Endocannabinoid signaling mediates oxytocin-driven social reward.
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.
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
Don
http://orcid.org/0000-0003-2198-5921
D
Wei
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
DaYeon
D
Lee
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
Conor D
CD
Cox
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
Carley A
CA
Karsten
Department of Pharmacology, School of Medicine, University of the Basque Country, Barrio Sarriena s/n, Leioa 48940, Spain;
Olga
O
Peñagarikano
Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095;
Daniel H
DH
Geschwind
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697;
Christine M
CM
Gall
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697; Unit of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova 16163, Italy piomelli@uci.edu.
Daniele
D
Piomelli
D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D000067877:Autism Spectrum Disorder / Q000503:physiopathology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D001892:Camphanes / Q000008:administration & dosage / Q000494:pharmacology; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism*; D007150:Immunohistochemistry; D057967:Infusions, Intraventricular; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000378:metabolism*; D010121:Oxytocin / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D012201:Reward; D015398:Signal Transduction / Q000502:physiology*; D012919:Social Behavior
C547280:4-(3,5-dihydroxybenzyl)-N-(2-methyl-4-((1-methyl-4,10-dihydropyrazolo(3,4-b)(1,5)benzodiazepin-5(1H)-yl)carbonyl)benzyl)piperazine-1-carboxamide; D001095:Arachidonic Acids; D001549:Benzamides; D001892:Camphanes; D002219:Carbamates; D063388:Endocannabinoids; D008055:Lipids; D010879:Piperazines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D001569:Benzodiazepines; C103505:AM 251; D010121:Oxytocin; C086206:L 368899; D003042:Cocaine; D003024:Clozapine; C079149:clozapine N-oxide; C078814:anandamide
anandamide; endocannabinoid; oxytocin; reward; social behavior