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The steroidogenic effect of histamine in isolated adrenocortical cells of the dog was investigated in the presence of prostaglandin E₂ (PGE₂) and/or dibutyryl cyclic AMP (dbcAMP) in the medium. The effect of histamine, in combination with PGE₂, was less than their total individual effects in the production of cortisol, but not of corticosterone. With dbcAMP the effect was just equal to them. However, the combination of histamine, PGE₂ and dbcAMP showed an increase twice that of their total individual effects in the production of both steroids. These results indicate that, in the dog, histamine, PGE₂ and dbcAMP may act synergistically in the adrenocortical cells.