The specificity of the response of an organism is an important variable influencing stress-related parameters and psychopathological states. We have shown that trait anxiety in C57BL/6 mice, determined by their emergence latencies in the free choice open field test, positively correlates with the long-term behavioral and neuroendocrinological changes induced by a stressor. Here, we show that this interindividual variability is caused by a different reactivity of the hypothalamus-pituitary-adrenal (HPA) axis upon exposure to a stressor. Mice with high trait anxiety (long emergence latency, LEL) display a more pronounced stress-induced activation of the HPA axis than mice with low trait anxiety (short emergence latency, SEL). Moreover, stress-induced activation of tyrosine hydroxylase and corticotropin-releasing hormone occurred in LEL but not SEL mice. In search of the molecular mechanisms underlying these differences, we found that under non-stressed conditions mRNA and protein levels of the glucocorticoid receptor in the hippocampus were higher in LEL mice compared to SEL mice. Also, systemic injection of the glucocorticoid receptor antagonist RU486 decreased the stress-induced activation of the HPA axis and the long-term anxiogenic effects of stress observed in LEL mice. Finally, the rewarding properties of cocaine were enhanced in LEL mice compared to SEL mice, suggesting a causal link between trait anxiety, stress activity and the behavioral responses to drugs of addiction.