Endocannabinoid and neuroendocrine contributions to fear learning in humans

Abstract

Fear learning is an important process that is essential for our survival. Impairments in this implicit form of emotion regulation is associated with several stress-related psychiatric disorders. Here, our goal was to determine the contributions of canonical stress systems, i.e., neuroendocrine and endocannabinoid systems, to fear learning in a population with histories of chronic stress exposure. In a 2×2 factorial design, adult participants (n=100) with or without histories of childhood trauma or substance use disorders completed a laboratory session to assess fear conditioning and extinction. Blood samples were collected to quantify peripheral levels of endocannabinoids and cortisol. Overall, 2-arachidonoyl glycerol (2AG), an endocannabinoid important for the termination of the stress response, was significantly negatively associated with self-reported anxiety and difficulties in emotion regulation, indicating that individuals with lower 2AG levels tend to be more anxious and have greater impairments in emotion regulation. Although there were no main effects of group on different aspects of fear learning, baseline levels of cortisol and endocannabinoids influenced fear learning in the sample overall. Specifically, higher baseline cortisol levels were associated with better acquisition of conditioned fear. Furthermore, baseline 2AG levels were related to the early extinction of conditioned fear such that higher levels of 2AG were coupled with greater distinction between the reinforced conditioned stimulus (CS+) and the non-reinforced conditioned stimulus (CS-). While additional analyses are ongoing, these results provide valuable insight into the neurobiology of fear learning and highlight potential molecular targets that could have therapeutic potential.