A marked diurnal variation in high-affinity binding of 2-[125I]iodomelatonin ([125I]MEL) in rat brain sections containing the suprachiasmatic nuclei (SCN) was observed. Binding was highest late in the light phase and lowest during darkness, in inverse correlation to the serum melatonin rhythm. Interestingly, only high-affinity sites were present during most of the light phase while both high- and low-affinity sites were detected just before and during darkness. Guanosine triphosphate (GTP) in combination with sodium converted all high affinity sites to a low affinity state suggesting that the two sites observed during darkness represent the two states of the melatonin receptor. Acute swim-stress caused a significant elevation of serum melatonin, together with a decrease in the density of [125I]MEL binding in the SCN. The inverse relationship between circulating melatonin levels and binding, under two different physiological conditions, indicates that this hormone is involved in regulating its own receptors in the SCN.