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

• Published in: British journal of pharmacology 2009-04, Vol.156 (7), p.1154-1166
• Main Authors: Riedel, Gernot, Fadda, Paola, McKillop‐Smith, Susan, Pertwee, Roger G, Platt, Bettina, Robinson, Lianne
• Format: Article
• Language: English
• Subjects: AM251; Animals; Appetite Depressants - pharmacology; Biological and medical sciences; Cannabinoid Receptor Antagonists; CB1 receptor; Dronabinol - administration & dosage; Dronabinol - analogs & derivatives; Dronabinol - pharmacology; Eating - drug effects; Fasting; Feeding Behavior - drug effects; home cage; hypophagia; Male; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Obesity; Pharmacology. Drug treatments; phytocannabinoids; Piperidines - administration & dosage; Piperidines - pharmacology; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Research Papers; Solvents; Weight Gain - drug effects; Δ9‐THCV
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2008.00107.x

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.