The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats

Abstract

Cannabinoid CB1 inverse agonists such as rimonabant and AM 251 hold therapeutic promise as appetite suppressants, but the extent to which non-motivational factors contribute to their anorectic effects is not fully known. Examination of the behavioral satiety sequence (BSS) in rats, the orderly progression from eating to post-prandial grooming and then resting, has revealed that these compounds preserve the order of events but differ markedly from natural satiation. The most notable difference is that grooming (particularly scratching) is profoundly enhanced at anorectic doses, while eating and resting are diminished, raising the possibility that the anorectic effect is simply secondary to the grooming effect. In the current design, the neutral CB1 antagonist AM 4113, which has been found to lack some of the undesirable effects of AM 251, produced nearly identical effects on the BSS as AM 251. The possibility that competition from enhanced grooming could account for the anorectic effect of AM 4113 was examined by yoking the pattern of disruptions caused by grooming in the AM 4113-treated group to forced locomotion in a different group fed in a modified running wheel. This response competition did not significantly reduce food intake. It was concluded that AM 4113, a CB1 neutral antagonist, produces the same effects on the BSS as AM 251, but that response competition from enhanced grooming may not be a sufficient explanation for the anorectic effects of CB1 antagonists/inverse agonists.

Fig. 1

Effects of the CB1 inverse agonist AM 251 are shown on the three primary behaviors of the behavioral satiety sequence (BSS), feeding (A), grooming (B), and resting (C). Dose × bin interactions are noted for feeding (A) and resting (C), and a significant dose effect of grooming was found (B). Analysis of the dose factor in each bin revealed dose-dependent decreases in feeding in bins 1, 2, 3, and 5, and an increase in resting in bin 9 (*P < .05, **P < .01 difference from vehicle via planned comparisons).

Fig. 2

Analysis of grooming components indicated a dose-dependent change in the profile of grooming with AM 251. Each component is expressed as a percentage of the total. Fur cleaning decreased, while scratching increased (*P < .05, **P < .01 difference from vehicle via planned comparisons). One-way ANOVA did not yield a dose effect of biting, but a significant linear trend was found.

Fig. 3

Effects of the CB1 antagonist AM 4113 are shown for the progression of feeding (A), grooming (B), and resting (C) on the BSS. A main effect of dose and dose × bin interaction were found for feeding, and dose-dependent decreases in feeding are found in bins 1–4 and 7 (*P < .05, **P < .01 difference from vehicle via planned comparisons). Grooming (B) was significantly enhanced, but resting (C) was unaffected.

Fig. 4

AM 4113 decreases the predominance of fur cleaning as a percentage of all grooming behaviors. Significant compensatory increases are found in biting, scratching, and wet dog shakes (*P < .05, **P < .01 difference from vehicle condition via planned comparisons).

Fig. 5

Response competition with eating was manipulated by forcing locomotion in a modified running wheel at identical times and durations to grooming recorded in the AM 4113 study (Experiment 2). The Baseline condition was not yoked to Experiment 2 and consisted of uninterrupted feeding sessions. Response competition did not significantly inhibit food intake.