Early life stress and development of the endocannabinoid system: A bidirectional process in programming future coping

Abstract

The endocannabinoid system (ECS) critically regulates stress responsivity and emotional behavior throughout development. It regulates anxiety‐like behaviors in humans and animal models. In addition, it is sensitive to early life stress at the gene expression level in a sex‐dependent and region‐dependent manner, and these changes are already evident in the adolescent brain. The ECS modulates the neuroendocrine and behavioral effects of stress, and is also capable of being affected by stress exposure itself. Early life stress interferes with the development of corticolimbic circuits, a major location of endocannabinoid receptors, and increases vulnerability to adult psychopathology. Early life stress alters the ontogeny of the ECS, resulting in a sustained deficit in its function, particularly within the hippocampus. Specifically, exposure to early stress results in bidirectional changes in anandamide and 2‐AG tissue levels within the amygdala and hippocampus and reduces hippocampal endocannabinoid function at puberty. CB1 receptor densities across all brain regions are downregulated later in life following exposure to early life stress. Manipulations affecting the glucocorticoid and the endocannabinoid systems persistently adjust individual emotional responses and synaptic plasticity. This review aims to show the bidirectional trajectories of endocannabinoid modulation of emotionality in reaction to early life stress.

Comparison and interaction of morphine and CB1 agonist conditioned place preference in the rat model of early life stress

“…Both clinical and experimental studies have shown that ELS affects the eCB system and increases the risk of psychopathologies, such as addiction and depression [for review, see (Goldstein Ferber et al., 2019)]. Our current results indicated that the rewarding properties of CB1R agonist decreased in the MS.…”

Becoming Stressed: Does the Age Matter? Reviewing the Neurobiological and Socio-Affective Effects of Stress throughout the Lifespan

“…For instance, mice exposed to maternal separation showed decreased CB1-R binding site densities within the amygdala, in both adolescence and adulthood. By contrast, alterations in the concentration of AEA and 2-AEG were only documented in infant rats after maternal separation stress [71,72] (Figure 3).…”

Discovering the Lost Reward: Critical Locations for Endocannabinoid Modulation of the Cortico–Striatal Loop That Are Implicated in Major Depression

“…Note that regions involved in the stress reaction are compromised by glucocorticoid mediated atrophy (i.e., hippocampus, PFC) [146] and they are also key regulators of mesolimbic and mesocortical dopaminergic pathways [145] indirectly affecting the reward circuits. The ECS is affected by stress and it only partially recovers with positive inputs [129]. However, recent reports show that the ECS, especially the CB1R, buffers the detrimental impact of stress on reward sensitivity [147,148].…”

“…Due to the potential of the endocannabinoid receptors to increase sensitivity to a reward in the behavioral and neural levels, their location within the reward circuits is crucial for cases of major depression lacking this sensitivity and pro-hedonic behavior related to it [127]. Recently, we discussed the epigenetic fragility of the ECS [128] and the bidirectional function of the system under stress [129]. Moreover, histone deacetylase (HDAC) inhibitors were found to interact with the ECS on the epigenetic level in preclinical studies of depression and chronic stress effects [130,131], suggesting that the crosstalk between ECS and DA receptors may be located at the epigenetic level.…”