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Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.
Doenni VM, Gray JM, Song CM, Patel S, Hill MN, Pittman QJ
(2016) Brain Behav Immun 58: 237-247
MeSH Terms: Amidohydrolases, Amygdala, Animals, Arachidonic Acids, Behavior, Animal, Endocannabinoids, Female, Glycerides, Inflammation, Lipopolysaccharides, Male, Polyunsaturated Alkamides, Pyridazines, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Signal Transduction, Social Behavior, Urea
Show Abstract · Added March 14, 2018
Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigated the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Oral administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.
Copyright © 2016 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Assay of Endocannabinoid Oxidation by Cyclooxygenase-2.
Kudalkar SN, Kingsley PJ, Marnett LJ
(2016) Methods Mol Biol 1412: 205-15
MeSH Terms: Animals, Arachidonic Acid, Arachidonic Acids, Biological Assay, Cell Line, Chromatography, Liquid, Cyclooxygenase 2, Endocannabinoids, Glycerides, In Vitro Techniques, Macrophages, Mice, Oxidation-Reduction, Polyunsaturated Alkamides, Substrate Specificity, Tandem Mass Spectrometry
Show Abstract · Added April 22, 2018
The endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide (AEA), are endogenous ligands for the cannabinoid receptors (CB1 and CB2) and are implicated in a wide array of physiological processes. These neutral arachidonic acid (AA) derivatives have been identified as efficient substrates for the second isoform of the cyclooxygenase enzyme (COX-2). A diverse family of prostaglandin glycerol esters (PG-Gs) and prostaglandin ethanolamides (PG-EAs) is generated by the action of COX-2 (and downstream prostaglandin synthases) on 2-AG and AEA. As the biological importance of the endocannabinoid system becomes more apparent, there is a tremendous need for robust, sensitive, and efficient analytical methodology for the endocannabinoids and their metabolites. In this chapter, we describe methodology suitable for carrying out oxygenation of endocannabinoids by COX-2, and analysis of products of endocannabinoid oxygenation by COX-2 and of endocannabinoids themselves from in vitro and cell assays.
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MeSH Terms
Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.
Gunduz-Cinar O, Flynn S, Brockway E, Kaugars K, Baldi R, Ramikie TS, Cinar R, Kunos G, Patel S, Holmes A
(2016) Neuropsychopharmacology 41: 1598-609
MeSH Terms: Amidohydrolases, Amygdala, Animals, Anti-Anxiety Agents, Arachidonic Acids, Endocannabinoids, Extinction, Psychological, Fear, Fluoxetine, Male, Mice, Mice, Inbred Strains, Polyunsaturated Alkamides
Show Abstract · Added March 14, 2018
Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.
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13 MeSH Terms
Neurobiological Interactions Between Stress and the Endocannabinoid System.
Morena M, Patel S, Bains JS, Hill MN
(2016) Neuropsychopharmacology 41: 80-102
MeSH Terms: Animals, Arachidonic Acids, Cannabinoid Receptor Modulators, Endocannabinoids, Glycerides, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Polyunsaturated Alkamides, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Stress, Psychological
Show Abstract · Added March 14, 2018
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
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12 MeSH Terms
Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.
Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, McLaughlin RJ, Hassan KI, Kühne C, Wotjak CT, Deussing JM, Patel S, Hill MN
(2015) J Neurosci 35: 3879-92
MeSH Terms: Adrenocorticotropic Hormone, Amidohydrolases, Amygdala, Animals, Anxiety, Arachidonic Acids, Corticotropin-Releasing Hormone, Endocannabinoids, Hydrolysis, Male, Mice, Mice, Knockout, Polyunsaturated Alkamides, Rats, Rats, Sprague-Dawley, Receptors, Corticotropin-Releasing Hormone, Stress, Psychological
Show Abstract · Added March 14, 2018
Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.
Copyright © 2015 the authors 0270-6474/15/353879-14$15.00/0.
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17 MeSH Terms
Identification of the major prostaglandin glycerol ester hydrolase in human cancer cells.
Manna JD, Wepy JA, Hsu KL, Chang JW, Cravatt BF, Marnett LJ
(2014) J Biol Chem 289: 33741-53
MeSH Terms: Animals, Arachidonic Acids, Cell Line, Tumor, Cyclooxygenase 2, Endocannabinoids, Escherichia coli, Esters, Gene Expression Regulation, Neoplastic, Glycerides, Glycerol, Humans, Hydrolysis, Kinetics, Macrophages, Mice, Polyunsaturated Alkamides, Prostaglandins, RNA, Small Interfering, Recombinant Proteins, Signal Transduction, Substrate Specificity, Thiolester Hydrolases
Show Abstract · Added February 22, 2016
Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol, by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE2-G hydrolysis was confirmed by siRNA knockdown. Purified recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity: PGE2-G > PGF2α-G > PGD2-G; LYPLA2 hydrolyzed 1- but not 2-arachidonoylglycerol or arachidonoylethanolamide. Chemical inhibition of LYPLA2 in the mouse macrophage-like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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22 MeSH Terms
Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation.
Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S
(2014) Transl Psychiatry 4: e408
MeSH Terms: Amidohydrolases, Animals, Anxiety, Arachidonic Acids, Behavior, Animal, Disease Models, Animal, Endocannabinoids, Male, Mice, Mice, Inbred ICR, Polyunsaturated Alkamides, Stress, Psychological
Show Abstract · Added January 20, 2015
Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light-dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light-dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.
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12 MeSH Terms
Diet-dependent modulation of hippocampal expression of endocannabinoid signaling-related proteins in cannabinoid antagonist-treated obese rats.
Rivera P, Luque-Rojas MJ, Pastor A, Blanco E, Pavón FJ, Serrano A, Crespillo A, Vida M, Grondona JM, Cifuentes M, Bermúdez-Silva FJ, de la Torre R, de Fonseca FR, Suárez J
(2013) Eur J Neurosci 37: 105-17
MeSH Terms: Amidohydrolases, Animals, Arachidonic Acids, Cannabinoid Receptor Agonists, Cannabinoid Receptor Antagonists, Diet, High-Fat, Dietary Carbohydrates, Dietary Fats, Endocannabinoids, Hippocampus, Lipoprotein Lipase, Male, Monoacylglycerol Lipases, Obesity, Phospholipase D, Piperidines, Polyunsaturated Alkamides, Pyrazoles, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1, Weight Gain
Show Abstract · Added April 10, 2014
Diet-induced obesity produces changes in endocannabinoid signaling (ECS), influencing the regulation of energy homeostasis. Recently, we demonstrated that, in high-fat-diet-fed rats, blockade of CB1 receptor by AM251 not only reduced body weight but also increased adult neurogenesis in the hippocampus, suggesting an influence of diet on hippocampal cannabinoid function. To further explore the role of hippocampal ECS in high-fat-diet-induced obesity, we investigated whether the immunohistochemical expression of the enzymes that produce (diacylglycerol lipase alpha and N-acyl phosphatidylethanolamine phospholipase D) and degrade (monoacylglycerol lipase and fatty acid amino hydrolase) endocannabinoids may be altered in the hippocampus of AM251 (3 mg/kg)-treated rats fed three different diets: standard diet (normal chow), high-carbohydrate diet (70% carbohydrate) and high-fat diet (60% fat). Results indicated that AM251 reduced caloric intake and body weight gain, and induced a modulation of the expression of ECS-related proteins in the hippocampus of animals exposed to hypercaloric diets. These effects were differentially restricted to either the 2-arachinodoyl glycerol or anandamide signaling pathways, in a diet-dependent manner. AM251-treated rats fed the high-carbohydrate diet showed a reduction of the diacylglycerol lipase alpha : monoacylglycerol lipase ratio, whereas AM251-treated rats fed the high-fat diet showed a decrease of the N-acyl phosphatidylethanolamine phospholipase D : fatty acid amino hydrolase ratio. These results are consistent with the reduced levels of hippocampal endocannabinoids found after food restriction. Regarding the CB1 expression, AM251 induced specific changes focused in the CA1 stratum pyramidale of high-fat-diet-fed rats. These findings indicated that the cannabinoid antagonist AM251 modulates ECS-related proteins in the rat hippocampus in a diet-specific manner. Overall, these results suggest that the hippocampal ECS participates in the physiological adaptations to different caloric diets.
© 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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22 MeSH Terms
Enzymatic formation of N-acylethanolamines from N-acylethanolamine plasmalogen through N-acylphosphatidylethanolamine-hydrolyzing phospholipase D-dependent and -independent pathways.
Tsuboi K, Okamoto Y, Ikematsu N, Inoue M, Shimizu Y, Uyama T, Wang J, Deutsch DG, Burns MP, Ulloa NM, Tokumura A, Ueda N
(2011) Biochim Biophys Acta 1811: 565-77
MeSH Terms: Animals, Arachidonic Acids, Brain, COS Cells, Chlorocebus aethiops, Endocannabinoids, Ethanolamines, Male, Mice, Mice, Mutant Strains, Models, Biological, Oleic Acids, Phospholipase D, Plasmalogens, Polyunsaturated Alkamides, Signal Transduction
Show Abstract · Added April 10, 2014
Bioactive N-acylethanolamines include anandamide (an endocannabinoid), N-palmitoylethanolamine (an anti-inflammatory), and N-oleoylethanolamine (an anorexic). In the brain, these molecules are formed from N-acylphosphatidylethanolamines (NAPEs) by a specific phospholipase D, called NAPE-PLD, or through NAPE-PLD-independent multi-step pathways, as illustrated in the current study employing NAPE-PLD-deficient mice. Although N-acylethanolamine plasmalogen (1-alkenyl-2-acyl-glycero-3-phospho(N-acyl)ethanolamine, pNAPE) is presumably a major class of N-acylethanolamine phospholipids in the brain, its enzymatic conversion to N-acylethanolamines is poorly understood. In the present study, we focused on the formation of N-acylethanolamines from pNAPEs. While recombinant NAPE-PLD catalyzed direct release of N-palmitoylethanolamine from N-palmitoylethanolamine plasmalogen, the same reaction occurred in the brain homogenate of NAPE-PLD-deficient mice, suggesting that this reaction occurs through both the NAPE-PLD-dependent and -independent pathways. Liquid chromatography-mass spectrometry revealed a remarkable accumulation of 1-alkenyl-2-hydroxy-glycero-3-phospho(N-acyl)ethanolamines (lyso pNAPEs) in the brain of NAPE-PLD-deficient mice. We also found that brain homogenate formed N-palmitoylethanolamine, N-oleoylethanolamine, and anandamide from their corresponding lyso pNAPEs by a Mg(2+)-dependent "lysophospholipase D". Moreover, the brain levels of alkenyl-type lysophosphatidic acids, the other products from lyso pNAPEs by lysophospholipase D, also increased in NAPE-PLD-deficient mice. Glycerophosphodiesterase GDE1 can hydrolyze glycerophospho-N-acylethanolamines to N-acylethanolamines in the brain. In addition, we discovered that recombinant GDE1 has a weak activity to generate N-palmitoylethanolamine from its corresponding lyso pNAPE, suggesting that this enzyme is at least in part responsible for the lysophospholipase D activity. These results strongly suggest that brain tissue N-acylethanolamines, including anandamide, can be formed from N-acylated plasmalogen through an NAPE-PLD-independent pathway as well as by their direct release via NAPE-PLD.
Copyright © 2011 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Dietary fat decreases intestinal levels of the anorectic lipids through a fat sensor.
Diep TA, Madsen AN, Holst B, Kristiansen MM, Wellner N, Hansen SH, Hansen HS
(2011) FASEB J 25: 765-74
MeSH Terms: Animals, Dietary Fats, Dose-Response Relationship, Drug, Eating, Gene Expression Regulation, Enzymologic, Intestinal Mucosa, Intestines, Linoleic Acids, Lipids, Male, Polyunsaturated Alkamides, RNA, Messenger, Random Allocation, Rats, Rats, Sprague-Dawley
Show Abstract · Added April 10, 2014
This study was undertaken to investigate the link between dietary fat content and intestinal levels of anorectic N-acylethanolamines (NAEs), including oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA). Male rats were fed high-fat diets (HFDs) with variable percentages of fat [20-45% of total energy (E%)] for 1-7 d; afterward, the jejunums were isolated, and jejunal NAE levels were measured by liquid-chromatography mass spectrometry. Enzyme activities and mRNA expression levels were measured for two synthesizing enzymes, N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and glycerophosphodiesterase (GDE1), and one degrading enzyme, fatty acid amide hydrolase (FAAH). We found a dose-response relation between the quantity/percentage of dietary fat, irrespective of the energy density, and the reduction of intestinal levels of OEA, PEA, and LEA. The reductions were present after 1 d of 45E% HFD. LEA, the major NAE species, was shown to have an anorectic potency slightly less than that of OEA but higher than PEA. Regulation at the enzyme level seems not to explain the changes in NAE levels. The results suggest the presence of a fat sensor, mediating the reduced intestinal NAE levels. The intestinal NAE levels are reduced in a dose- and time-dependent manner in response to dietary fat intake, and this may contribute to the well-known hyperphagic effect of HFDs.
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15 MeSH Terms