The possibility that stress associated with morphine and amphetamine administration or withdrawal will influence the blood-brain barrier (BBB) and brain dysfunction was examined in a rodent model. Repeated daily administration of morphine (10 mg/kg, i.p.) resulted in drug dependence in rats on the sixth day and onwards. Measurement of the BBB permeability to large molecule tracers normally bound to proteins, e.g., Evans blue albumin and radioiodine (([131])Iodine) did not show any leakage on the 12th day of drug dependence. On the other hand, spontaneous withdrawal of morphine on day 1 resulted in profound stress symptoms. These symptoms were much more intense on the second day of morphine withdrawal. Alterations in the BBB to protein tracers were seen in several regions of the brain. This increase in BBB to protein tracers was most pronounced on the second day of morphine withdrawal. These rats also exhibited abnormal neuronal, glial and stress protein, the heat-shock protein 72 kD (HSP-72 kD) response. On the other hand, acute administration of methamphetamine (40 mg/kg, i.p.) in mice resulted in marked extravasation of endogenous serum protein as seen with increased expression of albumin immunohistochemistry. These observations suggest that psychostimulants and associated stress are capable to influence the brain function, probably through modifying the BBB function, not reported earlier.