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

Abstract

Tonic activation of neurokinin‐3 (NK₃) 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 NK₃ receptor activation within this neuronal network, we used confocal and electron microscopy to examine NK₃ 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 (NK₁) receptors, which are also present, but less abundant then NK₃ receptors, in dopaminergic and GABAergic VTA neurons. There were no observable differences between NK₃ and NK₁ 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 NK₃ or less NK₁ immunogold particles (plasmalemmal + cytoplasmic) then those retrogradely labeled following FG injection in the Acb. Moreover, only the NK₃ receptors were detected in neuronal nuclei in the VTA and in the nuclei of human HEK‐293T NK₃‐transfected cells. The enrichment of NK₃ receptors in mesocortical projection neurons and nuclear distribution of these receptors may provide insight for understanding the selective antipsychotic effectiveness of NK₃ antagonists. Synapse 63:484–501, 2009.