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      G Protein-Coupled Receptor Heteromers as Putative Pharmacotherapeutic Targets in Autism

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          Abstract

          A major challenge in the development of pharmacotherapies for autism is the failure to identify pathophysiological mechanisms that could be targetable. The majority of developing strategies mainly aim at restoring the brain excitatory/inhibitory imbalance described in autism, by targeting glutamate or GABA receptors. Other neurotransmitter systems are critical for the fine-tuning of the brain excitation/inhibition balance. Among these, the dopaminergic, oxytocinergic, serotonergic, and cannabinoid systems have also been implicated in autism and thus represent putative therapeutic targets. One of the latest breakthroughs in pharmacology has been the discovery of G protein-coupled receptor (GPCR) oligomerization. GPCR heteromers are macromolecular complexes composed of at least two different receptors, with biochemical properties that differ from those of their individual components, leading to the activation of different cellular signaling pathways. Interestingly, heteromers of the above-mentioned neurotransmitter receptors have been described (e.g., mGlu2–5HT2A, mGlu5–D2–A2A, D2–OXT, CB1–D2, D2–5HT2A, D1–D2, D2–D3, and OXT–5HT2A). We hypothesize that differences in the GPCR interactome may underlie the etiology/pathophysiology of autism and could drive different treatment responses, as has already been suggested for other brain disorders such as schizophrenia. Targeting GPCR complexes instead of monomers represents a new order of biased agonism/antagonism that may potentially enhance the efficacy of future pharmacotherapies. Here, we present an overview of the crosstalk of the different GPCRs involved in autism and discuss current advances in pharmacological approaches targeting them.

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          Most cited references 92

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          The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior.

           Thomas Insel (2010)
          Social neuroscience is rapidly exploring the complex territory between perception and action where recognition, value, and meaning are instantiated. This review follows the trail of research on oxytocin and vasopressin as an exemplar of one path for exploring the "dark matter" of social neuroscience. Studies across vertebrate species suggest that these neuropeptides are important for social cognition, with gender- and steroid-dependent effects. Comparative research in voles yields a model based on interspecies and intraspecies variation of the geography of oxytocin receptors and vasopressin V1a receptors in the forebrain. Highly affiliative species have receptors in brain circuits related to reward or reinforcement. The neuroanatomical distribution of these receptors may be guided by variations in the regulatory regions of their respective genes. This review describes the promises and problems of extrapolating these findings to human social cognition, with specific reference to the social deficits of autism. (c) 2010 Elsevier Inc. All rights reserved.
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            Promoting social behavior with oxytocin in high-functioning autism spectrum disorders.

            Social adaptation requires specific cognitive and emotional competences. Individuals with high-functioning autism or with Asperger syndrome cannot understand or engage in social situations despite preserved intellectual abilities. Recently, it has been suggested that oxytocin, a hormone known to promote mother-infant bonds, may be implicated in the social deficit of autism. We investigated the behavioral effects of oxytocin in 13 subjects with autism. In a simulated ball game where participants interacted with fictitious partners, we found that after oxytocin inhalation, patients exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference. Also, during free viewing of pictures of faces, oxytocin selectively increased patients' gazing time on the socially informative region of the face, namely the eyes. Thus, under oxytocin, patients respond more strongly to others and exhibit more appropriate social behavior and affect, suggesting a therapeutic potential of oxytocin through its action on a core dimension of autism.
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              Social reward requires coordinated activity of accumbens oxytocin and 5HT

              Social behaviors in species as diverse as honey bees and humans promote group survival but often come at some cost to the individual. Although reinforcement of adaptive social interactions is ostensibly required for the evolutionary persistence of these behaviors, the neural mechanisms by which social reward is encoded by the brain are largely unknown. Here we demonstrate that in mice oxytocin (OT) acts as a social reinforcement signal within the nucleus accumbens (NAc) core, where it elicits a presynaptically expressed long-term depression of excitatory synaptic transmission in medium spiny neurons. Although the NAc receives OT receptor-containing inputs from several brain regions, genetic deletion of these receptors specifically from dorsal raphe nucleus, which provides serotonergic (5-HT) innervation to the NAc, abolishes the reinforcing properties of social interaction. Furthermore, OT-induced synaptic plasticity requires activation of NAc 5-HT1b receptors, the blockade of which prevents social reward. These results demonstrate that the rewarding properties of social interaction in mice require the coordinated activity of OT and 5-HT in the NAc, a mechanistic insight with implications for understanding the pathogenesis of social dysfunction in neuropsychiatric disorders such as autism.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                30 October 2020
                2020
                : 14
                Affiliations
                1Department of Pharmacology, University of the Basque Country (UPV/EHU) , Leioa, Spain
                2Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM) , Leioa, Spain
                Author notes

                Edited by: Yu-Chih Lin, Hussman Institute for Autism, United States

                Reviewed by: Terence Hébert, McGill University, Canada; Jia-Da Li, Central South University, China

                These authors have contributed equally to this work

                Specialty section: This article was submitted to Cellular Neuropathology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2020.588662
                7662108
                Copyright © 2020 DelaCuesta-Barrutia, Peñagarikano and Erdozain.

                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.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 92, Pages: 9, Words: 7184
                Funding
                Funded by: Ministerio de Ciencia e Innovación 10.13039/501100004837
                Award ID: RTI2018-101427-B-I00
                Funded by: European Regional Development Fund 10.13039/501100008530
                Funded by: Euskal Herriko Unibertsitatea 10.13039/501100003451
                Categories
                Cellular Neuroscience
                Mini Review

                Neurosciences

                gpcr receptor heteromers, pharmacotherapy, glutamate, oxytocin, serotonin, dopamine, asd, cannabinoid

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