Enkephalin-deficient knockout mice, a genetic model of enhanced anxiety responses, and wild-type controls were housed in two separate facilities on the same campus using different caging systems. Stress reactivity was evaluated in these animals using a zero-maze test followed by c-Fos expression analysis in limbic brain regions. Animals with genetically or pharmacologically enhanced anxiety reared and tested in the same facility displayed similar behavioral reactivity and c-Fos induction. However, we found much stronger anxiety-related behavioral responses and higher c-Fos levels when animals were house in individually ventilated cages, independent of their genetic background.