Timing is everything: evidence for a role of corticolimbic endocannabinoids in modulating hypothalamic-pituitary-adrenal axis activity across developmental periods.

Growing evidence suggests that the endocannabinoid system is vital to ensuring normative maturation of the brain into adulthood. Endocannabinoid signaling contributes to guiding pro-neurogenic processes in early life and the development of neurotransmitter systems. Moreover, there is extensive evidence that recruitment of the endocannabinoid system is crucial in the regulation of neuroendocrine responses to stress via the hypothalamic-pituitary-adrenal (HPA) axis, and contributes to subsequent psychopathological consequences associated with emotionality and anxiety. These stress-induced physiological and behavioural sequelae are regulated by neural structures within the corticolimbic circuit, including the amygdala, hypothalamus, hippocampus, and prefrontal cortex. Based on evidence demonstrating endocannabinoid system involvement in both development and stress-induced changes in HPA axis function, it is reasonable to suggest that endocannabinoid signaling is an important mediator of interactions between stress responsivity and maturational stage. In this review, we discuss the ontogeny of the endocannabinoid system in the central nervous system, clinical and rodent models demonstrating short- and long-term effects of stress exposure, regulation of HPA axis responsivity by endocannabinoid signaling, as well as pharmacological and stress models indicating involvement of the endocannabinoid system in early post-natal and adolescent development on stress reactivity of the HPA, the corticolimbic system, and behaviour.