Research reportCannabinoids & Stress: Impact of HU-210 on behavioral tests of anxiety in acutely stressed mice

- We examined the effects of HU-210 on anxiety behaviors in an acute stress mouse model.
- In stressed mice, both high and low doses of cannabinoids were anxiogenic.
- Locomotor deficits appeared at high doses of HU-210, but only in stressed mice.
- HU-210 produces different behavioral phenotypes in stressed and unstressed subjects.
- A summation hypothesis is proposed to explain this phenomenon.

Anxiety disorders are one of the most prevalent classes of mental disorders affecting the general population, but current treatment strategies are restricted by their limited efficacy and side effect profiles. Although the cannabinoid system is speculated to be a key player in the modulation of stress responses and emotionality, the vast majority of current research initiatives had not incorporated stress exposure into their experimental designs. This study was the first to investigate the impact of exogenous cannabinoid administration in an acutely stressed mouse model, where CD1 mice were pre-treated with HU-210, a potent CB1R agonist, prior to acute stress exposure and subsequent behavioral testing. Exogenous cannabinoid administration induced distinct behavioral phenotypes in stressed and unstressed mice. While low doses of HU-210 were anxiolytic in unstressed subjects, this effect was abolished when mice were exposed to an acute stressor. The administration of higher HU-210 doses in combination with acute stress exposure led to severe locomotor deficits that were not previously observed at the same dose in unstressed subjects. These findings suggest that exogenous cannabinoids and acute stress act synergistically in an anxiogenic manner. This study underlies the importance of including stress exposure into future anxiety-cannabinoid research due to the differential impact of cannabinoid administration on stressed and unstressed subjects.