Appetite suppression and weight loss after the cannabinoid antagonist SR 141716

Colombo, Giancarlo; Agabio, Roberta; Diaz, Giacomo; Lobina, Carla; Reali, Roberta; Gessa, Gian Luigi

doi:10.1016/s0024-3205(98)00322-1

Cited by 460 publications

(320 citation statements)

References 9 publications

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“…However, when intake data were expressed as a percentage of baseline consumption, these differences between diet groups disappeared. It must also be emphasized that there was indeed a significant overall suppression of lab chow intake, consistent with previous studies showing effects of antagonist/inverse agonists on lab chow consumption (Colombo et al, 1998;Gómez et al, 2002;McLaughlin et al, 2003McLaughlin et al, , 2006Verty et al, 2004). Taken together, these results suggest that AM4113 is not preferentially suppressing feeding of highly palatable diets, but that apparent interactions with diet type or palatability may be owing to differences in baseline consumption and/or scaling.…”

Section: Discussionsupporting

confidence: 89%

“…SR141716 attenuated the hyperphagia induced by CB1 agonists (Jamshidi and Taylor, 2001;Kirkham et al, 2002;Williams and Kirkham, 1999), and when administered alone it reduced food intake in a number of different animal models (Arnone et al, 1997;Colombo et al, 1998;Simiand et al, 1998;Williams and Kirkham, 1999). Feeding suppression induced by CB1 antagonists/inverse agonists has been demonstrated in both satiated and food-deprived animals following systemic or central administration, and after either acute or chronic treatment (Chen et al, 2004;Colombo et al, 1998;Shearman et al, 2003;Wiley et al, 2005). Although it is clear that drugs that interfere with CB1 transmission can suppress food intake, the mechanisms by which they accomplish this are less well understood.…”

Section: Introductionmentioning

confidence: 98%

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The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Sink

McLaughlin

Wood

et al. 2007

Neuropsychopharmacol

143

193

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Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dosedependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists. Neuropsychopharmacology (2008) 33, 946-955;

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 98%

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Sink

McLaughlin

Wood

et al. 2007

Neuropsychopharmacol

143

193

View full text Add to dashboard Cite

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“…11,[23][24][25] Although the molecular basis and cellular basis for the action of inverse agonists have been well documented and the physiological endpoints are well defined, the detailed physiological mechanisms through which modulation of CB1R translate to changes in peripheral tissue metabolism can be difficult to dissect. The following sections will address the physiological MOA related to the site of action for inverse agonists and the physiological pathways involved.…”

Section: Molecular and Cellular Moamentioning

confidence: 99%

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong

Heymsfield

2009

Int J Obes

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Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

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“…[5][6][7] An important step toward understanding the biological role of endocannabinoids was the introduction by the sanofi-aventis company of selective cannabinoid receptor antagonists for both major types of cannabinoid receptor: 8,9 the CB1 receptor expressed at very high levels in the brain 10 but also present in various peripheral tissues, 11 and CB2 receptors expressed predominantly in immune and hematopoietic cells. 12 In the late 1990s, several studies have demonstrated that treatment with the CB1 selective antagonist, now called rimonabant, reduces food intake in rodents, [13][14][15] and both anandamide 16,17 and 2-AG 18 were found to stimulate food intake. However, it was not possible to conclude that the effect of rimonabant was due to blocking of the tonic orexigenic effect of an endocannabinoid because of the well-known inverse agonist properties of rimonabant.…”

Section: Endocannabinoid Regulation Of Appetitive Behaviormentioning

confidence: 99%

The role of the endocannabinoid system in the control of energy homeostasis

et al. 2006

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The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1 À/À mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

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Appetite suppression and weight loss after the cannabinoid antagonist SR 141716

Cited by 460 publications

References 9 publications

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

The role of the endocannabinoid system in the control of energy homeostasis

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