The aim of this study was to determine whether extracellular dopamine (DA) in the prefrontal cortex (PFC) might originate other than from DA neurons, also from noradrenergic (NA) ones. To this aim, we compared the levels of DA and NA in the dialysates from the PFC, a cortical area innervated by NA and DA neurons, and cortices that receive NA but minor or no DA projections such as the primary motor, the occipital-retrosplenial, and the cerebellar cortex. Moreover, the effect of α[SUB2]-ligands and D)2(-ligands that distinctly modify NA and DA neuronal activity on extracellular NA and DA in these areas was studied. Extracellular NA concentrations were found to be similar in the different cortices, as expected from the homogeneous NA innervation, however, unexpectedly, also DA concentrations in the PFC were not significantly different from those in the other cortices. The α[SUB2] -adrenoceptor agonist clonidine, intraperitoneally (i.p.) injected or locally perfused into the PFC, reduced not only extracellular NA levels, as expected from its ability to inhibit NA neuron activity, but also markedly reduced extracellular DA levels. Conversely, the α[SUB2] -adrenoceptor antagonist idazoxan, i.p. injected or locally perfused into the PFC, not only increased extracellular NA levels, in line with its ability to activate NA neuron activity, but also increased those of DA. Conversely, in contrast to its ability to inhibit DA neuronal activity, the D[SUB2] receptor agonist quinpirole only modestly and transiently reduced extracellular DA levels, while γ-butyrolactone failed to modify DA levels in the PFC; conversely, haloperidol, at variance from its ability to activate DA neurons, failed to significantly modify extracellular DA levels in the PFC. Both haloperidol and quinpirole were totally ineffective after local perfusion into the PFC. Systemically injected or locally perfused, clonidine and idazoxan also modified both DA and NA concentrations in... [ABSTRACT FROM AUTHOR]