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

Background and purpose:

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.

Experimental approach:

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 Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV), which behaves like a CB₁ antagonist, were also determined in free-feeding animals.

Key results:

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 Δ⁹-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 Δ⁹-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in the extract. This Δ⁹-THC effect was overcome by the co-administration of cannabidiol.

Conclusions and implications:

The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Δ⁹-THCV is a novel compound with hypophagic properties and a potential treatment for obesity.