The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats

被引:122
作者
Sink, Kelly S.
McLaughlin, Peter J.
Wood, Jodi Anne T.
Brown, Cara
Fan, Pusheng
Vemuri, V. Kiran
Pang, Yan
Olzewska, Teresa
Thakur, Ganesh A.
Makriyannis, Alex
Parker, Linda A.
Salamone, John D.
机构
[1] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA
[2] Northeastern Univ, Ctr Drug Discover, Boston, MA USA
[3] Univ Guelph, Dept Psychol, Guelph, ON, Canada
关键词
appetite; motivation; operant; feeding; THC; rimonabant;
D O I
10.1038/sj.npp.1301476
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 dose-dependent 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.
引用
收藏
页码:946 / 955
页数:10
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