title: Interleukin-1β causes anxiety by interacting with the endocannabinoid system.
abstract: Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1β-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1β-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1β caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1β-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1β-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-1β and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1β on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Monica
authors.initials: M
authors.lastname: Bari
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology*; D002784:Cholesterol / Q000032:analysis; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D004291:Dominance-Subordination; D063388:Endocannabinoids / Q000502:physiology*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D007276:Injections, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D008297:Male; D008563:Membrane Lipids / Q000032:analysis; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D013315:Stress, Psychological / Q000139:chemically induced / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000172:deficiency / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D063388:Endocannabinoids; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008563:Membrane Lipids; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005680:gamma-Aminobutyric Acid; D002784:Cholesterol