It was shown previously that alpha-MSH levels in peripheral blood of rats subjected to passive avoidance training did not correlate with the behavioral performance of the animals. We have investigated whether alpha-MSH levels in cerebrospinal fluid (CSF) change during passive avoidance behavior. It appeared that throughout adaptation, acquisition and retention of this avoidance behavior, alpha-MSH levels in the CSF did not change significantly. In an additional experiment in which the effects of an electric footshock versus a psychological stimulus were tested, alpha-MSH levels in CSF also remained unchanged. Since CSF alpha-MSH levels appear to be relatively stable under these behavioral conditions, it seems unlikely that the CSF functions as a direct and specific route for the afferent transport of the behaviorally active neuropeptide alpha-MSH to its sites of action in the brain. However, the psychological stimulus, which consisted of the fear of receiving an unavoidable electric footshock, did induce a significant enhancement of alpha-MSH levels in peripheral blood, suggesting that psychological stress may be involved in the release of alpha-MSH into the peripheral circulation. These results support the idea of a differentiated system of secretion of alpha-MSH into CSF and peripheral blood.