The neurokinin-3 (NK3) and the neurokinin-1 (NK1) receptors are differentially targeted to mesocortical and mesolimbic projection neurons and to neuronal nuclei in the rat ventral tegmental area.

Tonic activation of neurokinin-3 (NK(3)) receptors in dopamine neurons of the ventral tegmental area (VTA) has been implicated in the pathophysiology of schizophrenia. This psychiatric disorder is associated with a dysfunctional activity in VTA projection neurons that can affect cognitive function at the level of the medial prefrontal cortex (mPFC) as well as motor and motivational states controlled in part by mesolimbic output to the nucleus accumbens (Acb). To determine the relevant sites for NK(3) receptor activation within this neuronal network, we used confocal and electron microscopy to examine NK(3) receptors (Cy5; immunogold) and retrograde labeling of fluorogold (FG, FITC; immunoperoxidase) in the VTA of rats receiving either Acb or mPFC injections of FG. Comparison was made with neurokinin-1 (NK(1)) receptors, which are also present, but less abundant then NK(3) receptors, in dopaminergic and GABAergic VTA neurons. There were no observable differences between NK(3) and NK(1) receptors in their primary locations in the cytoplasm and on the plasma membrane of VTA somata and dendrites with or without FG. Dendrites labeled with FG retrogradely transported from mPFC, however, contained more NK(3) or less NK(1) immunogold particles (plasmalemmal + cytoplasmic) then those retrogradely labeled following FG injection in the Acb. Moreover, only the NK(3) receptors were detected in neuronal nuclei in the VTA and in the nuclei of human HEK-293T NK(3)-transfected cells. The enrichment of NK(3) receptors in mesocortical projection neurons and nuclear distribution of these receptors may provide insight for understanding the selective antipsychotic effectiveness of NK(3) antagonists.