Abstract
BackgroundCannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance.Methodology/Principal FindingsHere, we show that peripherally administered CB1-R antagonist (AM251) or agonist equally suppressed or stimulated feeding respectively in Ay , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA) equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA) release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals.Conclusions/SignificanceOur results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.
Highlights
Obesity is a major health epidemic in developed nations
To investigate whether the melanocortin system is involved in central cannabinoid effects on appetite, we studied the effects of a CB1-R antagonist AM251 and a non-selective agonist WIN 55,212-2 on feeding behavior in agouti yellow (Ay) mice
There was no significant difference in a-MSH levels in explants incubated with AM251 or WIN 55, 212-2 compared to explants incubated with artificial cerebrospinal fluid (aCSF) (Figure S1)
Summary
Obesity is a major health epidemic in developed nations. A number of drugs have entered clinical trials as therapies for obesity. A novel class of drug undergoing clinical trials are the cannabinoid receptor-1 (CB1-R) antagonists, such as Rimonabant (Accomplia, sanofi-aventis, SR141716). Cannabinoids, the active components of marijuana, stimulate appetite and feeding and CB1-R antagonists reduce feeding in animals and humans [2,3]. Rimonabant is in late-stage clinical trials as a therapy for obesity and metabolic syndrome, little is known about how CB1-R antagonists affect the central neurocircuitry that regulates energy balance. Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, the melanocortin system that regulates energy balance
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