Effects of Acute Stress on Cardiac Endocannabinoids, Lipogenesis, and Inflammation in Rats

Holman, E. Alison; Guijarro, Ana; Lim, Jinhwan; Piomelli, Daniele

doi:10.1097/psy.0000000000000025

Cited by 23 publications

(17 citation statements)

References 43 publications

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“…Studying individual differences that influence post-trauma adaptation may generate clues about how anxiety states are triggered. Consistent with published data,~25% of TMT-exposed rats in our study failed to develop long-term anxiety-like behavior in the EPM (Fendt et al, 2005;Holman et al, 2014). In addition, TMT-resistant rats did not exhibit elevated levels of 2-AG in the amygdala compared with TMT-sensitive animals.…”

Section: Discussionsupporting

confidence: 81%

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Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Lim

Igarashi

Jung

et al. 2015

Neuropsychopharmacol

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Individuals who experience life-threatening psychological trauma are at risk of developing a series of chronic neuropsychiatric pathologies that include generalized anxiety, depression, and drug addiction. The endocannabinoid system has been implicated in the modulation of these responses by regulating the activity of the amygdala and the hypothalamic-pituitary-adrenal axis. However, the relevance of this signaling complex to the long-term consequences of traumatic events is unclear. Here we use an animal model of predatory stress-induced anxiety-like behavior to investigate the role of the endocannabinoid system in the development of persistent anxiety states. Our main finding is that rats exposed to the fox pheromone 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a life-threatening stimulus for rodents, display a marked and selective increase in the mobilization of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the amygdala. This effect lasts for at least 14 days after the stress has occurred. In addition, systemic or local pharmacological inhibition of monoacylglycerol lipase (MGL)-a lipid hydrolase that degrades 2-AG in presynaptic nerve terminals-elevates 2-AG levels and suppresses the anxiety-like behavior elicited by exposure to TMT. The results suggest that predator threat triggers long-term changes in 2-AG-mediated endocannabinoid signaling in the amygdala, and that pharmacological interventions targeting MGL might provide a therapeutic strategy for the treatment of chronic brain disorders initiated by trauma.

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Section: Discussionsupporting

confidence: 81%

“…Consistent with published data (Fendt et al, 2005;Holman et al, 2014), we found that~25% of the rats exposed to TMT did not develop long-term anxiety-like behavior. This led us to hypothesize that TMT exposure might differentially regulate 2-AG levels in resistant vs sensitive rats.…”

Section: Exposure To Tmt Mobilizes 2-ag In the Amygdalasupporting

confidence: 81%

Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Lim

Igarashi

Jung

et al. 2015

Neuropsychopharmacol

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“…Cardiac levels of 2-AG, but not AEA, are increased in preconditioning (Wagner et al 2006). However, acute stress was recently shown to decrease cardiac endocannabinoid levels (Holman et al 2014), which might indicate that an upregulation of the endocannabinoid system in the heart is a chronic effect. Upregulation of cannabinoid receptors has been shown in cardiac pathologies, particularly CB 2 , which is upregulated in chronic heart failure (Weis et al 2010), in aortic stenosis (Duerr et al 2013) and in ischaemia/reperfusion (Duerr et al 2014).…”

Section: Cardioprotective Effects Of Endocannabinoidsmentioning

confidence: 99%

Endocannabinoids and the Cardiovascular System in Health and Disease

O’Sullivan

2015

Handbook of Experimental Pharmacology

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The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

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“…Animal research has repeatedly shown a decrease in AEA in almost all brain regions investigated in response to both acute and chronic stress, which seems to contribute to HPA axis activation, as well as an anxiety phenotype (Morena et al, 2015). Furthermore, a peripheral decline of the N-acylethanolamides PEA and OEA in the aftermath of predator stress was observed in animals, too (Holman et al, 2014). Correspondingly, knockout of endocannabinoid receptors was associated with impaired stress coping and enhanced anxiety and depressive-like symptoms, while stimulation of the ECS reduced anxiety and stress-related behavioral impairments in stress-exposed rats (reviewed in Hill and Patel (2013)).…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoid concentrations in hair are associated with PTSD symptom severity

Wilker

Pfeiffer

Elbert

et al. 2016

Psychoneuroendocrinology

101

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a b s t r a c tThe endocannabinoid system has been implicated in the regulation of the stress response, fear memory formation, and inflammatory processes. Posttraumatic stress disorder (PTSD) can result from exposure to extreme stress and is characterized by strong, associative memories for the traumatic events experienced. Furthermore, an elevated physical disease risk has been observed in PTSD, likely to be mediated by inflammatory processes. Therefore, altered endocannabinoid regulation can be expected in individuals with PTSD. However, attempts to assess PTSD-associated differences in the endocannabinoid system from human blood samples have provided inconsistent results, possibly due to fluctuating levels of endocannabinoids. In hair, these neuromodulators are accumulated over time and thus give access to a more stable and reliable assessment.We therefore investigated PTSD-associated differences in hair concentrations of endocannabinoids (Nacyl-ethanolamides palmitoylethanolamide [PEA], oleoylethanolamide [OEA] and stearoylethanolamide [SEA]) in 38 rebel war survivors from Northern Uganda suffering from PTSD and N = 38 healthy rebel war survivors without current and lifetime PTSD. PTSD diagnosis and symptom severity were assessed in structured clinical interviews employing the Posttraumatic Diagnostic Scale (PDS). A significant group difference was observed for OEA, with PTSD patients showing reduced hair concentrations. Regression analyses further revealed strong negative relationships between all investigated N-acyl-ethanolamides and symptom severity of PTSD. The observed reductions in endocannabinoids might account for the increased inflammatory state as well as for the failure to extinguish fear memories observed in PTSD. Our findings add to the accumulating evidence suggesting the endocannabinoid system as a target for pharmacological enhancement of exposure-based psychotherapy for PTSD.

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Effects of Acute Stress on Cardiac Endocannabinoids, Lipogenesis, and Inflammation in Rats

Cited by 23 publications

References 43 publications

Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Endocannabinoids and the Cardiovascular System in Health and Disease

Endocannabinoid concentrations in hair are associated with PTSD symptom severity

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