title: The neurokinin-3 receptor (NK3R) antagonist SB222200 prevents the apomorphine-evoked surface but not nuclear NK3R redistribution in dopaminergic neurons of the rat ventral tegmental area.
abstract: Schizophrenia is a severe condition that has been associated with functional abnormalities in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides modulate the activity of VTA DA neurons and might be involved in DA abnormalities relevant to schizophrenia. Recent work from our lab showed that systemic injection of the dopamine D1/D2 receptor agonist apomorphine in rats, which mimics schizophrenia-like behaviors in humans, also evoked a redistribution of NK3Rs in DA neurons of the rat VTA. In the present study, VTA microinjection of the selective NK3R antagonist SB222200 (1 nmol/0.2 μl) or the nuclear import blocker SN50 (2 μg/0.2 μl) was performed in awake rats 10 min prior to systemic injection of apomorphine. VTA sections were dual immunolabeled for the NK3R (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK3 immunogold particles were compared in rats receiving central and systemic injections. In DA (TH-labeled) dendrites, VTA microinjection of SB222200 prevented the apomorphine-evoked decrease in surface NK3R density as well as the apomorphine-induced increase in cytoplasmic NK3R density. In contrast, VTA microinjection of SN50, but not SB222200, prevented the apomorphine-induced increase in nuclear NK3R density. VTA microinjection of SB222200 or SN50 without apomorphine had no effect on the NK3R distribution or density in TH and non-TH profiles within the VTA. In non-TH, presumably GABAergic neurons of the VTA, the NK3R densities in somata and dendrites were not significantly changed by apomorphine with or without SB222200. The results suggest that the NK3R antagonist SB222200 is effective against the apomorphine-evoked NK3R internalization in VTA DA dendrites, but does not prevent nuclear NK3R trafficking in VTA DA neurons. These results might have important implications in targeting NK3R antagonists in basic or clinical studies.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, United States.
authors.forename: S
authors.initials: S
authors.lastname: Hether
authors.forename: K
authors.initials: K
authors.lastname: Misono
authors.forename: A
authors.initials: A
authors.lastname: Lessard
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage*; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002467:Cell Nucleus / Q000187:drug effects* / Q000648:ultrastructure; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008845:Microinjections; D011804:Quinolines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D011804:Quinolines; D018042:Receptors, Neurokinin-3; C109112:SB 222200; D001058:Apomorphine
keywords: ANOVA; Acb; BDMA; DA; DDSA; DMSO; DPX; EMbed 812; G protein-coupled receptors; GPCRs; NF-κB; NK(1,2,3); NK(3)R; NK(3)Rs; NKA; NKB; NLS; NMA; PB; SHR; SNc; SNr; SP; TH; VTA; analysis of variance; benzyldimethylamine; dibutyl phthalate xylene; dimethyl sulfoxide; dodecenyl succinic anhydride; dopaminergic; dopaminergic neurons; epichlorohydrin epoxin resin for embedding; mPFC; medial prefrontal cortex; mesocorticolimbic circuitry; nadic(R),methyl anhydride; neurokinin A; neurokinin B; neurokinin-1,2,3; neurokinin-3 receptor; neurokinin-3 receptors; nuclear factor kappa-B; nuclear localization signal motif; nucleus accumbens; peptide receptors; phosphate buffer; schizophrenia; spontaneously hypertensive rat; substance P; substantia nigra pars compacta; substantia nigra pars reticulata; tachykinin; tyrosine hydroxylase; ventral tegmental area