Stress regulates endocannabinoid-CB1 receptor signaling

Hillard, Cecilia J.

doi:10.1016/j.smim.2014.04.001

Cited by 106 publications

(90 citation statements)

References 144 publications

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“…So far, very few studies have analyzed the impact of either acute 22 or chronic stress 23, 24 in lipid signaling using a lipidomic approach, and predominantly the focus has been put on the role of endocannabinoids as modulators of stress associated pathways 25 .…”

Section: Discussion/conclusionmentioning

confidence: 99%

The impact of chronic stress on the rat brain lipidome

et al. 2015

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Chronic stress is a major risk factor for several human disorders that affect modern societies. The brain is a key target of chronic stress. In fact, there is growing evidence indicating that exposure to stress affects learning and memory, decision making and emotional responses, and may even predispose for pathological processes, such as Alzheimer’s disease (AD) and depression. Lipids are a major constituent of the brain, and specifically signaling lipids have been shown to regulate brain function. Here, we used a mass spectrometry-based lipidomic approach to evaluate the impact of a chronic unpredictable stress paradigm on the rat brain in a region-specific manner. We found that the prefrontal cortex (PFC) was the area with the highest degree of changes induced by chronic stress. Although the hippocampus presented relevant lipidomic changes, the amygdala and to a more extent, the cerebellum, presented few lipid changes upon chronic stress exposure. The sphingolipid and phospholipid metabolism were profoundly affected, showing an increase in ceramide and a decrease in sphingomyelin and dihydrosphingomyelin levels, and decreased phosphatidylethanolamine and ether phosphatidylcholine and increased lysophosphatidylethanolamine levels, respectively. Furthermore, the fatty acyl profile of phospholipids and diacylglycerol revealed that chronic stressed rats had higher 38 carbon(38C)-lipid levels in the hippocampus and a decrease in 36C-lipid levels in the PFC. Finally, lysophosphatidylcholine levels in the PFC were found to be correlated with blood corticosterone levels. In summary, lipidomic profiling of the effect of chronic stress allowed for the identification of dysregulated lipid pathways, revealing putative targets for pharmacological intervention that may potentially be used to modulate stress-induced deficits.

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Section: Discussion/conclusionmentioning

confidence: 99%

The impact of chronic stress on the rat brain lipidome

et al. 2015

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“…Today, we know about the complexity of the endocannabinoid system, which includes a variety of receptors such as CB1 (Hillard 2014); cannabinoid receptor type 2 (CB2; Dhopeshwarkar and Mackie 2014) and transient receptor potential vanilloid receptor type 1 (TRPV1; Edwards et al 2012); and several ligands such as 2-arachidonoylglycerol (2-AG; Savinainen et al 2012) and anandamide (AEA; GunduzCinar et al 2013a), to name the two most prominent, and their synthesizing and degrading enzymes and, likely, specific transporters responsible for their uptake (Fowler 2013; for review, see Mechoulam and Parker 2013). Interestingly, AEA and 2-AG levels might be differentially affected by increasing shock intensities (Morena et al 2014).…”

Section: Introductionmentioning

confidence: 99%

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

Llorente-Berzal

Terzian

Marzo³

et al. 2015

Psychopharmacology

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“…Additionally, many studies have shown the importance of the endocannabinoid system in modulating hypothalamic-pituitary-adrenal (HPA) axis activity throughout development (for review, Lee and Gorzalka, 2012). CB1 receptor signaling is stress responsive, and repeated exposure to chronic unpredictable stress in adulthood has been shown to reduce CB1 receptor signaling, a change associated with anhedonia and anxiety (for review, Hillard 2014; McEwen et al, 2015). Prenatal stress is widely known to alter behavior and neuroendocrine responses throughout life.…”

Section: Introductionmentioning

confidence: 99%

Sexually-dimorphic alterations in cannabinoid receptor density depend upon prenatal/early postnatal history

Dow-Edwards

Frank

Wade

et al. 2016

Neurotoxicology and Teratology

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Recent research has demonstrated that the endogenous cannabinoid system is central to the brain’s response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5 days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48-50 within 2 hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system.

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Stress regulates endocannabinoid-CB1 receptor signaling

Cited by 106 publications

References 144 publications

The impact of chronic stress on the rat brain lipidome

The impact of chronic stress on the rat brain lipidome

2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons

Sexually-dimorphic alterations in cannabinoid receptor density depend upon prenatal/early postnatal history

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