Chronic social defeat stress increases brain permeability to ghrelin in male mice.

Ghrelin is a stomach-derived hormone that increases feeding and is elevated in response to chronic psychosocial stressors. The effects of ghrelin on feeding are mediated by the binding of ghrelin to the growth hormone secretagogue receptor (GHSR), a receptor located in hypothalamic and extra-hypothalamic regions important for regulating food intake and metabolic rate. The ability of ghrelin to enter the brain, however, seems to be restricted to circumventricular organs like the median eminence and the brain stem area postrema (AP), whereas ghrelin does not readily enter other GHSR expressing regions like the ventral tegmental area (VTA). Interestingly, social stressors result in increased blood brain barrier permeability, and this could therefore facilitate the entry of ghrelin into the brain. To investigate this, we exposed mice to social defeat stress for 21 days, then peripherally injected a Cy5-labelled biologically active ghrelin analogue. Results demonstrate that chronically stressed mice exhibit higher Cy5-ghrelin fluorescence in several hypothalamic regions in addition to the ARC, including the hippocampus and midbrain. Furthermore, Cy5-ghrelin injections resulted in increased FOS expression in regions associated with the reward system in the chronically stressed mice. Further histologic analyses identified a reduction in branching of hypothalamic astrocytes in the ARC-median eminence junction, suggesting increased blood-brain barrier permeability. These data support the hypothesis that during metabolically challenging conditions like chronic stress, ghrelin may be more able to cross the blood brain barrier and diffuse throughout the brain to target GHSR expressing brain regions away from circumventricular organs.Significance Statement Ghrelin is secreted in response to negative energy balance states including stress and is associated with changes in food intake and energy balance. The receptors for ghrelin are found throughout the brain but ghrelin seems to only reach circumventricular regions where the blood brain barrier is more porous. In this paper we demonstrate that chronic social defeat stress increases brain permeability to ghrelin to allow for entry and activation of target sites in the mesolimbic dopaminergic system that are not accessible to ghrelin under non-stress conditions. Overall, these results provide for an explanation as to how ghrelin can access the mesolimbic dopaminergic system in a state dependent manner.

Effects of prenatal THC vapor exposure on body weight, glucose metabolism, and feeding behaviors in chow and high-fat diet fed rats.

BACKGROUND: 4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for developing of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. METHODS: Pregnant Sprague Dawley rats were exposed to vaporized THC (100 mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE (n = 24) or control (n = 24) litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. RESULTS: PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when on HFD/LFD, regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. CONCLUSIONS: PCE may not promote obesity development but may increase risk for diabetes and abnormal eating habits under certain biological and environmental conditions. Overall, this data enhances current understanding of the potential impacts of PCE.

Circadian Influence on Acute Stress-induced Changes in Cortico-limbic Endocannabinoid Levels in Adult Male Rats.

The endocannabinoid (eCB) system plays an important role in regulating the stress response, including glucocorticoid release and the generation of avoidance behaviour. Its two major ligands, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), are dynamically influenced by psychological stress to gate the generation of the stress response and facilitate recovery upon stress termination. Many biological systems exhibit circadian "daily" rhythms, including glucocorticoids and endocannabinoids, and the behavioural and endocrine impact of stress is modulated by the time of day. Nonetheless, most preclinical experiments investigating the interaction between stress and endocannabinoids occur in the light, "inactive" phase. We therefore tested if circadian phase influences stress-induced changes in eCB levels in the hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY). Adult male rats were exposed to 15 min swim stress or immediately euthanized, and brains were collected. Testing occurred either early in the light or early in the dark phase of their cycle to compare circadian effects. We found that overall, stress decreased AEA in the AMY and HIP, with an effect in the PFC dependent on the time of day. Conversely, stress increased 2-AG in the AMY, with an effect in the PFC and HIP dependent on the time of day. This suggests that stress has a similar overall impact on eCB levels regardless of circadian phase, but that subtle differences may occur depending on the brain region, especially the PFC.