The cortical contribution to the maintenance of preproenkephalin (PPE) and preprotachykinin (PPT) mRNA levels in the rat striatum was investigated using quantitative in situ hybridization histochemistry. The effects of knife-cut transections of the frontal cortical pole on the expression of PPE and PPT mRNA in rat striatal neurons was studied in intact striata and in striata previously denervated by a 6-hydroxydopamine (6-OHDA) lesion of the mesencephalic dopamine pathways. Lesions of the dopaminergic striatal afferents resulted in marked increases in the mRNA encoding PPE throughout the striatum, including the ventral striatum and nucleus accumbens, while the levels of PPT mRNA were considerably reduced in these structures. Knife-cut lesions of the frontal cortical pole, transecting the prefrontal corticostriatal projection at the level of the foreceps minor, displayed little or no effect on the expression of either PPE or PPT mRNA in the dopamine-intact striatum. Conversely, frontal cortical transections performed 4 weeks after the 6-OHDA lesions reversed the 6-OHDA-lesion-induced increase in PPE mRNA in the striatum as well as in the ventral striatum and nucleus accumbens. The down-regulation of PPE mRNA in the dopaminergically denervated striatum was most pronounced in the medial part, which is the area most densely innervated by the frontal cortical pole. Here, the level of PPE mRNA expression per striatal cell was similar to the intact striatum. In contrast, the cellular expression of PPE mRNA remained up-regulated in the lateral striatum, which receives more sparse innervation from the frontal cortical pole. Cortical transections did not significantly affect the 6-OHDA-lesion-induced down-regulation of PPT mRNA in any of the striatal regions analysed. The present results demonstrate that knife-cut transections of the frontal corticostriatal pathway are capable of reversing the increased striatal PPE mRNA levels, but not the decreased PPT mRNA levels, induced by a 6-OHDA lesion of the dopaminergic input. These observations suggest that in the absence of a functional striatal dopamine input, augmented glutamatergic transmission in corticostriatal afferents is necessary to maintain increased levels of PPE mRNA expression, and hence also enkephalin synthesis, in striatal projection neurons.