Endocannabinoid signaling mediates oxytocin-driven social reward
Open accessAbstract
Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.
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The coupling in paired voles between OXTR and the eCB system may reinforce the value of social interactions.
“Given OXT’s well-documented involvement in social-specific behaviors 19,46, the coupling in paired voles between OXTR and the eCB system may therefore reinforce the value of social interactions 39.”
From Social experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles (2022) · cites this paper as [39]
Oxytocin drives anandamide-mediated signaling at CB1 receptors to control the rewarding properties of social interactions.
“we identified a signaling mechanism by which oxytocin drives anandamide-mediated signaling at CB1 receptors to control the rewarding properties of social interactions.15”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [15]
Consequent activation of CB1 receptors is necessary and sufficient to regulate social reward.
“Consequent activation of CB1 receptors is necessary and sufficient to regulate social reward.”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [15]
Anandamide enhancement offsets the effects of oxytocin receptor blockade on social reward and NAc activity.
“Anandamide enhancement offsets the effects of oxytocin receptor blockade on social reward and NAc activity.15”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [15]
In isolated male mice, specifically stimulating oxytocin neurons in the paraventricular nucleus of the hypothalamus drives anandamide mobilization in the NAc.
“Conversely, in isolated male mice, specifically stimulating oxytocin neurons in the paraventricular nucleus of the hypothalamus drives anandamide mobilization in the NAc.”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [15]
Social contact among male mice stimulates the mobilization of anandamide in the nucleus accumbens in an oxytocin-dependent manner.
“Social contact among male mice stimulates the mobilization of anandamide in the nucleus accumbens (NAc), a key brain region for reward signaling, in an oxytocin-dependent manner.”
From Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment (2016) · cites this paper as [15]
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BackgroundSocial experience alters oxytocinergic modulation in the nucleus accumbens of female prairie voles
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- Authors
- Wei, D., Lee, D., Cox, C. D., Karsten, C. A., Peñagarikano, O., Geschwind, D. H., Gall, C. M., & Piomelli, D.
- Affiliations
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
- University of California, Irvine (US)
- University of the Basque Country (ES)
- University of California, Los Angeles (US)
- Corresponding author
- Piomelli, Daniele
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-10-26
- Volume
- 112
- Issue
- 45
- Pages
- 14084-14089
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4653148
- OpenAlex
- W2162507318
- Cited by
- 218
- References
- 38
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 21 · 2023: 13 · 2022: 28 · 2021: 24 · 2020: 25 · 2019: 20 · 2018: 14 · 2017: 21 · 2016: 21
- FWCI
- 13.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Institute on Drug Abuse (DA012413)
- Autism Science Foundation (Predoctoral Fellowship)
- UC Irvine Center for Autism Research and Translation (CART)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- endocannabinoid signaling, anandamide, oxytocin, social reward, CB1 receptor, nucleus accumbens, social isolation, conditioned place preference, oxytocin receptor, paraventricular nucleus, autism spectrum disorder, social behavior
- MeSH terms
- Autism Spectrum Disorder, Analysis of Variance, Animals, Arachidonic Acids, Benzamides, Benzodiazepines, Camphanes, Carbamates, Clozapine, Cocaine, Immunohistochemistry, Lipids, Male, Mice, Inbred C57BL, Nucleus Accumbens, Oxytocin, Piperazines, Piperidines, Pyrazoles, Reward, Social Behavior, Signal Transduction, Receptors, Cannabinoid, Mice, Polyunsaturated Alkamides, Infusions, Intraventricular, Endocannabinoids
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