CB1 cannabinoid receptor-mediated modulation of food intake in mice

Abstract

1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.

Figure 1

Chemical structures of SR141716A, O-3257, and O-3259.

Figure 2

Effects of SR141716A on food intake (top panel) and % inhibition of locomotor activity (bottom panel). Bars represent the mean (±s.e.m.) of data from the same 10 mice at each dose for food intake and data from five separate mice at each dose for assessment of locomotor activity. ^* indicates significant difference from vehicle control (P<0.05). (Note: On all graphs that illustrate % inhibition, negative numbers represent stimulation of locomotor activity.)

Figure 3

Effects of Δ⁹-THC on food intake (top panel) and % inhibition of locomotor activity (bottom left panel). Also shown are the effects of combination of 3 mg kg⁻¹ SR141716A and different doses of Δ⁹-THC (bottom right panel). Bars represent the mean (±s.e.m.) of data from the same 9–10 mice across doses for food intake (but different mice for each Δ⁹-THC dose–effect curve) and data from six separate mice at each dose of each drug for assessment of locomotor activity. ^* indicates significant difference from vehicle control (P<0.05).

Figure 4

Effects of diazepam (left panels) and amphetamine (right panels) on food intake (top panels) and % inhibition of locomotor activity (bottom panels). Bars represent the mean (±s.e.m.) of data from the same 10 mice across doses for food intake (but different mice for each drug) and data from 5–6 separate mice at each dose of each drug for assessment of locomotor activity. ^* indicates significant difference from vehicle control (P<0.05).

Figure 5

Effects of two structural analogs of SR141716A, O-3257 (left panels) and O-3259 (right panels), on food intake (top panels) and % inhibition of locomotor activity (bottom panels). Bars represent the mean (±s.e.m.) of data from the same 10 mice across doses for food intake (but different mice for each analog) and data from 4–5 separate mice at each dose of each analog for assessment of locomotor activity. ^* indicates significant difference from vehicle control (P<0.05).

Figure 6

Effects of the CB2 antagonist SR144528 (left panels) and cannabidiol (right panels) on food intake (top panels) and % inhibition of locomotor activity (bottom panels). Bars represent the mean (±s.e.m.) of data from the same 10 mice across doses for food intake (but different mice for each drug) and data from five separate mice at each dose of each drug for assessment of locomotor activity. ^* indicates significant difference from vehicle control (P<0.05).

Figure 7

Effects of SR141716A (top panels) and amphetamine (bottom panels) in wild-type (left panels) and CB₁ knockout (right panels) mice. Bars represent the mean (±s.e.m.) of data from the same six CB₁ knockout and six wild-type mice across all doses of both drugs. For each test drug, a main effect of genotype was found (P<0.05), indicating that basal food intake for CB₁ knockout mice was decreased compared to that of wild-type mice. ^* indicates significant difference from vehicle control (P<0.05). # indicates significant difference from vehicle control (main effect of amphetamine dose) (P<0.05).