title: Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.
abstract: Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.
authors.affiliation: Department of Biochemistry and Molecular Biology I and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, School of Biology, Complutense University-Instituto Universitario de Investigación Neuroquímica, 28040 Madrid, Spain.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bellocchio
authors.forename: Edgar
authors.initials: E
authors.lastname: Soria-Gómez
authors.forename: Carmelo
authors.initials: C
authors.lastname: Quarta
authors.forename: Mathilde
authors.initials: M
authors.lastname: Metna-Laurent
authors.forename: Pierre
authors.initials: P
authors.lastname: Cardinal
authors.forename: Elke
authors.initials: E
authors.lastname: Binder
authors.forename: Astrid
authors.initials: A
authors.lastname: Cannich
authors.forename: Anna
authors.initials: A
authors.lastname: Delamarre
authors.forename: Martin
authors.initials: M
authors.lastname: Häring
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.forename: David
authors.initials: D
authors.lastname: Vega
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Francis
authors.initials: F
authors.lastname: Chaouloff
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzman
authors.forename: Daniela
authors.initials: D
authors.lastname: Cota
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001069:Appetite Regulation; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001068:Feeding and Eating Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission
chemical_list: D043884:Receptor, Cannabinoid, CB1