Uncoupling proteins in the inner mitochondrial membrane uncouples oxidative phosphorylation from ATP synthesis. It has been suggested that these proteins are involved in thermogenesis as well as in the regulation of reactive oxygen species production in the mitochondria. The present work was conducted to investigate the localization of the uncoupling protein 2-like immunoreactivity (uncoupling protein 2/3 immunoreactivity) in the main catecholaminergic projection fields in the rat brain as well as in the areas of the dopaminergic and noradrenergic nerve cell groups. In particular, the relationships of tyrosine hydroxylase, dopamine beta-hydroxylase and uncoupling protein 2/3 immunoreactivity were assessed by double immunolabeling and confocal laser microscopy analysis associated with computer-assisted image analysis. Uncoupling protein 2/3 immunoreactivity was observed in discrete dopaminergic terminals in the nucleus accumbens and in the cerebral cortex whereas it was found in scattered noradrenergic terminals in the caudate putamen and Islands of Calleja Magna. One interesting finding was that uncoupling protein 2/3 immunoreactivity together with tyrosine hydroxylase immunoreactivity in the shell of nucleus accumbens was observed surrounding the previously characterized D1 receptor rich nerve cell column system characterized by a relative lack of tyrosine hydroxylase immunoreactivity. Moreover, in animal models of dopaminergic pathway degeneration, plastic changes in uncoupling protein 2/3 terminals have been shown in the cerebral cortex and striatum as seen from the increased size and intensity of uncoupling protein 2/3 immunoreactivity of their varicosities. Taken together, these findings open up the possibility that uncoupling protein 2/3 could play an important role modulating the dopaminergic and noradrenergic neurotransmission within discrete brain regions.