Acute treatment with cannabinoid receptor agonist WIN55212.2 improves prepulse inhibition in psychosocially stressed mice

Cannabis, similar to psychosocial stress, is well known to exacerbate psychotic experiences and can precipitate psychotic episodes in vulnerable individuals. Cannabinoid receptors 1 (CB1) are widely expressed in the brain and are particularly important to mediate the effects of cannabis. Chronic cannabis use in patients and chronic cannabinoids treatment in animals is known to cause reduced prepulse inhibition (PPI). Similarly, chronic psychosocial stress in mice impairs PPI. In the present study, we investigated the synergistic effects of substances modulating the CB1-receptors and chronic psychosocial stress on PPI.For this purpose, adult C57Bl/6J mice were exposed to chronic psychosocial stress using the resident-intruder paradigm. The cannabinoid receptor agonist WIN55212.2 served as a surrogate marker for the effects of cannabis in the brain. After exposure to stress mice were acutely injected with WIN55212.2 (3 mg/kg) with or without pre-treatment with Rimonabant (3 mg/kg), a specific CB1-receptor antagonist, and subjected to behavioral testing.Stressed mice displayed a higher vulnerability to WIN55212.2 in the PPI test than control animals. The effects of WIN55212.2 on PPI were antagonized by Rimonabant suggesting an involvement of CB1-receptors in sensorimotor gating. Interestingly, WIN55212.2 increased PPI in psychosocially stressed mice although previous studies in rats showed the opposite effects. It may thus be possible, that depending on the doses of cannabinoids/CB1-receptor agonists applied and environmental conditions (psychosocial stress), opposite effects can be evoked in different experimental animals.Taken together, our data imply that CB1-receptors might play a crucial role in the synergistic effects of psychosocial stress and cannabinoids in brain.

Research highlights▶ Chronic psychosocial stress leads to diminished spontaneous activity in open field and impairment of prepulse inhibition (PPI) in adult mice. ▶ Acute treatment with a high dose of a cannabinoid receptor 1 (CB1) agonist WIN55212.2 reverses deficits in PPI evoked by psychosocial stress. ▶ Psychosocially stressed mice display higher vulnerability to acute treatment with WIN55212.2 in PPI test. ▶ Rimonabant, a specific CB1-receptor antagonist, antagonizes the effects of WIN55212.2 on PPI suggesting an involvement of CB1-receptors in sensorimotor gating.