The direct effect of melatonin and related agonists on Li(+)-amplified phosphoinositide breakdown was studied in chick brain slices prelabeled with myo-[2-3H]-inositol. The melatonin receptor agonist 6-chloromelatonin (10-100 microM) increased, in a concentration-dependent manner, the accumulation of inositol phosphates (IP) in chick brain slices. This effect of 6-chloromelatonin (10 microM) was rapid as transient increases in IP3/IP4 (maximal increase, 29% at 20 s) and IP2 levels (maximal increase, 36% at 1 min) were observed, followed by a slower but sustained increase in IP1 level (30% at 5 min), when the amount of IP3/IP4 and IP2 had already been decreased to the control level. The phosphoinositide response elicited by 6-chloromelatonin (10 microM) was dependent on the presence of extracellular calcium. Direct stimulation of membrane phospholipase C by 6-chloromelatonin (10 microM) in isolated myo-[2-3H]inositol-prelabeled optic tectum membranes was dependent on the presence of guanosine-5'-O-(3-thio)triphosphate (1 microM), thus suggesting that G protein(s) link melatonin receptor activation to phospholipase C stimulation. The competitive melatonin receptor antagonist luzindole (10-100 microM) inhibited in a concentration-dependent manner the IP1 accumulation stimulated by 6-chloromelatonin (10-100 microM); however, it did not affect the accumulation stimulated by 5-hydroxytryptamine (10 microM). By contrast, methysergide (10 microM) completely inhibited 5-hydroxy-tryptamine (10 microM)-, but not 6-chloromelatonin (10 microM)-, induced IP1 accumulation. Melatonin receptor agonists increased IP1 accumulation in a concentration-dependent manner reaching different maximal responses.(ABSTRACT TRUNCATED AT 250 WORDS)