Apomorphine-evoked redistribution of neurokinin-3 receptors in dopaminergic dendrites and neuronal nuclei of the rat ventral tegmental area

Abstract

Mammalian neurokinin-3 (NK3) receptors of the tachykinin family of neuropeptides have been shown to activate dopaminergic neurons of the ventral tegmental area (VTA), a midbrain area displaying dopaminergic dysfunctional activity in schizophrenia. The recent finding of NK3 receptors in VTA neuronal nucleus highlights a new level of neuromodulation, in addition to the traditional tachykinin-induced NK3 receptor internalization and activation of second messenger signaling pathways. The function of nuclear NK3 receptors is still unknown. It is also unclear how dopaminergic activation is affecting the NK3 receptor distribution in the VTA. In the present study, trafficking of the NK3 receptor in somatodendritic profiles of dopaminergic and non-dopaminergic neurons of the rat VTA was investigated following acute systemic administration of the dopamine D1/D2 receptor agonist apomorphine. VTA sections were dual immunolabeled for the NK3 receptor (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK3 immunogold particles with or without TH immunolabeling were compared in vehicle-injected or apomorphine-injected rats. In dopaminergic (TH) neurons, apomorphine evoked a significant increase in NK3 receptor densities in cytoplasmic and nuclear portions of the soma. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK3 receptor densities in dopaminergic dendrites. In non-TH neurons, presumably GABAergic neurons of the VTA, the NK3 receptor densities in somata and dendrites were not significantly altered by apomorphine. The results suggest that dopaminergic receptor activation is inducing a rapid mobilization of NK3 receptors in VTA dopaminergic neurons. The apomorphine-evoked NK3 receptors plasticity might reflect dendritic internalization and translocation of NK3 receptors toward the soma and nucleus. This trafficking is not observed in non-dopaminergic neurons of the VTA. The selective apomorphine-evoked redistribution of VTA NK3 receptors might have important implications in normal or pathological conditions such as schizophrenia.