Cannabinoid use generalizes stress responses by altering the astrocyte plasticity through extracellular matrix signaling 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 cannabis use promotes two PTSD-like symptoms: avoidance coping behaviors and the generalization of stress-coping responses to a neutral stimulus not previously linked to stress. To investigate the neuroadaptations behind these changes, we used in vivo zymography and confocal microscopy to examine how stress and cannabinoid use influence multipartite synaptic plasticity in the nucleus accumbens core (NAcore), including astroglial plasticity, Synapsin-I density, and matrix metalloproteinases (MMP-2,9) activity. For this purpose, rats were restraint stressed for 2h and simultaneously exposed to an odor that became the stress-conditioned stimulus (stress-CS). Three weeks later, rats self-administered cannabinoids (delta9-tetrahydrocannabinol + cannabidiol; THC + CBD) for 10 days, followed by 10 days of withdrawal. We then evaluated the effect of stress-CS or neutral odor (NS) on coping strategies in a defensive burying task. We demonstrated for the first time that THC + CBD generalized stress responses to the NS by causing astrocytes to retract from synapses and decreasing Synapsin-I density in the NAcore. Furthermore, cannabinoid use promoted avoidant coping behaviors in response to a stress-CS by triggering strong activation of MMP-2,9, driven largely by MMP-2, causing a re-association of astrocytes to synapses along with an increase of Synapsin-I density and astrocyte atrophy. However, these neuroadaptations only occurred in males. Overall, these findings highlight potential therapeutic targets like MMPs and astrocytes for treating co-occurring CUD/PTSD.