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Abstract
Cannabinoids are lipophilic signaling molecules produced endogenously in the body, in the Cannabis plant, and synthetically in the laboratory. Decades ago, researchers confirmed in the laboratory what Cannabis users have known for centuries: cannabinoids augment eating behavior. Since then, the field has made great strides in understanding how cannabinoids confer their hyperphagic effect, which is namely through the broad expression of cannabinoid type-1 (CB1) receptor in the central nervous system. Despite the advances, there are still many unknowns, and this work seeks to fill several gaps. The preclinical study of cannabinoids is vital to determining their utility, e.g. in hypophagic disorders, but its paramount that preclinical studies implement translationally relevant methodology to achieve this goal. For this reason, we developed a model of edible consumption for rodents. We show that gelatin-based edibles increase food intake in rodents, importantly, through distinct behavioral mechanisms between the sexes. Males acutely increase their chow intake via an increase in meal frequency while females do so via an increase in meal size. There is a general dearth of behavioral data in females following cannabinoid administration; therefore, we explored the effects of cannabinoid receptor agonism on several behaviors of interest in the context of psychoactive drug use: impulsivity, motivation, and anxiety-like behavior. Females given a hyperphagic dose of the cannabinoid receptor agonist display elevated impulsive behavior toward a sucrose reinforcer, but this did not coincide with changes in motivation or anxiety-like behavior. Males displayed an acute increase in meal frequency following cannabinoid receptor agonist consumption, which suggests an increase in appetitive behavior. Known for its role in appetitive behavior, the neuropeptide orexin/hypocretin (OH) is produced in the lateral hypothalamus and has anatomical and physiological interactions with the endocannabinoid system. We therefore investigated the necessity of the OX1 receptor, responsible for the food-seeking properties of OH, in cannabinoid-induced hyperphagia in males and found that OX1 receptor signaling is required for the hyperphagic properties of cannabinoids. Taken together, these data further our understanding of the neural and behavioral mechanisms that underscore the hyperphagic effect of cannabinoid signaling