Acute anorectic response to cannabinoid CB1 receptor antagonist/inverse agonist AM 251 in rats: indirect behavioural mediation.

Despite a large and consistent literature on the suppressant effects of cannabinoid CB1 receptor antagonists/inverse agonists (e.g. rimonabant, AM 251) on food intake and weight gain in rodents, surprisingly little is known about the behavioural selectivity of such effects. In this study, ethological scoring was used to characterize the acute behavioural effects of the rimonabant analogue AM 251 (1.5 and 3.0 mg/kg, intraperitoneally) in nondeprived male rats during a 1-h test with palatable mash. Data were also collected on daily weight gain and on retest food intake 7 days after dosing. Results showed that the higher dose of AM 251 significantly inhibited mash consumption (32% decrease relative to vehicle control), reduced time spent feeding during the test and suppressed body weight gain over the 48-h period that followed acute dosing. No effects on mash consumption were observed when the animals were retested drug-free 1 week after drug treatment. Detailed video analysis of the test sessions showed that, over the dose range tested, AM 251 did not significantly interfere with the vast majority of noningestive behaviours. Both doses of the compound, however, significantly increased the incidence of and the time spent on scratching, whereas the higher dose additionally increased both the number and duration of grooming episodes. The latter effect in particular disrupted the normal structure of behaviour (behavioural satiety sequence) with atypically high levels of grooming displacing feeding during the middle part of the test session. Overall, the behavioural profile of AM 251 in a free-feeding context is very similar to (but approximately two-fold less potent than) that recently reported for the parent molecule, rimonabant. Together, these data strongly suggest that the acute anorectic response to CB1 receptor antagonists/inverse agonists is indirectly mediated via major alterations to other components of the behavioural repertoire.