From 1963 to 1970 the possibility of humoral transmission of delta (SWS)-EEG sleep in rabbits by, i.c.v. infusion of extracorporal dialysate from blood of the sinus confluens of donors kept asleep by electrical stimulation of the ventromedian intralaminar thalamus, has been established. From 1970 to 1977 we isolated, characterized and synthesized a nonapeptide called delta-sleep-inducing peptide (DSIP) responsible for this effect. Subsequently, intravenous administration of DSIP was shown to produce, in different animals, sleep lasting for hours. Analogs with exchanged amino acids in the sequence or shortening the peptide by one or two amino acids decreased or abolished the effect, as did breakdown products, suggesting a close structure-specificity. In contrast sleep-induction per se was found to be species specific, i.e. in cats REM-sleep was predominantly produced. I.c.v., i.v. and s.c. administration yielded, in contrast to pharmaka, a parabolic dose-response curve with different effective optima. Additionally to sleep-induction, DSIP acts upon the circadian rhythmicity of the locomotor activity and transmitter concentrations in the brain and on that of plasma proteins and cortisol levels. We then synthesized a manyfold more powerful derivative by phosphorylation of the serine in position 7 (DSIP-P). Both forms, DSIP and DSIP-P occur in human CSF. Immunoreactive DSIP-like material was found in plasma of several mammals and humans, in human urine, CSF and milk. The penetration of the blood-brain barrier by the peptide has been proven and it was shown that unweaned rats are able to take up DSIP by the intestinal tract. The half-life time for proteolytic split-off of tryptophan by brain slices and homogenates is 15 min. Endogenous immunoreactive DSIP-like material in plasma, urine and CSF was found to be bound to a larger protein (carrier ?) and thus protected from proteolysis. Immunohistochemically DSIP was shown to occur in different regions of the rat brain. The multivariate activity of the peptide was then suggested by its interaction with acute and chronic stress and with drug-effects such as morphine, d-amphetamine and barbiturates. An induction of MAO-A and RNA synthesis in the brain was observed and the brain concentration of DSIP increased during progressed hibernation. Finally, alcohol addictism produced a substantial decrease of the DSIP-concentration in the rat brain and a specific electrophysiological effect on isolated neurons of rats and rabbits was established.(ABSTRACT TRUNCATED AT 400 WORDS)