Endocannabinoids and Stress Resilience: Is Deficiency Sufficient to Promote Vulnerability?

Abstract

Over the past 2 decades, there has been rapidly growing interest in the role of the endocannabinoid (eCB) system in the regulation of stress and emotional processes. Several lines of converging evidence provide strong evidence that eCB signaling is a key player in these processes. First, genetic ablation or pharmacologic antagonism of the cannabinoid type 1 receptor (CB1R) results in exaggerated neuroendocrine and behavioral responses to acute stress (1). More so, sustained disruption of CB1R signaling produces an array of neurobiological changes consistent with alterations seen after chronic stress or in mood disorders, such as reductions in neurotrophin levels, neuro-genesis and dendritic complexity, and increased levels of central neuroinflammation (2,3). Second, facilitation of eCB signaling can dampen the impact of both acute and chronic stress on almost every variable examined, including alterations in anxiety, reward sensitivity, hyperalgesia, morphologic changes in the amygdala, and hippocampal synaptic plasticity (1). Third, the eCB system is highly sensitive to stress exposure. Specifically, under conditions of acute stress, the eCB system plays an important buffering role by limiting the magnitude of the stress response and facilitating recovery to basal function after cessation of stress exposure (1). However, under conditions of chronic stress, the eCB system appears to “collapse” in the sense that CB1Rs downregulate and lose their ability to modulate the synaptic release of neurotransmitters, such as glutamate and gamma-aminobutyric acid (1).