland and this increase correlated with the secretion of ACTH. These data demonstrate the brain areas undergoing genomic activation following complex behavior paradigms such as introduction to a novel environment.