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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00479

Reward-related behavioral, neurochemical and electrophysiological changes in a rat model of autism based on prenatal exposure to valproic acid

 Sara Schiavi1, Daniela Iezzi2, Antonia Manduca1, Stefano Leone1, Francesca Melancia1,  Carmen Carbone2,  Michele Petrella3,  Guido Mannaioni2,  Alessio Masi2, 4 and  Viviana Trezza1*
  • 1Department of Science, Roma Tre University, Italy
  • 2Department of Neurosciences, Psychology, Drugs and Child Health Area, School of Psychology, University of Florence, Italy
  • 3School of Pharmaceutical Sciences and Health Products, University of Camerino, Italy
  • 4University of Camerino, Italy

Prenatal exposure to the antiepileptic drug valproic acid (VPA) induces autism spectrum disorder (ASD) in humans and autistic-like behaviors in rodents, which makes it a good model to study the neural underpinnings of ASD. Rats prenatally exposed to VPA show profound deficits in the social domain. The altered social behavior displayed by VPA-exposed rats may be due to either a deficit in social reward processing or to a more general inability to properly understand and respond to social signals.
To address this issue, we performed behavioral, electrophysiological and neurochemical experiments and tested the involvement of the brain reward system in the social dysfunctions displayed by rats prenatally exposed to VPA (500 mg/kg).
We found that, compared to control animals, VPA-exposed rats showed reduced play responsiveness together with impaired sociability in the three-chamber test and altered social discrimination abilities. In addition, VPA-exposed rats showed altered expression of dopamine receptors together with inherent hyperexcitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). However, when tested for socially-induced conditioned place preference, locomotor response to amphetamine and sucrose preference, control and VPA-exposed rats performed similarly, indicating normal responses to social, drug and food rewards.
On the basis of the results obtained, we hypothesize that social dysfunctions displayed by VPA-exposed rats are more likely caused by alterations in cognitive aspects of the social interaction, such as the interpretation and reciprocation of social stimuli and/or the ability to adjust the social behavior of the individual to the changing circumstances in the social and physical environment, rather than to inability to enjoy the pleasurable aspects of the social interaction. The observed neurochemical and electrophysiological alterations in the NAc may contribute to the inability of VPA-exposed rats to process and respond to social cues, or, alternatively, represent a compensatory mechanism towards VPA-induced neurodevelopmental insults.

Keywords: autism, valproate, Social play, Dopamine, electrophyiology

Received: 20 Jun 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Schiavi, Iezzi, Manduca, Leone, Melancia, Carbone, Petrella, Mannaioni, Masi and Trezza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Viviana Trezza, Department of Science, Roma Tre University, Rome, 00146, Lazio, Italy,