Mesocortical dopamine (DA) is a key neurotransmitter in cognitive processes and is involved in schizophrenia and antipsychotic drug action. DA exerts a highly complex modulation of network activity in prefrontal cortex (PFC), possibly due to the recruitment of multiple signaling pathways and to specialized cellular localizations of DA receptors in cortical microcircuits. Using double in situ hybridization, we quantitatively assessed the expression of D₁ and D₂ receptor messenger RNAs (mRNAs) in pyramidal and γ-aminobutyric acidergic (GABAergic) neurons of rat PFC. The proportion of pyramidal and GABA cells expressing these transcripts shows great regional variability in PFC, with little overlap (layer V). More pyramidal and GABA cells express D₁ than D₂ receptors. D₁ receptors are expressed by a greater proportion of GABA than pyramidal neurons, yet the number of D₁-positive pyramidal cells outnumbers D₁-positive interneurons due to the greater abundance of pyramidal neurons. Occasional PFC cells show high levels of mRNA, similar to those in striatal neurons. Finally, pyramidal and GABAergic cells expressing the same transcript were almost never found in close apposition, yet D₂-containing pyramidal neurons were often found close to non-D₂ GABA neurons. Thus, cellular and network DA actions in PFC are region and layer specific and may depend on precise cellular interactions.