Endocannabinoid regulation of homeostatic feeding and stress‐induced alterations in food intake in male rats

Sticht, Martin A.; Lau, David J; Keenan, Catherine M.; Morena, Maria; Vemuri, V. Kiran; Makriyannis, Alexandros; Cravatt, Benjamin F.; Sharkey, Keith A.; Hill, Matthew N.

doi:10.1111/bph.14453

Cited by 22 publications

(15 citation statements)

References 74 publications

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“…Doses and timing were chosen based on previously published papers (Colangeli et al, 2017; Kathuria et al, 2003; Morena et al, 2018; Ratano, Palmery, Trezza, & Campolongo, 2017; Sticht et al, 2019) and pilot experiments performed in our laboratory. All drug solutions were freshly prepared before each experiment.…”

Section: Methodsmentioning

confidence: 99%

“…URB597, MJN110, or their vehicle were injected 60 min before the extinction training session; AM251, capsazepine or their vehicle were injected 90 min before the extinction training session. Doses and timing were chosen based on previously published papers (Colangeli et al, 2017;Kathuria et al, 2003;Ratano, Palmery, Trezza, & Campolongo, 2017;Sticht et al, 2019) and pilot experiments performed in our laboratory. All drug solutions were freshly prepared before each experiment.…”

Section: Methodsmentioning

confidence: 99%

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Sex‐dependent effects of endocannabinoid modulation of conditioned fear extinction in rats

Morena

Nastase

Santori

et al. 2021

British J Pharmacology

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Background and Purpose: Women are twice as likely as men to develop posttraumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. Experimental Approach: To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear and measured both passive (freezing) and active (darting) conditioned responses. Key Results: Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid 1 (CB 1) receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex-and brain region-specific changes. Conclusion and Implications: We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Sex‐dependent effects of endocannabinoid modulation of conditioned fear extinction in rats

Morena

Nastase

Santori

et al. 2021

British J Pharmacology

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“…On the three consecutive days before drug infusion and testing, rats were exposed to daily mock infusions. Two hours prior to EPM testing, animals received icv infusions (2 µL; 1 µL/min) of solutions containing vehicle (0.9% saline:dimethylsulfoxide (DMSO):Tween-80 [80:10:10; vol:vol:vol]) or a FAAH inhibitor (PF-04457845 (PF); Pfizer, New York, NY, USA; 100 ng and 1 µg) [ 98 – 100 ]. Infusers extended 2 mm past guide cannula and were left in place 1 min following infusion.…”

Section: Methodsmentioning

confidence: 99%

Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

Vecchiarelli

Morena

Keenan

et al. 2021

Neuropsychopharmacol.

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Peripheral inflammatory conditions, including those localized to the gastrointestinal tract, are highly comorbid with psychiatric disorders such as anxiety and depression. These behavioral symptoms are poorly managed by conventional treatments for inflammatory diseases and contribute to quality of life impairments. Peripheral inflammation is associated with sustained elevations in circulating glucocorticoid hormones, which can modulate central processes, including those involved in the regulation of emotional behavior. The endocannabinoid (eCB) system is exquisitely sensitive to these hormonal changes and is a significant regulator of emotional behavior. The impact of peripheral inflammation on central eCB function, and whether this is related to the development of these behavioral comorbidities remains to be determined. To examine this, we employed the trinitrobenzene sulfonic acid-induced model of colonic inflammation (colitis) in adult, male, Sprague Dawley rats to produce sustained peripheral inflammation. Colitis produced increases in behavioral measures of anxiety and elevations in circulating corticosterone. These alterations were accompanied by elevated hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which hydrolyzes the eCB anandamide (AEA), throughout multiple corticolimbic brain regions. This elevation of FAAH activity was associated with broad reductions in the content of AEA, whose decline was driven by central corticotropin releasing factor type 1 receptor signaling. Colitis-induced anxiety was reversed following acute central inhibition of FAAH, suggesting that the reductions in AEA produced by colitis contributed to the generation of anxiety. These data provide a novel perspective for the pharmacological management of psychiatric comorbidities of chronic inflammatory conditions through modulation of eCB signaling.

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“…In this study, appetite suppression was reversed by vagotomy, suggesting a mechanistical involvement of MGL in the gut-brain axis regulation of appetite[ 26 ]. In keeping, administration of an MGL inhibitor called MJN110, reduced food intake in rats[ 27 ]. Notably, pharmacological blockade of MGL with JZL184 caused increased systemic 2-AG levels in a mouse model of myocardial infarction[ 28 ].…”

Section: Pre-clinical Studies On Monoacylglycerol Lipase Deletion/inhmentioning

confidence: 99%

Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease

Tardelli¹

2020

WJG

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Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which eventually progress to cirrhosis and hepatocellular carcinoma. Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides, generating glycerol and fatty acids (FAs), which are signaling precursors in physiology and disease. Notably, monoacylglycerol lipase (MGL) also hydrolyzes 2-arachidonoylglycerol, which is a potent ligand within the endocannabinoid system, into arachidonic acid - a precursor for prostaglandin synthesis; thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation, pain and appetite. MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury, fibrogenesis and de- activate immune cells, however the complexity of MGL network system still needs further and deeper understanding. The present review will focus on MGL function and FA partitioning in the horizons of liver disease.

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Endocannabinoid regulation of homeostatic feeding and stress‐induced alterations in food intake in male rats

Abstract: Our data reveal diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress.

Cited by 22 publications

References 74 publications

Sex‐dependent effects of endocannabinoid modulation of conditioned fear extinction in rats

Sex‐dependent effects of endocannabinoid modulation of conditioned fear extinction in rats

Comorbid anxiety-like behavior in a rat model of colitis is mediated by an upregulation of corticolimbic fatty acid amide hydrolase

Monoacylglycerol lipase reprograms lipid precursors signaling in liver disease

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