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.

Characterization of nuclear neurokinin 3 receptor expression in rat brain

“…In SON and PVN, immunoreactivity for NK3-R observed with either confocal or electron microscopy has a clustered appearance in the neuronal nuclei (Howe et al, 2004; Haley and Flynn, 2006; Jensen et al, 2008). The nuclear immunoreactivity for NK3-R reported in globus pallidus and VTA has a similar clustered appearance (Levesque et al, 2006; Lessard et al, 2009). This clustered appearance is consistent with localization of NK3-R to nuclear suborganelles some of which are rich in histones (Handwerger and Gall, 2006; Misteli, 2007).…”

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

“…DOP may play a role in clinical comorbidities to pain (e.g., depression and anxiety) and has recently been implicated in the facilitation of CPP induced by morphine but not reinforcement, indicating a role in contextual cues (Lutz and Kieffer, 2013). The interdependency of opioid receptors with the neurokinin system in reward/motivation pathways (Lessard et al, 2009;Commons, 2010) is reported. SP administration induces CPP, whereas NK 1 receptor antagonism decreases morphine reinforcement in self-administration studies (Holzhauer-Oitzl et al, 1988;Placenza et al, 2006).…”

Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge

“…For example, under basal conditions, NK3R is found within the nucleus of neurons in the ventral tegmental area of rat (VTA) (40) and globus pallidus of squirrel monkeys (41). Limited NK3R is found in nuclei of SON neurons under basal conditions, but nuclear NK3R increases significantly in response to hypotension (26).…”

“…Although the present focus is on the PVN, the same may apply to multiple other brain regions that express NK3R. Indeed, NK3R is detected within the nuclei of neurons in the globus pallidus and ventral tegmental area (40,41). Additional techniques were not used to identify whether nuclear NK3R in these brain areas associated with transcriptionally active chromatin, but the presence of the NK3R in nuclei of neurons in a variety of brain regions suggests that NK3R may affect gene activation under multiple conditions.…”