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The brain and plasma levels of immunoactive delta sleep-inducing peptide (DSIP) as well as the permeability of the blood-brain barrier (BBB) to radioiodinated N-Tyr-DSIP (125I-DSIP) were measured at 0400, 0800, 1200, 1600, 2000, and 2400 hr in rats in a normal 12-hr-light/12-hr-dark cycle and at 0800 in rats in constant light or constant dark. Both brain and blood levels of immunoactivity showed statistically significant diurnal changes, whereas the measurement of BBB permeability varied in a regular fashion over time without the changes reaching statistical significance. Immunoactive levels of DSIP in both the plasma and the brain were higher and permeability of the BBB to 125I-DSIP increased in both the constant light and especially the constant dark groups in comparison with the cycled 0800 group. Diurnal variations continued to occur in the blood levels of immunoactive DSIP in the constant dark animals. Studies with radioiodinated serum albumin (RISA) showed that these findings did not result from a change in brain hemodynamics. Immunoactive levels of DSIP in the plasma correlated with brain immunoactive levels and with BBB permeability to 125I-DSIP. The increase in penetration of 125I-DSIP into the brain that occurred with changes in the lighting cycle appeared to be magnified by pre-treatment with aluminum. The results show interrelationships among various aspects of the neuroendocrine axis for DSIP and their modulation by physiological factors.