Cannabinoid use generalizes stress responses: involvement of astrocyte plasticity and activation of matrix metalloproteinases in the nucleus accumbens core

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.