Tolerance, physical dependence, and Δ⁹-THC-like interoceptive effects of cannabinol in mice

Cannabinoids, including Δ⁹-tetrahydrocannabinol (THC) and synthetic CB₁ agonists elicit acute psychotropic effects that undergo tolerance with repeated exposure. In contrast, the effects of prolonged cannabinol (CBN) use are unknown. This study examined (1) the effects of repeated CBN administration on classic cannabimimetic outcomes, (2) whether these effects undergo tolerance or induce physical dependence, and (3) the THC-like discriminative stimulus effects of CBN, including whether CBN alters THC's discriminative stimulus.

Adult C57BL/6 mice were administered CBN twice daily for five days and tested in the tetrad battery to measure tolerance. On the sixth day, rimonabant was administered and somatic signs of withdrawal (i.e., head twitches and paw tremors) and struggling in the tail suspension test were assessed. Cross-tolerance to the CB₁/CB₂ agonist WIN 55,212-2 was also assessed in mice repeatedly administered CBN. A separate cohort of mice was trained to discriminate THC from vehicle.

Mice displayed tolerance to CBN-induced catalepsy, antinociception, and hypothermia. Cannabimimetic effects of WIN 55,212-2 were attenuated in CBN-treated mice, indicating cross-tolerance. Similarly, rimonabant induced somatic withdrawal signs and increased struggling in CBN-treated mice. Finally, CBN fully substituted for THC. Although rimonabant substantially lowered the psychoactive effects of THC, the specific dose tested was less effective in lowering CBN's psychoactive effects. Administration of CBN plus THC also attenuated THC's psychoactive effects.

These data indicate that repeated CBN administration induces tolerance and physical dependence and that CBN reduces THC's psychoactive effects.