It has been suggested that the hypothalamic-pituitary-adrenocortical (HPA) system contributes to individual differences in sensitivity towards drug abuse. Therefore, we studied the effects of the prototypic drug morphine in transgenic mice with impaired glucocorticoid receptor function. This mouse model has a profoundly dysfunctional HPA feedback. Since morphine-induced locomotor stimulation is positively correlated with the rewarding effects of morphine, we examined morphine-induced locomotor activity of transgenic mice and control mice (B6C3F1). Because morphine-induced locomotor activity depends on an intact mesolimbic system, dopaminergic (DAergic) neuronal activity was also estimated within the mesolimbic system. Results indicated that the activity after vehicle injection do not differ between these two mouse lines. Compared to vehicle injections, morphine (7.5 and 15 mg/kg; i.p.) dose-dependently increased motor activity for 3 h in control and transgenic mice. However, morphine-induced locomotion was significantly more pronounced in transgenic mice. Further, morphine-induced mesolimbic DAergic activity was enhanced in transgenic animals as compared to control animals. These results parallel endocrine data that show that the plasma ACTH level of transgenic mice reach higher levels compared to those levels observed in control mice after morphine injections. Altogether, this transgenic mouse line shows an enhanced locomotor-stimulant effect to morphine, a response that is reflected by an enhanced DAergic activity within the mesolimbic system and is also associated with increased HPA activity. We submit that the dysregulation of the HPA system in these transgenic mice influences the enhanced vulnerability to drug-seeking behavior.