Dehydroepiandrosterone sulfate (DHEAS), a neuroactive steroid, has been demonstrated to bind to sigma 1 receptors, and it has antidepressive effects in the forced swimming test. We used the conditioned fear stress, which is useful for investigating the pathogenesis of mood disorders. DHEAS attenuated the conditioned fear stress response in mice, the effects being antagonized by a sigma 1 receptor antagonist. It is interesting that, the DHEAS contents and number of apoptotic cells in the brain of mice showing conditioned fear stress response were decreased and increased, respectively, compared with those in the nonstressed mice. DHEAS prevented the expression of apoptosis induced by conditioned fear stress. These findings suggest that the imbalance of neuroactive steroids and the expression of apoptosis play an important role in the expression of conditioned fear stress response and that the use of DHEAS is a novel therapeutic approach for at least some mood disorders.