The effect of cannabidiol (CBD) on behavioral and neuroinflammatory consequences of comorbid AUD and PTSD in a rat model

Alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are debilitating conditions that often co-occur, with an estimated 41-79% comorbidity rate. A major concern with the co-occurrence of these disorders is the tendency for one to exacerbate the other. Specifically, symptoms related to PTSD are a significant risk factor for the development of AUD, and alcohol abuse worsens PTSD symptoms. This cycle, along with a lack of effective pharmacological treatment options, leads to significant behavioral and physiological deficits. Additionally, remission for comorbid AUD and PTSD is much more difficult to attain due to exacerbated symptomology and a lack of FDA-approved medications. In recent years, cannabidiol (CBD), a non-psychoactive compound found in cannabis, has been a focus of study due to its therapeutic potential. Researchers have demonstrated the anxiolytic and anti-inflammatory effects of CBD in both humans and animals, showing its promise as a novel therapeutic agent in the treatment of psychiatric disorders. The purpose of this study is to investigate the hypothesis that CBD will reduce fear-related behaviors and neuroinflammation in a rat model of comorbid AUD and PTSD. Our AUD/PTSD model utilized restraint stress and chronic intermittent ethanol exposure procedures. To investigate changes in future stress sensitivity all animals were exposed to a contextual fear conditioning paradigm, which was used to train the animals to associate environmental and auditory cues (environment appearance and tone) with an aversive stimulus (mild foot-shock). 30 minutes prior to each conditioning session, rats received an intraperitoneal injection of CBD (20mg/kg) or 0.9% Saline. Once the animals learned to associate the cues with a shock, they were exposed to an extinction learning procedure that involved presentation of the cue alone (no shock). This procedure parallels exposure therapy in humans, allowing for the assessment adaptations to fear learning. The amount of time the rats remain still (freezing) during the tone represents fear-related behavior. Our current results indicate rats with a history of stress and alcohol exposure displayed significantly higher freezing behaviors and this effect was significantly decreased with CBD treatment. This suggests that when CBD is administered during fear learning, it is able to attenuate heightened stress sensitivity associated with AUD/PTSD. To evaluate how CBD mediates the neuroinflammatory response associated with AUD and PTSD, brains from the rats were extracted and analyzed for the inflammatory cytokine tumor necrosis factor a (TNF-a). Specific regions of interest included the medial prefrontal cortex and hippocampus, areas associated with anxiety, memory, and addiction. Neuroinflammation analyses are still ongoing, however it is predicted that rats who received CBD will show a reduction in inflammation in the medial prefrontal cortex and hippocampus. Taken together, the current results show promise for CBD to reduce enhanced fear-related behavior associated with comorbid AUD and PTSD