Colocalization of proenkephalin and prodynorphin mRNAs with each other as well as with D1, D2, and D3 dopamine receptor mRNAs was analyzed in the nucleus accumbens of the rat. Distinct combinations were detected in the rostral pole, core, and shell subdivisions of the nucleus accumbens. Proenkephalin and prodynorphin mRNAs were principally localized in separate cells in the core. All detectable prodynorphin cells in the core expressed D1 mRNA but not D2 mRNA. Conversely, approximately 95% of the proenkephalin-positive cells in this region expressed D2 mRNA but not D1 mRNA. This pattern was identical to that observed in the caudate putamen. In the rostral pole and the shell, embedded in a background of this "typical" colocalization pattern, clusters of cells expressing a distinct configuration were found. In these clusters, proenkephalin-positive cells expressed both prodynorphin and D1 mRNAs, but they did not express D2 mRNA. D3 and prodynorphin mRNAs were colocalized in "limbic" striatal areas, including the ventromedial caudate putamen, the rostral pole, and the medial shell. In contrast, D3 mRNA was not detected in any proenkephalin-positive cells. Together with the prodynorphin/D1 data, this suggests that a subset of prodynorphin cells expresses both D1 and D3 mRNAs. It is concluded that 1) clusters of cells that coexpress proenkephalin, prodynorphin, and D1 mRNAs overlap extensively with previously defined cytoarchitectural cell clusters in the nucleus accumbens and 2) a subset of the prodynorphin cells in the ventromedial caudate putamen and the nucleus accumbens contains both D1 and D3 mRNAs.