Endocannabinoid Signaling Mediates Oxytocin-Driven Social Reward

Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):14084-9. doi: 10.1073/pnas.1509795112. Epub 2015 Oct 26.

Abstract

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.

Keywords: anandamide; endocannabinoid; oxytocin; reward; social behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Arachidonic Acids / metabolism*
  • Autism Spectrum Disorder / physiopathology
  • Benzamides / administration & dosage
  • Benzamides / pharmacology
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / pharmacology
  • Camphanes / administration & dosage
  • Camphanes / pharmacology
  • Carbamates / administration & dosage
  • Carbamates / pharmacology
  • Clozapine / administration & dosage
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Endocannabinoids / metabolism*
  • Immunohistochemistry
  • Infusions, Intraventricular
  • Lipids / analysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nucleus Accumbens / metabolism*
  • Oxytocin / metabolism*
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Piperidines / administration & dosage
  • Piperidines / pharmacology
  • Polyunsaturated Alkamides / metabolism*
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology
  • Receptors, Cannabinoid / metabolism*
  • Reward*
  • Signal Transduction / physiology*
  • Social Behavior*

Substances

  • 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
  • Arachidonic Acids
  • Benzamides
  • Camphanes
  • Carbamates
  • Endocannabinoids
  • Lipids
  • Piperazines
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Receptors, Cannabinoid
  • cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
  • Benzodiazepines
  • AM 251
  • Oxytocin
  • L 368899
  • Cocaine
  • Clozapine
  • clozapine N-oxide
  • anandamide