Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.
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We thank the members of the Malenka and Heifets labs for helpful comments on the project. We thank Claire Ellis for her help with breeding, maintaining, and delivering many of the mouse lines. We also thank Jason M. Tucciarone for his expertise in timed pregnancies for the generation of the valproic acid mice. MDMA was a gift from R. Doblin, Multidisciplinary Association for Psychedelic Studies (MAPS).
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Walsh, J.J., Llorach, P., Cardozo Pinto, D.F. et al. Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacol. 46, 2000–2010 (2021). https://doi.org/10.1038/s41386-021-01091-6