Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB ₁ receptor blockade

Abstract

Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB 1 ) 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 CB 1 receptor blockade, we combined the acute injection of the CB 1 receptor antagonist rimonabant with the use of conditional CB 1 -knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB 1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB 1 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 nutrientspecific component acutely regulated by CB 1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB 1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB 1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB 1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.fear and anxiety | sympathetic system

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

“…Interestingly, recent data revealed that the anorectic and anxiogenic effects of rimonabant require peripheral activation of sympathetic activity (26). Consistently, the present data indicate that control of adrenergic/noradrenergic transmission by CB1 receptors is involved in the central-peripheral control of behavior.…”

Neurobiological Interactions Between Stress and the Endocannabinoid System

“…Given that the physiological actions of cannabis are mediated by activation of the CB1 receptor, this suggested that a normative function of the eCB system could be to dampen or buffer against the effects of stress. Consistent with this hypothesis, pharmacological or genetic disruption of eCB signaling reliably produces a neurobehavioral phenotype, which directly parallels the classical manifestation of a stress response, including activation of the HPA axis, increased anxiety, suppressed feeding behavior, reduced responsiveness to rewarding stimuli, hypervigilance and arousal, enhanced grooming behavior, and impaired cognitive flexibility (Bellocchio et al, 2013;Friemel et al, 2014;Haller et al, 2004;Marsicano et al, 2002;Patel et al, 2004;Sanchis-Segura et al, 2004;Santucci et al, 1996;Shonesy et al, 2014;Tallett et al, 2007;Varvel and Lichtman, 2002). As such, these data indicate that there is a prominent stressinhibitory role of the eCB system.…”

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

“…Additionally, genetic deletion of CB 1 R in the PVN causes phenotypic changes due to increased SNSdriven energy expenditure and BAT thermogenesis (97). Finally, also the rapid hypophagic effect of rimonabant observed within 1-h from its administration relies on β-adrenergic transmission (98).…”