A continuous 8 h of immobilization stress in conscious young rats increased the blood-brain barrier (BBB) permeability to 131I-sodium in 12 out of 14 brain regions studied. A flattening of electroencephalographic (EEG) activity was noted during this time period. The mean cerebral blood flow (CBF) was reduced by 17% (during this time period) but the regional flow reduction was not related to the regional increase in BBB permeability. On the other hand, a correlation was observed between increased plasma and brain 5-HT levels and increased BBB permeability. p-Chloro-phenylalanine (p-CPA) pretreatment has prevented the occurrence of increased BBB permeability, and the flattening of EEG activity as well as 5-HT levels in plasma and brain. These results suggest that the long-term immobilization stress induces causally related sequential events in rats: enhancement of circulating 5-HT, impairment of BBB, free access of 5-HT into the brain, and eventually flattening of EEG.