Disruption of peri-adolescent endocannabinoid signaling modulates adult neuroendocrine and behavioral responses to stress in male rats.

The endocannabinoid (eCB) system is known to regulate neural, endocrine and behavioral responses to stress in adults; however there is little knowledge regarding how this system governs the development and maturation of these responses. Previous work has reported dynamic and time-specific changes in CB1 receptor expression, N-arachidonylethanolamine (AEA) content and fatty acid amide hydrolase (FAAH) activity within corticolimbic structures throughout the peri-adolescent period. To examine whether fluctuations in adolescent eCB activity contribute to the development of adult stress responsivity and emotionality, we treated male Sprague-Dawley rats daily with the CB1R antagonist, AM-251 (5 mg/kg), or vehicle between post-natal days (PND) 35-45. Following this treatment, emotional behavior, HPA axis stress reactivity and habituation to repeated restraint stress, as well as corticolimbic eCB content were examined in adulthood (PND 75). Behaviorally, AM-251-treated males exhibited more active stress-coping behavior in the forced swim test, greater risk assessment behavior in the elevated plus maze and no significant differences in general motor activity. Peri-adolescent AM-251 treatment modified corticosterone habituation to repeated restraint exposure compared to vehicle. Peri-adolescent CB1R antagonism induced moderate changes in adult corticolimbic eCB signaling, with a significant decrease in amygdalar AEA, an increase in hypothalamic AEA and an increase in prefrontal cortical CB1R expression. Together, these data indicate that peri-adolescent endocannabinoid signaling contributes to the maturation of adult neurobehavioral responses to stress.