The cannabinoid CB1 antagonist AM 251 produces food avoidance and behaviors associated with nausea but does not impair feeding efficiency in rats

Abstract

The CB1 antagonist AM 251 may reduce food intake in part by inducing nausea or malaise, but not because of incoordination or motor slowing related to feeding.

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

“…SR141716 potentiated lithium chloride-induced conditioned rejection reactions in rats , and this drug also produced emesis in the least shrew (Darmani, 2001) and nausea in humans (Despres et al, 2005). Although rats do not vomit, recent studies from our laboratory demonstrated that administration of AM251 led to the production of conditioned gaping in rats (McLaughlin et al, 2005b), which is thought to be a selective marker of nausea in that species (Parker et al, 1998;Parker and Limebeer, 2006). These gaping responses are elicited by treatments that produce vomiting in emetic species (Parker et al, 1998), and treatments that attenuate toxin-induced vomiting in emetic species also attenuate toxin-induced conditioned gaping in rats Parker, 2000, 2003;Limebeer et al, 2004; for a review, see Parker et al, 2003).…”

“…CB1 receptors are present in the brain stem dorsal vagal complex, and CB1 receptors in this area are associated with triggering emetic responses (Van Sickle et al, 2003). Conditioned taste avoidance can be produced by administration of the CB1 inverse agonists SR141716 (De Vry et al, 2004) and AM251 (McLaughlin et al, 2005b). SR141716 potentiated lithium chloride-induced conditioned rejection reactions in rats , and this drug also produced emesis in the least shrew (Darmani, 2001) and nausea in humans (Despres et al, 2005).…”

“…Experiment 2 characterized the CB1 antagonist activity of AM4113 by assessing the ability of this drug to reverse the behavioral effects of the CB1 agonist AM411 (McLaughlin et al, 2005a) using tests that are associated with cannabinoid receptor activation (eg Martin et al, 1991). Experiments 3-5 assessed the behavioral effects of AM4113, employing the same food-related tasks previously used to characterize the actions of AM251, AM1387, and SR141716 (McLaughlin et al, 2003(McLaughlin et al, , 2005b(McLaughlin et al, , 2006. Experiment 3 examined the effects of AM4113 on food-reinforced lever pressing using two different fixed-ratio (FR) schedules.…”

“…Experiment 3 examined the effects of AM4113 on food-reinforced lever pressing using two different fixed-ratio (FR) schedules. Experiment 4 studied the effects of AM4113 on the consumption of diets with different macronutrient compositions (eg high fat, high carbohydrate, and lab chow; McLaughlin et al, 2003McLaughlin et al, , 2005bMcLaughlin et al, , 2006. Finally, experiment 5 employed the taste reactivity test developed by Grill and Norgren (1978) to determine if AM4113 can produce conditioned gaping in a manner similar to that previously shown to occur after administration of AM251 (McLaughlin et al, 2005b).…”

“…Experiment 4 studied the effects of AM4113 on the consumption of diets with different macronutrient compositions (eg high fat, high carbohydrate, and lab chow; McLaughlin et al, 2003McLaughlin et al, , 2005bMcLaughlin et al, , 2006. Finally, experiment 5 employed the taste reactivity test developed by Grill and Norgren (1978) to determine if AM4113 can produce conditioned gaping in a manner similar to that previously shown to occur after administration of AM251 (McLaughlin et al, 2005b). It was hypothesized that AM4113 would display neurochemical characteristics of a CB1 neutral antagonist without inverse agonist properties, would be able to block behavioral effects of a CB1 agonist, and would attenuate appetite and foodreinforced behaviors without inducing behaviors associated with nausea and malaise.…”