Targeting the endocannabinoid/paracannabinoid systems in binge eating behavior: Efficacy of dual ligands in a preclinical model.

Binge eating disorder (BED) is characterized by compulsive overeating of palatable food in small intervals of time. Numerous studies focus on discovering mechanisms for BED pathophysiology and effective treatments for this disease. In our research, we used a well-established preclinical model of binge eating (BE) behavior in female rats, induced by intermittent cycles of food restriction and frustration stress. As the first aim of this study, we investigated the underlying mechanisms of aberrant eating behavior by analyzing hormone and biochemical mediator concentrations in plasma, as well as variations in gene and protein expression within the hypothalamus, the brain region primarily responsible for integrating hunger and satiety signals. Our results evidenced that BE rats presented altered hypothalamus-pituitary axis activation and notable changes in leptin, opioid, and cannabinoid signaling, which disrupted food intake through the POMC/AgRP/NPY pathways. As second aim of this study, we tested the effect of the administration of three dual ligands targeting receptors of the endocannabinoid (CB1 receptors) or the paracannabinoid systems (Peroxisome Proliferator-activated receptors alfa/gamma or Transient receptor potential vanilloid 1, PPARa/g and TRPV1 respectively): NF10-360 (double PPARa/PPARg agonist); OLS (PPARa/TRPV1 agonist); OLHHA (CB1 antagonist/PPARa agonist). OLHHA 0.3 mg/kg and OLS 6 mg/kg successfully reduced aberrant palatable food consumption during BE tests and restored part of the alterations detected in plasma and hypothalamus in BE rats. This evidence suggests that dual ligands may be considered effective and innovative putative pharmacological alternatives for clinical treatment.