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This study was carried out to explore whether the postulated interaction between alpha-MSH and dopamine (DA) could be explained on the basis of variations in tissular cyclic AMP (cAMP) levels. We used slices containing caudate putamen and accumbens nuclei incubated in the presence of alpha-MSH, DA, or both simultaneously. Exposure of slices to alpha-MSH or DA resulted in an increase in cAMP levels. The simultaneous presence of alpha-MSH and DA resulted in a reduction in the accumulation of the cyclic nucleotide in the tissues as compared with those treated only with DA or alpha-MSH. The effect of alpha-MSH and DA on cAMP efflux was also tested. Incubation of slices with DA led to a marked increase in cAMP efflux; this efflux could be prevented if alpha-MSH was present in the medium. The results suggest that the inhibition by alpha-MSH of DA-induced striatal cAMP accumulation and efflux are a consequence of an interaction between the peptide and the neurotransmitter; DA and alpha-MSH transducing mechanisms could be biochemically linked.