THE ENDOCANNABINOID SYSTEM AND ANOREXIA NERVOSA: BIOCHEMICAL AND PHARMACOLOGICAL STUDIES IN THE ACTIVITY-BASED MODEL IN RATS

Anorexia nervosa (AN) is a chronic eating disorder with the highest mortal¬ity rate of any other psychiatric disease (APA, 2013). Patients affected by AN develop aberrant eating patterns and weight-control behaviors, such as excessive dieting and physical hyperactivity, aimed to control their altered body image perception. The endocannabinod system (ECs) is an important neuromodulator of different brain circuits and physiological functions and has a key role in the regulation of both homeostatic and hedonic aspects of eating behavior (Di Marzo et al., 2009). In recent years, several lines of evidence have raised the hypothesis of a strong link between a defected ECs and AN that may contribute to its onset and development. For example, significantly enhanced plasma levels of the endogenous cannabinoid anandamide were found in patients affected by AN (Monteleone et al., 2005). Moreover, brain imaging studies showed a global cannabinoid type 1 receptor (CB1R) up regulation in cortical and subcortical brain areas of AN patients (Gérard et al., 2011). Using the activity-based anorexia (ABA) model of AN, which reproduces some key aspects of the human condition, such as a massive decline in body weight coupled with physical hyperactivity (Routtemberg and Kuznesof, 1967) and endocrine dysregulation, we performed a study to deeply investigate the involvement of the ECs in the physiopathology of AN. Firstly, we analyzed arachidonic acid (AA), endocannabinoids levels and CB1R density in both feeding and reward-related brain areas of animals subjected to the ABA paradigm, and then, we evaluated whether pharmacological modulation with both cannabinoid receptors agonists and antagonist was able to modify typical symptomatology in anorexic-like animals. Our results showed that female rats exposed to the ABA paradigm developed an anorexic-like state characterized by marked body weight loss and increased running wheel activity (RWA). According to literature, our data showed that plasma levels of the anorexic mediator leptin were decreased in ABA animals, while, levels of the orexigenic mediator ghrelin and of the stress hormone corticosterone were increased. Moreover, we have seen that this anorexic-like phenotype was associated with an altered ECs signalling. In particular, we found a significant alteration of AA and endocannabinoids levels, as well as of the CB1R density in different brain areas involved in circuits regulating eating behavior, but also mood and cognition (i.e. hypothalamus, nucleus accumbens, amygdala and prefrontal cortex). Then, we have seen that the administration of the natural CB1/CB2 receptor agonist Δ9-tetrahydrocannabinol and the synthetic CB1R agonist CP-55,940 significantly reduced both body weight loss and physical activity, and increased food intake. Conversely, administration of the CB1R inverse agonist/antagonist rimonabant did not modify body weight loss, physical activity and food intake. Furthermore, the administration of both agonists tested partially reverted the altered hormone levels found in ABA animals. To conclude, we have seen that animals subjected to the ABA model showed an alteration of the ECs that could have a key involvement in the pathophysiology of AN, and that pharmacological therapies active on cannabinoid signalling might be effective in the treatment of this dramatic eating disorder.