The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies
Open accessAbstract
Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
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Melanocortin receptor agonists facilitate OT-dependent partner preferences in prairie voles.
“facilitate OT-dependent partner preferences in prairie voles (35, 37, 39, 40)”
From Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies (2016) · cites this paper as [35]
In “Enhancing endogenous OT release” (page unavailable), the paper says preliminary, unpublished studies suggest a melanocortin receptor agonist promotes partner preference in prairie voles. It proposes that MC4R agonists increase central OT release, drawing on evidence from rats, but does not establish that the vole partner-preference effect is OT-dependent. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBoth AVP and OXT have been implicated in ASD and other social disorders and are currently being tested in clinical trials.
“since both neuropeptides have been implicated in ASD and other social disorders (Meyer-Lindenberg et al., 2011; Modi and Young, 2012) and are currently being tested in clinical trials (clinicaltrials.gov).”
From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as Modi and Young, 2012
The Introduction links oxytocin to ASD and other psychiatric disorders with social impairments. The Social information processing and recognition section also describes a possible alteration of both oxytocin and vasopressin systems in ASD, but does not establish vasopressin’s involvement in the other disorders. The clinical-trials clause is cited to clinicaltrials.gov, not to Modi and Young. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDisrupted oxytocin regulation might play an important role in social reward dysfunctions in ASD by impeding accurate association of social stimuli and motivation values.
“disrupted oxytocin regulation might play an important role in social reward dysfunctions in ASD [81] by impeding the accurate association of social stimuli and motivation values [37]”
From The social motivation theory of autism (2012) · cites this paper as [81]
OXT is known to enhance social salience and has been found to increase performance in a range of social cognitive tasks.
“In this respect, OXT –which is known to enhance social salience [37]– can be seen as a promising therapeutic target and has been indeed been found to increase performance in a range of social cognitive tasks [81].”
From The social motivation theory of autism (2012) · cites this paper as [81]
Dysfunctions in the actions of OT and AVP have been linked to psychiatric disorders such as autism, anxiety, and schizophrenia.
“Dysfunctions in the actions of OT and AVP have been linked to psychiatric disorders such as autism, anxiety and schizophrenia.”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [82]
The prairie vole is the premier animal model for the neurobiology of social bonding and is increasingly used to screen drugs with therapeutic potential for social disorders such as autism.
“The prairie vole (Microtus ochrogaster), a socially monogamous rodent native to the American Midwest (24), is the premier animal model for the neurobiology of social bonding (25) and increasingly used to screen drugs that have therapeutic potential for social disorders such as autism (26,27).”
From Chronic intranasal oxytocin causes long-term impairments in partner preference formation in male prairie voles (2013) · cites this paper as [26]
Mechanisms underlying pair bond formation may be useful for improving many aspects of social cognition in human subjects, including in psychiatric conditions characterized by social impairments, such as autism spectrum disorder.
“Thus, the mechanisms underlying pair bond formation may be useful for improving many aspects of social cognition in human subjects, including in psychiatric conditions characterized by social impairments, such as autism spectrum disorder”
From Oxytocin and Social Relationships: From Attachment to Bond Disruption (2017) · cites this paper as Modi and Young 2012
Centrally, the release of oxytocin and its expression are influenced by estrogen in animal models.
“Centrally, the release of oxytocin and its expression are influenced by estrogen in animal models, 85”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [85]
The oxytocin system is altered in ASD.
“Evidence is emerging that the oxytocin system is altered in ASD [164]”
From Social “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications (2012) · cites this paper as [164]
Oxytocin pharmacotherapy alone will probably have only limited long-term beneficial effects on pro-social functioning.
“most recent literature reviews conclude that oxytocin pharmacotherapy alone will probably have only limited long-term beneficial effects on pro-social functioning [120,149,152,164].”
From Social “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications (2012) · cites this paper as [164]
Administering oxytocin or other substances that enhance central oxytocin turnover might be effective in ASD even in the presence of a disrupted oxytocin system.
“Therefore, administering oxytocin (for example, in the form of a nasal spray), or other substances that enhance central oxytocin turnover might be effective in ASD even in the presence of a disrupted oxytocin system [164].”
From Social “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications (2012) · cites this paper as [164]
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The social motivation theory of autism
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Statistical and Methodological Considerations for the Interpretation of Intranasal Oxytocin Studies
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“For example, melanocortin receptor agonists potentiate central OT release in the brain (37, 38), facilitate OT-dependent partner preferences in prairie voles (35, 37, 39, 40), and mimic the prosocial effects of OT in a mouse model of autism (41).”
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“spectrum disorder (ASD) and schizophrenia (12-17), and one report suggests that OXTR expression may be reduced in ASD (18).”
Self-citationSocial “wanting” dysfunction in autism: neurobiological underpinnings and treatment implications
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“The OT system is a potential target for enhancing social cognition in psychiatric disorders (Modi and Young, 2012), and several studies have now shown that IN-OT improves some aspects of social functioning in autism spectrum disorder (Andari et al.”
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Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice
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Oxytocin and Social Relationships: From Attachment to Bond Disruption
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The BTBR T+tf/J mouse model for autism spectrum disorders–in search of biomarkers
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Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques
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Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques
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Intranasal oxytocin selectively attenuates rhesus monkeys’ attention to negative facial expressions
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Self-citationCortical variability in the sensory-evoked response in autism
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Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors
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Editorial comment: Oxytocin, vasopressin and social behavior
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Investigation of an F-18 oxytocin receptor selective ligand via PET imaging
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Anxiolytic drug discovery: What are the novel approaches and how can we improve them?
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- Authors
- Modi, M. E., & Young, L. J.
- Affiliations
- Emory University (US)
- Corresponding author
- Young, Larry J.
- ORCID
- Young, Larry J.
- Venue
- Hormones and Behavior
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 61
- Issue
- 3
- Pages
- 340-350
- ISSN
- 0018-506X (ISSN-L)
- PMC
- PMC3483080
- OpenAlex
- W2051273046
- Cited by
- 218
- References
- 99
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 2 · 2022: 10 · 2021: 14 · 2020: 19 · 2019: 6 · 2018: 15 · 2017: 21 · 2016: 21 · 2015: 26 · 2014: 24 · 2013: 24 · 2012: 20
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Hormones and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health (P51OD011132)
- National Institute of Mental Health (K02MH064692, MH064692)
- National Center for Research Resources (RR-00 165, P51RR000165)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- oxytocin, autism spectrum disorder, social cognition, social dysfunction, animal models, oxytocin receptor, CD38, knockout mice, BTBR mice, Microtus ochrogaster, pharmacotherapy, drug discovery
- MeSH terms
- Administration, Intranasal, Animals, Anxiety, Autistic Disorder, Behavior Therapy, Arvicolinae, Disease Models, Animal, Genotype, Humans, Models, Psychological, Oxytocin, Cystinyl Aminopeptidase, Phenotype, Social Behavior, Receptors, Oxytocin, Recognition, Psychology, Mice, Drug Discovery
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