Abstract
Endocannabinoids play a role in adaptation to stress and regulate the release of glucocorticoids in stressed and unstressed conditions. We recently found that basal corticosterone pulsatility may significantly impact the vulnerability for developing post-traumatic-stress-disorder (PTSD), suggesting that the endocannabinoid system may contribute to its development. To examine this, we exposed rats to predator scent stress (PSS). Behavioral reactions were recorded seven days post-PSS. Cerebrospinal fluid (CSF) was collected from anesthetized rats shortly after PSS exposure to determine the levels of 2-arachidonoyl glycerol (2-AG) and anandamide (AEA). To correlate between endocannabinoids and corticosterone levels, rats were placed in metabolic cages for urine collection. To assess the levels of endocannabinoids in specific brain regions, rats’ brains were harvested one day after behavioral analysis for staining and fluorescence quantification. Moreover, 2-AG was elevated in the CSF of PTSD-phenotype rats as compared with other groups and was inversely correlated with corticosterone urinary secretion. Eight days post-PSS exposure, hippocampal and hypothalamic 2-AG levels and hippocampal AEA levels were significantly more reduced in the PTSD-phenotype group compared to other groups. We posit that maladaptation to stress, which is propagated by an abnormal activation of endocannabinoids, mediates the subsequent stress-induced behavioral disruption, which, later, reduces neuronal the expression of endocannabinoids, contributing to PTSD symptomology.
Highlights
Hypothalamus-pituitary-adrenal (HPA) negative feedback inhibition occurs on a rapid time scale and is known to act via non-genomic routes
This GC-stress-induced increase in 2-arachidonoyl glycerol (2-AG) that modulates PVN neurons is important for several aspects of the stress response; mainly, it contributes to negative feedback and the termination of the stress response, in addition to the development of habituation and adaptation under conditions of repeated exposure to stress in animals [11,12,13] and in humans [14,15]
The HPA axis is activated by secreting its end product GC [35,36]
Summary
Hypothalamus-pituitary-adrenal (HPA) negative feedback inhibition occurs on a rapid time scale and is known to act via non-genomic routes These non-genomic routes are thought to be mediated through endocannabinoid release [1,2,3,4,5]. We have found that reduced basal, pre-trauma, corticosterone pulse amplitude is a pre-existing susceptibility factor for a blunted corticosterone stress response and the development of the subsequent PTSD-phenotype [34]. In theory, this dysregulation can be achieved through several pathways, among them is a disruption in the endocannabinoid system.
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