The interaction between locally applied D-Ala2-methionine enkephalinamide (2dA) and catecholamine inputs to frontal cortex was investigated in rats. Parenteral administration of antipsychotic agents known to block catecholamine receptors, i.e., spiroperidol, .alpha.-flupenthixol and (+)-butaclamol, reversibly antagonized enkephalin-induced depressions. The biochemically inactive isomers of these antipsychotics, .beta.-flupenthixol and (-)-butaclamol, manifested no such activity. Unilateral lesions of the catecholaminergic projections to frontal cortex, produced by interstitial injection of 6-hydroxydopamine, caused an ipsilateral decrease in 2dA efficacy and in an elimination of the antagonisms of 2dA depressions by antipsychotic agents. The depressions caused by 2dA were not antagonized by ionotophoretically applied Mg2+. Intact catecholaminergic transmission is required for the full expression of enkephalin-induced depressions in frontal cortex and that this mechanism probably does not involve presynaptic release. Catecholamines may act as postsynaptic modulators to augment responsiveness to enkephalins.