Effects of the Novel Cannabinoid, AM11101, on Food Intake, Activity-Based Anorexia, and Neuronal Activity in Brain Areas That Control Food Intake

The endocannabinoid system plays an important role in regulating energy balance. Administration of D9-tetrahydrocannabinol (THC), the main constituent of the Cannabis sativa plant, increases food intake and decreases energy expenditure by acting on cannabinoid receptor 1 (CB1R). Despite these well-documented effects, THC treatment has had mixed success in alleviating symptoms and reducing weight loss in anorexia nervosa (AN) patients and in the pre-clinical activity-based anorexia (ABA) rodent model of AN. To maximize medicinal benefits while minimizing potential side effects, the novel cannabinoid AM11101 was developed with the goal of having better efficacy than THC in treating AN symptoms. The goal of this dissertation was to provide the first examination of AM11101’s ability to increase food intake in healthy animals, attenuate weight loss in the pre-clinical ABA model, and identify brain areas that are activated by acute AM11101 treatment. In the first study, the orexigenic effects of AM11101 and THC were compared in pre-fed and free-fed female rats. Acute administration of AM11101 increased food intake for up to 4 h in pre-fed rats with no compensatory decrease in subsequent feeding. Although THC increased food intake in pre-fed rats, it was less reliable than AM11101 in increasing food intake in free-fed rats following both acute and chronic administration. Similar to THC, AM11101’s orexigenic effect was mediated by an increase in meal size. The second study examined whether daily treatment with AM11101 or THC would attenuate weight loss in female rats exposed to the ABA paradigm. We found that AM11101-treated rats displayed greater resilience to ABA than THC-treated rats. AM11101 attenuated ABA-induced weight loss and helped to preserve adipose tissue through a reduction in energy expenditure rather than an increase in food intake. Despite the well-characterized orexigenic effects of cannabinoids, the underlying neuronal mechanisms remain poorly understood. In the third study, we used the immunohistochemical detection of cFos, a marker of neuronal activity, to examine the effect of AM11101 treatment on cFos expression in brain areas that control food intake. We also examined whether AM11101 modulates feeding-induced changes in cFos expression. Acute administration of AM11101 produced a robust increase in cFos expression in multiple brain areas that control food intake. AM11101 was also found to increase feeding-induced cFos expression in one of these areas, the arcuate nucleus of the hypothalamus (ARC). These findings identify multiple brain areas where AM1101 could act to increase meal size. Taken together, these studies demonstrate for the first time that AM11101 increases food intake by a selective increase in meal size, attenuates the development of ABA with improved efficacy over THC, and increases feeding-induced neuronal activation in the ARC, a brain area that plays a critical role in controlling meal size. As such, AM11101 offers a promising new treatment to improve appetite in conditions that are characterized by undernutrition including AN.