Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.
Proceedings of the National Academy of Sciences. 2013-03-04; 110(12): 4786-4791
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1. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4786-91. doi:
10.1073/pnas.1218573110. Epub 2013 Mar 4.
Activation of the sympathetic nervous system mediates hypophagic and anxiety-like
effects of CB₁ receptor blockade.
Bellocchio L(1), Soria-Gómez E, Quarta C, Metna-Laurent M, Cardinal P, Binder E,
Cannich A, Delamarre A, Häring M, Martín-Fontecha M, Vega D, Leste-Lasserre T,
Bartsch D, Monory K, Lutz B, Chaouloff F, Pagotto U, Guzman M, Cota D, Marsicano
(1)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.
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.
PMID: 23487769 [Indexed for MEDLINE]