Melanocortin 4 receptor stimulation improves social deficits in mice through oxytocin pathway

Andrea Mastinu; Marika Premoli; Giuseppina Maccarinelli; Mariagrazia Grilli; Maurizio Memo; Sara Anna Bonini

doi:10.1016/j.neuropharm.2018.02.007

Melanocortin 4 receptor stimulation improves social deficits in mice through oxytocin pathway

Neuropharmacology. 2018 May 1:133:366-374. doi: 10.1016/j.neuropharm.2018.02.007. Epub 2018 Feb 15.

Authors

Andrea Mastinu¹, Marika Premoli², Giuseppina Maccarinelli², Mariagrazia Grilli³, Maurizio Memo², Sara Anna Bonini²

Affiliations

¹ Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. Electronic address: andrea.mastinu@unibs.it.
² Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
³ Laboratory of Neuroplasticity, Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy.

PMID: 29454840
DOI: 10.1016/j.neuropharm.2018.02.007

Abstract

Several studies on humans and mice support oxytocin's role in improving social behaviour, but its use in pharmacotherapy presents some important limiting factors. To date, it is emerging a pharmacological potential for melanocortin 4 receptor (MC4R) agonism in social deficits treatment. Recently, we demonstrated that the deletion of the NFKB1 gene, which encodes the p50 NF-κB subunit, causes impairment in social behaviours, with reductions in social interactions in mice. In this work, we tested the acute effects of THIQ, a selective melanocortin 4 receptor (MC4R) agonist. THIQ treatment increased social interactions both in wild type and p50^-/- mice. In particular, after treatment with THIQ, p50^-/- mice showed a prosocial behaviour analogous to that of basal WT mice. Moreover, intranasal treatment with an oxytocin antagonist blocked social interactions induced by THIQ, demonstrating that its prosocial effects are mediated by the oxytocin pathway. The data obtained reinforce using MC4R agonists to ameliorate social impairment in NDDs.

Keywords: Melanocortin 4 receptor; Oxytocin; Social behaviour; THIQ; p50 KO mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dose-Response Relationship, Drug
Exploratory Behavior / drug effects
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics
Interpersonal Relations
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B p50 Subunit / deficiency
NF-kappa B p50 Subunit / genetics
Oxytocin / genetics
Oxytocin / metabolism*
RNA, Messenger / metabolism
Radioimmunoassay
Receptor, Melanocortin, Type 4 / agonists
Receptor, Melanocortin, Type 4 / genetics
Receptor, Melanocortin, Type 4 / metabolism*
Receptors, Oxytocin / genetics
Receptors, Oxytocin / metabolism
Signal Transduction / drug effects
Signal Transduction / physiology*
Social Behavior Disorders / drug therapy
Social Behavior Disorders / genetics
Social Behavior Disorders / metabolism*
Tetrahydroisoquinolines / therapeutic use
Triazoles / therapeutic use

Substances

N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine
NF-kappa B p50 Subunit
RNA, Messenger
Receptor, Melanocortin, Type 4
Receptors, Oxytocin
Tetrahydroisoquinolines
Triazoles
Oxytocin