Striatal dopamine deafferentation has previously been found to diminish D1 dopamine receptor clustering in association with striatal cyclic AMP-immunoreactive neurons. The administration of the dopamine precursor levodopa (L-DOPA) to animals with unilaterally placed 6-hydroxydopamine nigrostriatal tract lesions now appears to partially restore D1 dopamine receptor morphochemical organization in the deafferented striatum. Differences in the mode of levodopa delivery produced dissimilar D1 recovery patterns. The prodrug, L-DOPA methyl ester, was administered in combination with the peripheral aromatic amino acid decarboxylase inhibitor, benserazide, to achieve consistent plasma levels of the dopamine precursor. Continuous levodopa infusion (100 mg/kg/day, ip) led to a slight dorsomedial reassociation of D1 receptor binding sites with the postsynaptic cyclic AMP transduction system on the deafferented side. In contrast, intermittent levodopa therapy (50 mg/kg, ip, bid) produced a noticeable down regulation of the dopamine receptor system and also contributed to some region-specific recovery of the morphochemical pattern of D1 receptor binding site reaggregation with the postsynaptic cyclic AMP second messenger transduction system. These results suggest that exogenous levodopa replacement therapy desensitizes striatal D1 dopamine receptors. This was substantiated using image analysis of densitometric histograms. The down regulation of D1 receptors is dependent on the levodopa treatment regimen employed. Our findings provide a potential morphological basis for the behavioral desensitization shown previously in response to chronic, intermittent levodopa administration.