Evaluation of Delta⁹ -Tetrahydrocannabinoland other Cannabinoids for Antidepressant-likeActions in the Mouse Forced Swim Test

Antidepressant actions of cannabis have been reported in chronic marijuana users. Research has shown that the pharmacological enhancement of the CB1 receptor can elicit antidepressant-like effects in the forced swim test [1]. However, other reports have demonstrated antidepressant activity with cannabinoid antagonists. Hence, this study was conducted to investigate the antidepressant-like activity in Δ⁹-THC and other cannabinoids. The forced swim test was used to evaluate the antidepressant-like effects in Swiss Webster mice. The tetrad assay was conducted to separate the psychoactive properties of the cannabinoids from the antidepressant activity. Desipramine was used as the positive control and it showed a dose dependent antidepressant activity that was statistically significant at 20 mg/kg (p < 0.001) in the forced swim test. Δ⁹-THC, a partial CB1 agonist, showed a u-shaped dose response curve with significant antidepressant-like effects at 2.5 mg/kg (p < 0.001) in the forced swim test, whereas the CB1 agonist CP55,940 showed antidepressant-like activity at 0.01 mg/kg (p < 0.01). The cannabinoids cannabicitran and cannabicyclol did not show activity in the forced swim test at 20 mg/kg. Results show that at low doses there may be potential antidepressant drug leads among the cannabinoids. Future work includes evaluation of other CB1 agonists, antagonists, and evaluation of compounds for anxiolytic actions in the elevated plus maze. Acknowledgements: This work was supported by grant number P20RR0021929 from the National Center for Research and Resources and by the National Institute of Drug Abuse, contract number NOIDA-5-7746. References: [1] Hill M, Gorzalka B (2005) European Neuropsychopharmacology 15: 593–599.