Previous reports have indicated that the cannabinoid CB₁ receptor antagonist SR 141716A induces hypophagia in rodents (Ravinet Trillou et al., 2003). In order to explore the underlying behavioural mechanisms we examined the effects of SR 141716A (0, 0.3, 1 & 3 mg/kg, i.p) on instrumental responding for food pellets under a second order schedule (FI5 min FR5(5:S)). Thus food-restricted Lister hooded rats were trained to lever press five times to obtain an 8s light conditioned stimulus; after five presentations of the light the rat also received five food pellets. Test sessions lasted for 30 minutes with an initial 5 min period in which food was not delivered. Evaluation of the animal's behaviour during the first 5 minutes when responding was high, yet no food was consumed, provides insight into the effects of SR 141716A on incentive motivation for food whereas the remainder of the session permits study of the interactions between drug administration and food consumption.

SR 141716A dose-dependently decreased instrumental behaviour specific to the reinforced lever over the entire session (0.3 mg/kg: 83% NS, 1 mg/kg: 70% p<0.01, 3 mg/kg: 38% p<0.001, all relative to vehicle baseline). Since the effect of SR 141716A on responding within the first 5 min period (0.3mg/kg: 82% NS, 1 mg/kg: 62% p<0.01, 3 mg/kg: 34% p<0.001, all relative to vehicle baseline) was as marked as at later time points, the hypophagic properties of this compound within this paradigm cannot be readily explained by an action on satiation or palatability. Analysis of drug free instrumental behaviour in the operant sessions two days following drug treatment revealed no differences in behaviour at any time point between drug and vehicle treated animals; thus SR 141716A did not induce long term devaluation of food reward.

In further test sessions non-drugged animals were given access to either 2g or 4g of chow 30 minutes prior to testing. There was a similar effect to that of SR 141716A on responding during the initial five minutes of the test session (2g: 56% p<0.01, 4g: 40% p<0.001), suggesting that both manipulations affect appetitive responding and incentive motivation. However the responding of presatiated animals recovered when food was subsequently made available (quadratic component of trend analysis p<0.05 and p<0.01 respectively), suggesting a positive feedback process that resulted from ingestion of food. This effect was not observed in rats treated with SR 141716A, suggesting that the drug may attenuate this positive feedback process.

We conclude that SR 141716A may have two separable effects on feeding motivation in this task. First it reduces appetitive responses for food and second it reduces the positive feedback that results from ingestion of palatable food items.

Ravinet Trillou C et al. (2003). Am J Physiol Regul Integr Comp Physiol 284:R345-353.