Investigating the role of CB1 endocannabinoid transmission in the anti-fear and anxiolytic-like effects of ventromedial prefrontal cortex deep brain stimulation

Deep brain stimulation (DBS) delivered to the ventromedial prefrontal cortex (vmPFC) of rats induces anti-fear and anxiolytic-like behaviours, while reducing principal cell firing in the basolateral amygdala (BLA). In parallel, the endocannabinoid system, particularly in the vmPFC and BLA, has emerged as a target for the amelioration of fear and stress-related behaviours. We tested whether DBS-related improvements in fear and anxiety-type behaviour are mediated by endocannabinoid signalling. First, we examined type-1 cannabinoid (CB1) receptor and fatty acid amide hydrolase (FAAH) expression in the vmPFC and BLA and found reduced CB1 expression in both loci in rats treated with DBS. Next, we conducted pharmacological experiments to test whether the inverse CB1 agonist AM251 could mitigate the behavioural effects of stimulation. Chronic vmPFC DBS was delivered to rats following conditioning and extinction. Animals were then tested for extinction recall and anxiety-type behaviour following the systemic administration of AM251 or vehicle. We found that DBS reduced freezing and induced anxiolytic-type effects in defensive burying and novelty supressed feeding paradigms. These responses were not countered by CB1 antagonism, suggesting that other mechanisms may be involved in the anti-fear and anxiolytic effects of DBS.