Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice

Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation. A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid Delta(9)-tetrahydrocannabivarin (Delta(9)-THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals. AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg.kg(-1)) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Delta(9)-THCV also induced hypophagia and weight reduction at doses as low as 3 mg.kg(-1). No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Delta(9)-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in the extract. This Delta(9)-THC effect was overcome by the co-administration of cannabidiol. The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Delta(9)-THCV is a novel compound with hypophagic properties and a potential treatment for obesity.