Cannabis alters stress processing in the brain, increasing vulnerability to PTSD-like responses

The rising legal acceptance of cannabis and the high comorbidity between cannabis use disorder (CUD) and post-traumatic stress disorder (PTSD) highlight the importance of understanding how stress and cannabis influence the brain. We recently discovered that cannabinoid use promotes two PTSD-like symptoms: avoidance coping behaviors and the generalization of stress-coping responses to a neutral stimulus. Here, we used in vivo zymography and confocal microscopy to examine how stress and cannabinoid use influence multipartite synaptic plasticity. Specifically, we assessed astroglial plasticity, Synapsin-I density, and matrix metalloproteinases (MMP-2,9) activity, in the nucleus accumbens core (NAcore). For this purpose, rats were restrained for 2 h and simultaneously exposed to an odor; the stress-conditioned stimulus (stress-CS). Three weeks later, rats were exposed to cannabinoid vapor (delta9-tetrahydrocannabinol+cannabidiol; THC + CBD) for 5 days, self-administered THC + CBD (i.v.) for 10 days, followed by 10 days of abstinence. We then evaluated the effect of stress-CS or neutral odor (NS) on coping strategies in a defensive burying task. We found that THC + CBD generalized stress responses to the NS, associated with astrocyte retraction from synapses and a decrease in Synapsin-I density. THC + CBD pretreatment promoted avoidant coping during stress-CS exposure, activated MMP-2,9, re-associated astrocytes with synapses, increased Synapsin-I density, and caused astrocyte atrophy. By inhibiting MMP-2,9, we found that stress-CS-induced plasticity required MMP-2,9 activation. MMP-2 inhibition also restored active coping behaviors during stress-CS exposure. Surprisingly, these neuroadaptations only occurred in males. Overall, these findings suggest a potential role for MMPs and astrocytes in the changes produced by THC + CBD use in responding to a stress-CS.