Elsevier

Journal of Psychiatric Research

Volume 57, October 2014, Pages 157-164
Journal of Psychiatric Research

Social deficits induced by peripubertal stress in rats are reversed by resveratrol

https://doi.org/10.1016/j.jpsychires.2014.05.017Get rights and content

Abstract

Adolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28–42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

Section snippets

Animals

The experimental subjects were the offspring of Wistar Han rats (Charles River Laboratories, L'Arbresle, France), bred in our animal house (behavioral experiment, n = 36; neurochemical assays, n = 20). As is our usual practice, at weaning male rats from different litters were mixed throughout the different home cages by placing equivalent numbers of animals from each litter into the different experimental groups and by avoiding having siblings in the same home cage. They were housed three per

Resveratrol normalizes the social investigation deficit induced by peripubertal stress

The beneficial, normalizing effect of resveratrol on the social investigation deficit can be seen in Fig. 1. A three-way ANOVA with Stress and Drug as between-subjects variables and Target as a within-subjects variable was conducted to determine whether there was an effect of resveratrol administration on the exploration of the social and inanimate target cues, according to peripubertal experience. Prior to running the ANOVAs, it was found that some of the assumptions were not met [normality

Discussion

Social relations have pervasive repercussions on health, well beyond the social interactions themselves, and their quality can depend on environmental and temperamental factors, such as sociability (Berkman et al., 2000, Cohen, 2004, House et al., 1988, Uchino, 2006). Here, using rats as the model system, we confirm that exposure to stress during the peripubertal period results in deficient social motivation at adulthood, with exploration levels similar to those previously reported (Márquez

Acknowledgments

We would like to thank Vandana Veenit for assistance with the peripubertal stress manipulations, and Fiona Hollis for technical discussions. Luminescence technical advice was kindly provided by Nathalie Ballanfat and Billy Breton of the EPFL Biomolecular Screening Facility. We would further like to express our gratitude to the anonymous reviewers for their constructive suggestions. This work was supported by grants from the Swiss National Science Foundation (CRSIK0-122691 and 31003AB-135710;

References (89)

  • Y. Dwivedi et al.

    Modulation in activation and expression of phosphatase and Tensin Homolog on Chromosome Ten, Akt1, and 3-Phosphoinositide-Dependent kinase 1: Further evidence demonstrating altered phosphoinositide 3-Kinase signaling in postmortem brain of suicide subjects

    Biol Psychiatry

    (2010)
  • L.E. Gonzalez et al.

    Medial prefrontal transection enhances social interaction I: Behavioral studies

    Brain Res

    (2000)
  • K. Heuer et al.

    Avoidance of emotional facial expressions in social anxiety: The Approach–Avoidance Task

    Behav Res Ther

    (2007)
  • S.S. Ho et al.

    Neurocircuits underlying cognition–emotion interaction in a social decision making context

    NeuroImage

    (2012)
  • M.E. Juan et al.

    Quantification of trans-resveratrol and its metabolites in rat plasma and tissues by HPLC

    J Pharm Biomed Anal

    (2010)
  • F. Karège et al.

    Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase Kinase-3β in ventral prefrontal cortex of depressed suicide victims

    Biol Psychiatry

    (2007)
  • L. Liang et al.

    Pharmacokinetics, tissue distribution and excretion study of resveratrol and its prodrug 3,5,4′-tri-O-acetylresveratrol in rats

    Phytomedicine

    (2013)
  • T. Maiuri et al.

    Regulation of adipocyte differentiation by distinct subcellular pools of protein kinase B (PKB/Akt)

    J Biol Chem

    (2010)
  • W.N. Marsden

    Synaptic plasticity in depression: Molecular, cellular and functional correlates

    Prog Neuropsychopharmacol Biol Psychiatry

    (2013)
  • G. Michels et al.

    Rapid actions of androgens

    Front Neuroendocrinol

    (2008)
  • M.I. Patel et al.

    Potentiation of neuronal insulin signaling and glucose uptake by resveratrol: The involvement of AMPK

    Pharmacol Rep

    (2011)
  • H.B. Patisaul et al.

    Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in gonadally intact male rats

    Horm Behav

    (2009)
  • W. Renthal et al.

    Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins

    Neuron

    (2009)
  • K. Roelofs et al.

    Hypothalamus–Pituitary–Adrenal Axis hyperresponsiveness is associated with increased social avoidance behavior in social phobia

    Biol Psychiatry

    (2009)
  • S.S. Sahu et al.

    Neuroprotective effect of resveratrol against prenatal stress induced cognitive 2 impairment and possible involvement of Na+,K+-ATPase activity

    Pharmacol Biochem Behav

    (2013)
  • J. Samardzic et al.

    P. 2.005 the trans-isomer of resveratrol acutely improves motivation in rat

    Eur Neuropsychopharmacol

    (2013)
  • S.N. Seidman et al.

    Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men

    Biol Psychiatry

    (2001)
  • A.A. Shah et al.

    Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests

    Brain Res

    (2003)
  • L.P. Spear

    The adolescent brain and age-related behavioral manifestations

    Neurosci Biobehav Rev

    (2000)
  • S.J. Stanton et al.

    Endogenous testosterone levels are associated with amygdala and ventromedial prefrontal cortex responses to anger faces in men but not women

    Biol Psychol

    (2009)
  • B. Taborsky et al.

    Social competence: An evolutionary approach

    Trends Ecol Evol

    (2012)
  • R.M. Uranga et al.

    Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress

    J Biol Chem

    (2013)
  • X. Vitrac et al.

    Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration

    Life Sci

    (2003)
  • Q. Wang et al.

    Control of synaptic strength, a novel function of Akt

    Neuron

    (2003)
  • Z. Wang et al.

    Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: The HPA axis, BDNF expression and phosphorylation of ERK

    Pharmacol Biochem Behav

    (2013)
  • Y. Xu et al.

    Antidepressant-like effect of trans-resveratrol: Involvement of serotonin and noradrenaline system

    Eur Neuropsychopharmacol

    (2010)
  • W. Zheng et al.

    The possible role of the Akt signaling pathway in schizophrenia

    Brain Res

    (2012)
  • M.E. Avale et al.

    Prefrontal nicotinic receptors control novel social interaction between mice

    FASEB J

    (2011)
  • M.D. Bauman et al.

    Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey

    Transl Psychiatry

    (2013)
  • J.A. Baur et al.

    Therapeutic potential of resveratrol: The in vivo evidence

    Nat Rev Drug Discov

    (2006)
  • D. Benitez et al.

    Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: Modulation of the phosphoinositide 3-kinase pathway

    Br J Cancer

    (2007)
  • J. Blanchard et al.

    Diagnostic differences in social anhedonia: A longitudinal study of schizophrenia and major depressive disorder

    J Abnorm Psychol

    (2001)
  • P. Brasnyó et al.

    Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients

    Br J Nutr

    (2011)
  • M. Cannon et al.

    Premorbid social functioning in schizophrenia and bipolar disorder: Similarities and differences

    Am J Psychiatry

    (1997)
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    Now at Center for Comparative NeuroImaging, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

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    Now at Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.

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