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Sample records for endocannabinoid system implications

  1. Endocannabinoid System and Synaptic Plasticity: Implications for Emotional Responses

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    María-Paz Viveros

    2007-01-01

    Full Text Available The endocannabinoid system has been involved in the regulation of anxiety, and proposed as an inhibitory modulator of neuronal, behavioral and adrenocortical responses to stressful stimuli. Brain regions such as the amygdala, hippocampus and cortex, which are directly involved in the regulation of emotional behavior, contain high densities of cannabinoid CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic and depressive-like behaviors as well as an altered hypothalamus pituitary adrenal axis activity, whereas enhancement of endocannabinoid signaling produces anxiolytic and antidepressant-like effects. Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states. Endocannabinoids have emerged as mediators of short- and long- term synaptic plasticity in diverse brain structures. Despite the fact that most of the studies on this field have been performed using in vitro models, endocannabinoid-mediated plasticity might be considered as a plausible candidate underlying some of the diverse physiological functions of the endogenous cannabinoid system, including developmental, affective and cognitive processes. In this paper, we will focus on the functional relevance of endocannabinoid-mediated plasticity within the framework of emotional responses. Alterations of the endocannabinoid system may constitute an important factor in the aetiology of certain neuropsychiatric disorders, and, in turn, enhancers of endocannabinoid signaling could represent a potential therapeutical tool in the treatment of both anxiety and depressive symptoms.

  2. Dynamic regulation of the endocannabinoid system: implications for analgesia

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    Wong Amy

    2009-10-01

    Full Text Available Abstract The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthetic pathways for endocannabinoids are expressed by various cell types, multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid-based analgesics.

  3. Endocannabinoids

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Petersen, G.; Artmann, A.

    2006-01-01

    The endocannabinoid system embraces a group of lipid molecules, enzymes and receptor proteins. This system appears to be involved in the modulation of neurotransmitter release thereby modifying learning and memory, in the regulation of food intake, and in the modulation of inflammation and pain...

  4. The endocannabinoid system and spermatogenesis

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    Paola eGrimaldi

    2013-12-01

    Full Text Available AbstractSpermatogenesis is a complex process in which male germ cells undergo a mitotic phase followed by meiosis and by a morphogenetic process to form mature spermatozoa. Spermatogenesis is under the control of gonadotropins, steroid hormones and it is modulated by a complex network of autocrine and paracrine factors. These modulators ensure the correct progression of germ cell differentiation to form mature spermatozoa. Recently, it has been pointed out the relevance of endocannabinoids as critical modulators of male reproduction. Endocannabinoids are natural lipids able to bind to cannabinoid receptors and whose levels are regulated by specific biosynthetic and degradative enzymes. Together with their receptors and metabolic enzymes, they form the endocannabinoid system (ECS. In male reproductive tracts, they affect Sertoli cell activities, Leydig cell proliferation, germ cell differentiation, sperm motility, capacitation and acrosome reaction. The ECS interferes with the pituitary-gonadal axis, and an intricate crosstalk between ECS and steroid hormones has been highlighted. This mini-review will focus on the involvement of the ECS in the control of spermatogenesis and on the interaction between ECS and steroid hormones.

  5. Targeting the endocannabinoid system : future therapeutic strategies

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    Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz

    2017-01-01

    The endocannabinoid system (ECS) is involved in many physiological regulation pathways in the human body, which makes this system the target of many drugs and therapies. In this review, we highlight the latest studies regarding the role of the ECS and the drugs that target it, with a particular

  6. Epigenetic mechanisms associated with addiction-related behavioural effects of nicotine and/or cocaine: implication of the endocannabinoid system.

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    Hayase, Tamaki

    2017-10-01

    The addictive use of nicotine (NC) and cocaine (COC) continues to be a major public health problem, and their combined use has been reported, particularly during adolescence. In neural plasticity, commonly induced by NC and COC, as well as behavioural plasticity related to the use of these two drugs, the involvement of epigenetic mechanisms, in which the reversible regulation of gene expression occurs independently of the DNA sequence, has recently been reported. Furthermore, on the basis of intense interactions with the target neurotransmitter systems, the endocannabinoid (ECB) system has been considered pivotal for eliciting the effects of NC or COC. The combined use of marijuana with NC and/or COC has also been reported. This article presents the addiction-related behavioural effects of NC and/or COC, based on the common behavioural/neural plasticity and combined use of NC/COC, and reviews the interacting role of the ECB system. The epigenetic processes inseparable from the effects of NC and/or COC (i.e. DNA methylation, histone modifications and alterations in microRNAs) and the putative therapeutic involvement of the ECB system at the epigenetic level are also discussed.

  7. The endocannabinoid system and nondrug rewarding behaviours.

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    Fattore, Liana; Melis, Miriam; Fadda, Paola; Pistis, Marco; Fratta, Walter

    2010-07-01

    Rewarding behaviours such as sexual activity, eating, nursing, parenting, social interactions, and play activity are conserved strongly in evolution, and they are essential for development and survival. All of these behaviours are enjoyable and represent pleasant experiences with a high reward value. Remarkably, rewarding behaviours activate the same brain circuits that mediate the positive reinforcing effects of drugs of abuse and of other forms of addiction, such as gambling and food addiction. Given the involvement of the endocannabinoid system in a variety of physiological functions of the nervous system, it is not surprising that it takes part in the complex machinery that regulates gratification and perception of pleasure. In this review, we focus first on the role of the endocannabinoid system in the modulation of neural activity and synaptic functions in brain regions that are involved in natural and nonnatural rewards (namely, the ventral tegmental area, striatum, amygdala, and prefrontal cortex). Then, we examine the role of the endocannabinoid system in modulating behaviours that directly or indirectly activate these brain reward pathways. More specifically, current knowledge of the effects of the pharmacological manipulation of the endocannabinoid system on natural (eating, sexual behaviour, parenting, and social play) and pathological (gambling) rewarding behaviours is summarised and discussed. Copyright 2010 Elsevier Inc. All rights reserved.

  8. The endocannabinoid system: emotion, learning and addiction.

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    Moreira, Fabrício A; Lutz, Beat

    2008-06-01

    The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named anandamide after the Sanskrit word 'ananda', meaning 'bliss'. However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses three properties of the endocannabinoid system as an attempt to understand these diverse effects. First, this system typically functions 'on-demand', depending on environmental stimuli and on the emotional state of the organism. Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli. Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate. Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.

  9. The endocannabinoid system in brain reward processes.

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    Solinas, M; Goldberg, S R; Piomelli, D

    2008-05-01

    Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.

  10. Beyond Cannabis: Plants and the Endocannabinoid System.

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    Russo, Ethan B

    2016-07-01

    Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. The Endocannabinoid System and Sex Steroid Hormone-Dependent Cancers

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    Thangesweran Ayakannu

    2013-01-01

    Full Text Available The “endocannabinoid system (ECS” comprises the endocannabinoids, the enzymes that regulate their synthesis and degradation, the prototypical cannabinoid receptors (CB1 and CB2, some noncannabinoid receptors, and an, as yet, uncharacterised transport system. Recent evidence suggests that both cannabinoid receptors are present in sex steroid hormone-dependent cancer tissues and potentially play an important role in those malignancies. Sex steroid hormones regulate the endocannabinoid system and the endocannabinoids prevent tumour development through putative protective mechanisms that prevent cell growth and migration, suggesting an important role for endocannabinoids in the regulation of sex hormone-dependent tumours and metastasis. Here, the role of the endocannabinoid system in sex steroid hormone-dependent cancers is described and the potential for novel therapies assessed.

  12. The skeletal endocannabinoid system: clinical and experimental insights.

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    Raphael, Bitya; Gabet, Yankel

    2016-05-01

    Recently, there has been a rapidly growing interest in the role of cannabinoids in the regulation of skeletal remodeling and bone mass, addressed in basic, translational and clinical research. Since the first publications in 2005, there are more than 1000 publications addressing the skeletal endocannabinoid system. This review focuses on the roles of the endocannabinoid system in skeletal biology via the cannabinoid receptors CB1, CB2 and others. Endocannabinoids play important roles in bone formation, bone resorption and skeletal growth, and are sometimes age, gender, species and strain dependent. Controversies in the literature and potential therapeutic approaches targeting the endocannabinoid system in skeletal disorders are also discussed.

  13. Motion sickness, stress and the endocannabinoid system.

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    Alexander Choukèr

    Full Text Available BACKGROUND: A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the activity of the ECS in human volunteers (n = 21 during parabolic flight maneuvers (PFs. During PFs, microgravity conditions (<10(-2 g are generated for approximately 22 s which results in a profound kinetic stimulus. Blood endocannabinoids (anandamide and 2-arachidonoylglycerol, 2-AG were measured from blood samples taken in-flight before start of the parabolic maneuvers, after 10, 20, and 30 parabolas, in-flight after termination of PFs and 24 h later. Volunteers who developed acute motion sickness (n = 7 showed significantly higher stress scores but lower endocannabinoid levels during PFs. After 20 parabolas, blood anandamide levels had dropped significantly in volunteers with motion sickness (from 0.39+/-0.40 to 0.22+/-0.25 ng/ml but increased in participants without the condition (from 0.43+/-0.23 to 0.60+/-0.38 ng/ml resulting in significantly higher anandamide levels in participants without motion sickness (p = 0.02. 2-AG levels in individuals with motion sickness were low and almost unchanged throughout the experiment but showed a robust increase in participants without motion sickness. Cannabinoid-receptor 1 (CB1 but not cannabinoid-receptor 2 (CB2 mRNA expression in leucocytes 4 h after the experiment was significantly lower in volunteers with motion sickness than in participants without N&V. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that stress and motion sickness in humans are associated with impaired endocannabinoid

  14. Endocannabinoids and the Cardiovascular System in Health and Disease.

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    O'Sullivan, Saoirse Elizabeth

    2015-01-01

    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.

  15. Western Blotting of the Endocannabinoid System.

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    Wager-Miller, Jim; Mackie, Ken

    2016-01-01

    Measuring expression levels of G protein-coupled receptors (GPCRs) is an important step for understanding the distribution, function, and regulation of these receptors. A common approach for detecting proteins from complex biological systems is Western blotting. In this chapter, we describe a general approach to Western blotting protein components of the endocannabinoid system using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and nitrocellulose membranes, with a focus on detecting type 1 cannabinoid (CB1) receptors. When this technique is carefully used, specifically with validation of the primary antibodies, it can provide quantitative information on protein expression levels. Additional information can also be inferred from Western blotting such as potential posttranslational modifications that can be further evaluated by specific analytical techniques.

  16. Role of the endocannabinoid system in human brain functions relevant for psychiatric disorders

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    Bossong, M.G.

    2012-01-01

    Impaired cognitive function is a fundamental characteristic of many psychiatric and neurological disorders such as schizophrenia or Alzheimer’s disease. The endocannabinoid (eCB) system, consisting of cannabinoid receptors and accompanying ligands, has been implicated in these disorders. In

  17. Effects of activation of endocannabinoid system on myocardial metabolism

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    Agnieszka Polak

    2016-05-01

    Full Text Available Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases - hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.

  18. Endocannabinoid involvement in reward and impulsivity in addiction

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    van Hell, H.H.

    2011-01-01

    Addiction is one of the most disabling diseases in the world. An important neurotransmitter system that has recently been implicated in addiction is the endocannabinoid system. The endocannabinoid system consists of cannabinoid receptors and endocannabinoid ligands that work on these receptors.

  19. The endocannabinoid system and its relevance for nutrition

    DEFF Research Database (Denmark)

    Maccarrone, Mauro; Gasperi, Valeria; Catani, Maria Valeria

    2010-01-01

    Endocannabinoids bind to cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. The biological actions of these polyunsaturated lipids are controlled by key agents responsible for their synthesis, transport and degradation, which together form an endocannabinoid system (ECS......). In the past few years, evidence has been accumulated for a role of the ECS in regulating food intake and energy balance, both centrally and peripherally. In addition, up-regulation of the ECS in the gastrointestinal tract has a potential impact on inflammatory bowel diseases. In this review, the main features...... of the ECS are summarized in order to put in better focus our current knowledge of the nutritional relevance of endocannabinoid signaling and of its role in obesity, cardiovascular pathologies, and gastrointestinal diseases. The central and peripheral pathways that underlie these effects are discussed...

  20. The endocannabinoid system and appetite: relevance for food reward

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    Jager, G.; Witkamp, R.F.

    2014-01-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the

  1. Regulation of brain reward by the endocannabinoid system: a critical review of behavioral studies in animals.

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    Vlachou, S; Panagis, G

    2014-01-01

    The endocannabinoid system has been implicated in the regulation of a variety of physiological processes, including a crucial involvement in brain reward systems and the regulation of motivational processes. Behavioral studies have shown that cannabinoid reward may involve the same brain circuits and similar brain mechanisms with other drugs of abuse, such as nicotine, cocaine, alcohol and heroin, as well as natural rewards, such as food, water and sucrose, although the conditions under which cannabinoids exert their rewarding effects may be more limited. The purpose of the present review is to briefly describe and evaluate the behavioral and pharmacological research concerning the major components of the endocannabinoid system and reward processes. Special emphasis is placed on data received from four procedures used to test the effects of the endocannabinoid system on brain reward in animals; namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure and the drug-discrimination procedure. The effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonists, antagonists and endocannabinoid modulators in these procedures are examined. Further, the involvement of CB1 and CB2 receptors, as well the fatty acid amid hydrolase (FAAH) enzyme in reward processes is investigated through presentation of respective genetic ablation studies in mice. We suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. Further research will provide us with a better understanding of these processes and, thus, could lead to the development of potential therapeutic compounds for the treatment of reward-related disorders.

  2. Peripheral Endocannabinoid System Activity in Patients Treated With Sibutramine

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    Engeli, Stefan; Heusser, Karsten; Janke, Jürgen; Gorzelniak, Kerstin; Bátkai, Sándor; Pacher, Pál; Harvey-White, Judith; Luft, Friedrich C.; Jordan, Jens

    2008-01-01

    Objective The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS. Methods and Procedures Twenty obese otherwise healthy patients received randomized, double-blind, crossover treatment with placebo and 15 mg/day sibutramine for 5 days each, followed by 12 weeks open-label sibutramine treatment. We determined circulating anandamide and 2-arachidonoylglycerol and expression levels of endocannabinoid genes in subcutaneous abdominal adipose tissue biopsies. Results Body weight was stable during the acute treatment period and decreased by 6.0 ± 0.8 kg in those patients completing 3 months of sibutramine treatment (P sibutramine treatment. Discussion The ECS is activated in obesity. We did not find any influence of 5% body weight loss induced by sibutramine on circulating levels of endocannabinoids and adipose-tissue expression of endocannabinoid genes in obese subjects. These data confirm our previous findings on dietary weight loss and suggest that the dysregulation of the ECS may be a cause rather than a consequence of obesity. PMID:18356837

  3. Endocannabinoid system: Role in depression, reward and pain control (Review).

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    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-10-01

    Depression and pain co-exist in almost 80% of patients and are associated with impaired health-related quality of life, often contributing to high mortality. However, the majority of patients who suffer from the comorbid depression and pain are not responsive to pharmacological treatments that address either pain or depression, making this comorbidity disorder a heavy burden on patients and society. In ancient times, this depression-pain comorbidity was treated using extracts of the Cannabis sativa plant, known now as marijuana and the mode of action of Δ9‑tetrahydrocannabinol, the active cannabinoid ingredient of marijuana, has only recently become known, with the identification of cannabinoid receptor type 1 (CB1) and CB2. Subsequent investigations led to the identification of endocannabinoids, anandamide and 2-arachidonoylglycerol, which exert cannabinomimetic effects through the CB1 and CB2 receptors, which are located on presynaptic membranes in the central nervous system and in peripheral tissues, respectively. These endocannabinoids are produced from membrane lipids and are lipohilic molecules that are synthesized on demand and are eliminated rapidly after their usage by hydrolyzing enzymes. Clinical studies revealed altered endocannabinoid signaling in patients with chronic pain. Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. However, the precise mode of action of endocannabinoids on different targets in the body and whether their effects on pain and depression follow the same or different pathways, remains to be determined.

  4. Endocannabinoid System: A Multi-Facet Therapeutic Target.

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    Kaur, Rimplejeet; Ambwani, Sneha R; Singh, Surjit

    2016-01-01

    Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve "protective role" in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson's disease, Huntington's disease, Alzheimer's disease and Tourette's syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish

  5. Updates in Reproduction Coming from the Endocannabinoid System

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    Bradshaw, Heather B.

    2014-01-01

    The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility. PMID:24550985

  6. Updates in Reproduction Coming from the Endocannabinoid System

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    Rosaria Meccariello

    2014-01-01

    Full Text Available The endocannabinoid system (ECS is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators—deeply modulated by the activity of biosynthetic and hydrolyzing machineries—regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility.

  7. The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction

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    Francisco-Javier Bermúdez-Silva

    2011-08-01

    Full Text Available The endocannabinoid system (ECS has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses. We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the Gi/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN and bulimia nervosa (BN are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug

  8. The endocannabinoid system and associative learning and memory in zebrafish.

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    Ruhl, Tim; Moesbauer, Kirstin; Oellers, Nadine; von der Emde, Gerhard

    2015-09-01

    In zebrafish the medial pallium of the dorsal telencephalon represents an amygdala homolog structure, which is crucially involved in emotional associative learning and memory. Similar to the mammalian amygdala, the medial pallium contains a high density of endocannabinoid receptor CB1. To elucidate the role of the zebrafish endocannabinoid system in associative learning, we tested the influence of acute and chronic administration of receptor agonists (THC, WIN55,212-2) and antagonists (Rimonabant, AM-281) on two different learning paradigms. In an appetitively motivated two-alternative choice paradigm, animals learned to associate a certain color with a food reward. In a second set-up, a fish shuttle-box, animals associated the onset of a light stimulus with the occurrence of a subsequent electric shock (avoidance conditioning). Once fish successfully had learned to solve these behavioral tasks, acute receptor activation or inactivation had no effect on memory retrieval, suggesting that established associative memories were stable and not alterable by the endocannabinoid system. In both learning tasks, chronic treatment with receptor antagonists improved acquisition learning, and additionally facilitated reversal learning during color discrimination. In contrast, chronic CB1 activation prevented aversively motivated acquisition learning, while different effects were found on appetitively motivated acquisition learning. While THC significantly improved behavioral performance, WIN55,212-2 significantly impaired color association. Our findings suggest that the zebrafish endocannabinoid system can modulate associative learning and memory. Stimulation of the CB1 receptor might play a more specific role in acquisition and storage of aversive learning and memory, while CB1 blocking induces general enhancement of cognitive functions. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Biomarkers of endocannabinoid system activation in severe obesity.

    Directory of Open Access Journals (Sweden)

    Jack C Sipe

    2010-01-01

    Full Text Available Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs, combined with genotyping for mutations in fatty acid amide hydrolase (FAAH would identify circulating biomarkers of ECS activation in severe obesity.Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI of > or = 40 kg/m(2, and 48 normal weight subjects with BMI of A (P129T mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1+/-1.4 pmol/ml and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml with wild-type FAAH genotype (p = 0.04, and significance was maintained after controlling for BMI.Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

  10. Involvement of the endocannabinoid system in periodontal healing

    International Nuclear Information System (INIS)

    Kozono, Sayaka; Matsuyama, Takashi; Biwasa, Kamal Krishna; Kawahara, Ko-ichi; Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi; Tancharoen, Salunya; Hashiguchi, Teruto; Noguchi, Kazuyuki; Maruyama, Ikuro

    2010-01-01

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  11. Involvement of the endocannabinoid system in periodontal healing

    Energy Technology Data Exchange (ETDEWEB)

    Kozono, Sayaka [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Matsuyama, Takashi, E-mail: takashi@dent.kagoshima-u.ac.jp [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Biwasa, Kamal Krishna [Department of Biochemistry and Molecular Biology, Rajshahi University, Rajshahi 6205 (Bangladesh); Kawahara, Ko-ichi [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Nakajima, Yumiko; Yoshimoto, Takehiko; Yonamine, Yutaka; Kadomatsu, Hideshi [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Tancharoen, Salunya [Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok 10400 (Thailand); Hashiguchi, Teruto [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Noguchi, Kazuyuki [Department of Periodontology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Maruyama, Ikuro [Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2010-04-16

    Endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are important lipid mediators for immunosuppressive effects and for appropriate homeostasis via their G-protein-coupled cannabinoid (CB) receptors in mammalian organs and tissues, and may be involved in wound healing in some organs. The physiological roles of endocannabinoids in periodontal healing remain unknown. We observed upregulation of the expression of CB1/CB2 receptors localized on fibroblasts and macrophage-like cells in granulation tissue during wound healing in a wound-healing model in rats, as well as an increase in AEA levels in gingival crevicular fluid after periodontal surgery in human patients with periodontitis. In-vitro, the proliferation of human gingival fibroblasts (HGFs) by AEA was significantly attenuated by AM251 and AM630, which are selective antagonists of CB1 and CB2, respectively. CP55940 (CB1/CB2 agonist) induced phosphorylation of the extracellular-regulated kinases (ERK) 1/2, p38 mitogen-activated protein kinase (p38MAPK), and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MAP kinase kinase (MEK), p38MAPK, and phosphoinositol 3-kinase (PI3-K). These findings suggest that endocannabinoid system may have an important role in periodontal healing.

  12. Marijuana, the Endocannabinoid System and the Female Reproductive System.

    Science.gov (United States)

    Brents, Lisa K

    2016-06-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles. Tolerance to these effects has been shown in rhesus monkeys, but the effects of chronic marijuana use on human female reproduction are largely unknown. Marijuana-induced analgesia, drug reinforcement properties, tolerance, and dependence are influenced by ovarian hormones, with estrogen generally increasing and progesterone decreasing sensitivity to marijuana. Carefully controlled regulation of the Endocannabinoid System (ECS) is required for successful reproduction, and the exogenous cannabinoids in marijuana may disrupt the delicate balance of the ECS in the female reproductive system.

  13. Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility.

    Science.gov (United States)

    du Plessis, Stefan S; Agarwal, Ashok; Syriac, Arun

    2015-11-01

    Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Male factor infertility is on the increase, and the exposure to the cannabinoid compounds released by marijuana could be a contributing cause. The endocannabinoid system (ECS) is deeply involved in the complex regulation of male reproduction through the endogenous release of endocannabinoids and binding to cannabinoid receptors. Disturbing the delicate balance of the ECS due to marijuana use can negatively impact reproductive potential. Various in vivo and in vitro studies have reported on the empirical role that marijuana plays in disrupting the hypothalamus-pituitary-gonadal axis, spermatogenesis, and sperm function such as motility, capacitation, and the acrosome reaction. In this review, we highlight the latest evidence regarding the effect of marijuana use on male fertility and also provide a detailed insight into the ECS and its significance in the male reproductive system.

  14. The endocannabinoid system and appetite: relevance for food reward.

    Science.gov (United States)

    Jager, Gerry; Witkamp, Renger F

    2014-06-01

    Mounting evidence substantiates the central role of the endocannabinoid system (ECS) in the modulation of both homeostatic and hedonic elements of appetite and food intake. Conversely, feeding status and dietary patterns directly influence activity of the ECS. Following a general introduction on the functioning of the ECS, the present review specifically addresses its role in the modulation of hedonic eating. Humans possess strong motivational systems triggered by rewarding aspects of food. Food reward is comprised of two components: one appetitive (orienting towards food); the other consummatory (hedonic evaluation), also referred to as 'wanting' and 'liking', respectively. Endocannabinoid tone seems to influence both the motivation to feed and the hedonic value of foods, probably by modifying palatability. Human physiology underlying hedonic eating is still not fully understood. A better understanding of the role of the ECS in the rewarding value of specific foods or diets could offer new possibilities to optimise the balance between energy and nutrient intake for different target groups. These groups include the obese and overweight, and potentially individuals suffering from malnutrition. Examples for the latter group are patients with disease-related anorexia, as well as the growing population of frail elderly suffering from persistent loss of food enjoyment and appetite resulting in malnutrition and involuntary weight loss. It has become clear that the psychobiology of food hedonics is extremely complex and the clinical failure of CB1 inverse agonists including rimonabant (Accomplia®) has shown that 'quick wins' in this field are unlikely.

  15. The endocannabinoid system: a new pharmacological target for obesity treatment?

    Science.gov (United States)

    Hu, Jia; Zhu, Chao; Huang, Mao

    2009-06-01

    Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.

  16. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Science.gov (United States)

    McPartland, John M

    2009-01-01

    Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor. A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME); analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors. The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  17. Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Daniel J. Liput

    2017-11-01

    Full Text Available Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs. The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs, and then evaluated the efficacy of fatty acid amide hydrolase (FAAH inhibition on attenuating alcohol-induced neurodegeneration. Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in [3H]-CP-55,940 binding in the entorhinal cortex and hippocampus following two days, but not four days, of treatment. Furthermore, binge alcohol treatment did not change the tissue content of the three NAEs quantified, including the endocannabinoid and anandamide. In a separate study, the FAAH inhibitor, URB597 was administered to rats during alcohol treatment and neuroprotection was assessed by FluoroJade B (FJB staining. The administration of URB597 during binge treatment did not significantly reduce FJB+ cells in the entorhinal cortex or hippocampus, however, a follow up “target engagement” study found that NAE augmentation by URB597 was impaired in alcohol intoxicated rats. Thus, potential alcohol induced alterations in URB597 pharmacodynamics may have contributed to the lack of neuroprotection by FAAH inhibition.

  18. Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex.

    Directory of Open Access Journals (Sweden)

    Mathieu Lafourcade

    2007-08-01

    Full Text Available Cannabinoids have deleterious effects on prefrontal cortex (PFC-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown.Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers v/vi of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha, the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca(2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602 but not of anandamide (with URB 597 converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses.Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies.

  19. Endocannabinoid system in cardiovascular disorders - new pharmacotherapeutic opportunities

    Directory of Open Access Journals (Sweden)

    Pedro Cunha

    2011-01-01

    Full Text Available The long history of Cannabis sativa had its development stimulated and oriented for medicine after the discovery and chemical characterization of its main active ingredient, the 9-tetrahydrocannabinol (9-THC. Consequently, a binding site for 9-THC was identified in rat brains and the first cannabinoid receptor (CB1 was cloned, followed by the CB2 and by the discover of two endogenous agonists: anandamide and 2-arachidonoyl glycerol. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze its synthesis and degradation constitute the endocannabinoid system (ECS, which plays an important role in the cardiovascular system. In vivo experiments with rats have demonstrated the action of anandamide and 2-AG on the development of atherosclerotic plaque, as well as an effect on heart rate, blood pressure, vasoactivity and energy metabolism (action in dyslipidemia and obesity. Recent studies with an antagonist of CB1 receptors showed that the modulation of ECS can play an important role in reducing cardiovascular risk in obese and dyslipidemic patients. Similarly, studies in rats have demonstrated the action of CB2 receptors in adhesion, migration, proliferation and function of immune cells involved in the atherosclerotic plaque formation process. The evidence so far gathered shows that the modulation of ECS (as agonism or antagonism of its receptors is an enormous potential field for research and intervention in multiple areas of human pathophysiology. The development of selective drugs for the CB1 and CB2 receptors may open a door to new therapeutic regimens.This review article aims to address the key findings and evidences on the modulation of ECS, in order to prospect future forms of therapeutic intervention at the cardiovascular level. A recent, emerging, controversial and of undoubted scientific interest subject, which states as a potential therapeutic target to reach in the 21 st century.

  20. Obesity, the endocannabinoid system, and bias arising from pharmaceutical sponsorship.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available Previous research has shown that academic physicians conflicted by funding from the pharmaceutical industry have corrupted evidence based medicine and helped enlarge the market for drugs. Physicians made pharmaceutical-friendly statements, engaged in disease mongering, and signed biased review articles ghost-authored by corporate employees. This paper tested the hypothesis that bias affects review articles regarding rimonabant, an anti-obesity drug that blocks the central cannabinoid receptor.A MEDLINE search was performed for rimonabant review articles, limited to articles authored by USA physicians who served as consultants for the company that manufactures rimonabant. Extracted articles were examined for industry-friendly bias, identified by three methods: analysis with a validated instrument for monitoring bias in continuing medical education (CME; analysis for bias defined as statements that ran contrary to external evidence; and a tally of misrepresentations about the endocannabinoid system. Eight review articles were identified, but only three disclosed authors' financial conflicts of interest, despite easily accessible information to the contrary. The Takhar CME bias instrument demonstrated statistically significant bias in all the review articles. Biased statements that were nearly identical reappeared in the articles, including disease mongering, exaggerating rimonabant's efficacy and safety, lack of criticisms regarding rimonabant clinical trials, and speculations about surrogate markers stated as facts. Distinctive and identical misrepresentations regarding the endocannabinoid system also reappeared in articles by different authors.The findings are characteristic of bias that arises from financial conflicts of interest, and suggestive of ghostwriting by a common author. Resolutions for this scenario are proposed.

  1. The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

    Science.gov (United States)

    Corcoran, Louise; Roche, Michelle; Finn, David P

    2015-01-01

    Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.

  2. The endocannabinoid system within the dorsal lateral geniculate nucleus of the vervet monkey

    DEFF Research Database (Denmark)

    Javadi, P.; Bouskila, J.; Bouchard, J. -F.

    2015-01-01

    The endocannabinoid system mainly consists of cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), their endogenous ligands termed endocannabinoids (eCBs), and the enzymes responsible for the synthesis and degradation of eCBs. These cannabinoid receptors have been well characterized in rodent a...... layers may explain some of the behavioral effects of cannabinoids associated with the integrity of the dorsal visual pathway that plays a role in visual-spatial localization and motion perception....

  3. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Science.gov (United States)

    McPartland, John M; Guy, Geoffrey W; Di Marzo, Vincenzo

    2014-01-01

    The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  4. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system.

    Directory of Open Access Journals (Sweden)

    John M McPartland

    Full Text Available The "classic" endocannabinoid (eCB system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA and 2-arachidonoylglycerol (2-AG, and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system--ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances--alcohol, tobacco, coffee, cannabis also modulate the eCB system.Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

  5. The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

    NARCIS (Netherlands)

    Witkamp, R.F.

    2014-01-01

    The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management

  6. Neurobiological Interactions Between Stress and the Endocannabinoid System.

    Science.gov (United States)

    Morena, Maria; Patel, Sachin; Bains, Jaideep S; Hill, Matthew N

    2016-01-01

    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.

  7. Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain

    Directory of Open Access Journals (Sweden)

    Jean-François Bouchard

    2016-01-01

    Full Text Available Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system. Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function. In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing. The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far. It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells. The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.

  8. Rare genetic variants in the endocannabinoid system genes CNR1 and DAGLA are associated with neurological phenotypes in humans.

    Directory of Open Access Journals (Sweden)

    Douglas R Smith

    Full Text Available Rare genetic variants in the core endocannabinoid system genes CNR1, CNR2, DAGLA, MGLL and FAAH were identified in molecular testing data from 6,032 patients with a broad spectrum of neurological disorders. The variants were evaluated for association with phenotypes similar to those observed in the orthologous gene knockouts in mice. Heterozygous rare coding variants in CNR1, which encodes the type 1 cannabinoid receptor (CB1, were found to be significantly associated with pain sensitivity (especially migraine, sleep and memory disorders-alone or in combination with anxiety-compared to a set of controls without such CNR1 variants. Similarly, heterozygous rare variants in DAGLA, which encodes diacylglycerol lipase alpha, were found to be significantly associated with seizures and neurodevelopmental disorders, including autism and abnormalities of brain morphology, compared to controls. Rare variants in MGLL, FAAH and CNR2 were not associated with any neurological phenotypes in the patients tested. Diacylglycerol lipase alpha synthesizes the endocannabinoid 2-AG in the brain, which interacts with CB1 receptors. The phenotypes associated with rare CNR1 variants are reminiscent of those implicated in the theory of clinical endocannabinoid deficiency syndrome. The severe phenotypes associated with rare DAGLA variants underscore the critical role of rapid 2-AG synthesis and the endocannabinoid system in regulating neurological function and development. Mapping of the variants to the 3D structure of the type 1 cannabinoid receptor, or primary structure of diacylglycerol lipase alpha, reveals clustering of variants in certain structural regions and is consistent with impacts to function.

  9. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    International Nuclear Information System (INIS)

    Wohlman, Irene M.; Composto, Gabriella M.; Heck, Diane E.; Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D.; Casillas, Robert P.; Croutch, Claire R.; Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B.; Laskin, Jeffrey D.

    2016-01-01

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  10. Mustard vesicants alter expression of the endocannabinoid system in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Wohlman, Irene M.; Composto, Gabriella M. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D. [Department of Chemistry, Lehigh University, Bethlehem, PA (United States); Casillas, Robert P.; Croutch, Claire R. [MRIGlobal, Kansas City, MO (United States); Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ (United States)

    2016-07-15

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

  11. The Endocannabinoid System in the Postimplantation Period: A Role during Decidualization and Placentation

    Directory of Open Access Journals (Sweden)

    B. M. Fonseca

    2013-01-01

    Full Text Available Although the detrimental effects of cannabis consumption during gestation are known for years, the vast majority of studies established a link between cannabis consumption and foetal development. The complex maternal-foetal interrelationships within the placental bed are essential for normal pregnancy, and decidua definitively contributes to the success of this process. Nevertheless, the molecular signalling network that coordinates strategies for successful decidualization and placentation are not well understood. The discovery of the endocannabinoid system highlighted new signalling mediators in various physiological processes, including reproduction. It is known that endocannabinoids present regulatory functions during blastocyst development, oviductal transport, and implantation. In addition, all the endocannabinoid machinery was found to be expressed in decidual and placental tissues. Additionally, endocannabinoid’s plasmatic levels were found to fluctuate during normal gestation and to induce decidual cell death and disturb normal placental development. Moreover, aberrant endocannabinoid signalling during the period of placental development has been associated with pregnancy disorders. It indicates the existence of a possible regulatory role for these molecules during decidualization and placentation processes, which are known to be particularly vulnerable. In this review, the influence of the endocannabinoid system in these critical processes is explored and discussed.

  12. Fatty Acid Modulation of the Endocannabinoid System and the Effect on Food Intake and Metabolism

    Directory of Open Access Journals (Sweden)

    Shaan S. Naughton

    2013-01-01

    Full Text Available Endocannabinoids and their G-protein coupled receptors (GPCR are a current research focus in the area of obesity due to the system’s role in food intake and glucose and lipid metabolism. Importantly, overweight and obese individuals often have higher circulating levels of the arachidonic acid-derived endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG and an altered pattern of receptor expression. Consequently, this leads to an increase in orexigenic stimuli, changes in fatty acid synthesis, insulin sensitivity, and glucose utilisation, with preferential energy storage in adipose tissue. As endocannabinoids are products of dietary fats, modification of dietary intake may modulate their levels, with eicosapentaenoic and docosahexaenoic acid based endocannabinoids being able to displace arachidonic acid from cell membranes, reducing AEA and 2-AG production. Similarly, oleoyl ethanolamide, a product of oleic acid, induces satiety, decreases circulating fatty acid concentrations, increases the capacity for β-oxidation, and is capable of inhibiting the action of AEA and 2-AG in adipose tissue. Thus, understanding how dietary fats alter endocannabinoid system activity is a pertinent area of research due to public health messages promoting a shift towards plant-derived fats, which are rich sources of AEA and 2-AG precursor fatty acids, possibly encouraging excessive energy intake and weight gain.

  13. Endocannabinoid system and drug addiction: new insights from mutant mice approaches.

    Science.gov (United States)

    Maldonado, Rafael; Robledo, Patricia; Berrendero, Fernando

    2013-08-01

    The involvement of the endocannabinoid system in drug addiction was initially studied by the use of compounds with different affinities for each cannabinoid receptor or for the proteins involved in endocannabinoids inactivation. The generation of genetically modified mice with selective mutations in these endocannabinoid system components has now provided important advances in establishing their specific contribution to drug addiction. These genetic tools have identified the particular interest of CB1 cannabinoid receptor and endogenous anandamide as potential targets for drug addiction treatment. Novel genetic tools will allow determining if the modulation of CB2 cannabinoid receptor activity and 2-arachidonoylglycerol tone can also have an important therapeutic relevance for drug addiction. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Prenatal cannabis exposure - The "first hit" to the endocannabinoid system.

    Science.gov (United States)

    Richardson, Kimberlei A; Hester, Allison K; McLemore, Gabrielle L

    As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the

  15. The Endocannabinoid System across Postnatal Development in Transmembrane Domain Neuregulin 1 Mutant Mice

    Directory of Open Access Journals (Sweden)

    Rose Chesworth

    2018-02-01

    Full Text Available The use of cannabis is a well-established component risk factor for schizophrenia, particularly in adolescent individuals with genetic predisposition for the disorder. Alterations to the endocannabinoid system have been found in the prefrontal cortex of patients with schizophrenia. Thus, we assessed whether molecular alterations exist in the endocannabinoid signalling pathway during brain development in a mouse model for the schizophrenia risk gene neuregulin 1 (Nrg1. We analysed transcripts encoding key molecules of the endocannabinoid system in heterozygous transmembrane domain Nrg1 mutant mice (Nrg1 TM HET, which is known to have increased sensitivity to cannabis exposure. Tissue from the prelimbic cortex and hippocampus of male and female Nrg1 TM HET mice and wild type-like littermates was collected at postnatal days (PNDs 7, 10, 14, 21, 28, 35, 49, and 161. Quantitative polymerase chain reaction was conducted to assess mRNA levels of cannabinoid receptor 1 (CB1R and enzymes for the synthesis and breakdown of the endocannabinoid 2-arachidonoylglycerol [i.e., diacylglycerol lipase alpha (DAGLα, monoglyceride lipase (MGLL, and α/β-hydrolase domain-containing 6 (ABHD6]. No sex differences were found for any transcripts in either brain region; thus, male and female data were pooled. Hippocampal and cortical mRNA expression of DAGLα, MGLL, and ABHD6 increased until PND 21–35 and then decreased and stabilised for the rest of postnatal development. Hippocampal CB1R mRNA expression increased until PND 21 and decreased after this age. Expression levels of these endocannabinoid markers did not differ in Nrg1 TM HET compared to control mice at any time point. Here, we demonstrate dynamic changes in the developmental trajectory of several key endocannabinoid system transcripts in the mouse brain, which may correspond with periods of endocannabinoid system maturation. Nrg1 TM HET mutation did not alter the developmental trajectory of the

  16. Stress Response Recruits the Hippocampal Endocannabinoid System for the Modulation of Fear Memory

    Science.gov (United States)

    Alvares, Lucas de Oliveira; Engelke, Douglas Senna; Diehl, Felipe; Scheffer-Teixeira, Robson; Haubrich, Josue; Cassini, Lindsey de Freitas; Molina, Victor Alejandro; Quillfeldt, Jorge Alberto

    2010-01-01

    The modulation of memory processes is one of the several functions of the endocannabinoid system (ECS) in the brain, with CB1 receptors highly expressed in areas such as the dorsal hippocampus. Experimental evidence suggested an important role of the ECS in aversively motivated memories. Similarly, glucocorticoids released in response to stress…

  17. Behavioral and electrophysiological effects of endocannabinoid and dopaminergic systems on salient stimuli

    Directory of Open Access Journals (Sweden)

    Daniela eLaricchiuta

    2014-05-01

    Full Text Available Rewarding effects have been related to enhanced dopamine (DA release in corticolimbic and basal ganglia structures. The DAergic and endocannabinoid interaction in the responses to reward is described. This study investigated the link between endocannabinoid and DAergic transmission in the processes that are related to response to two types of reward, palatable food and novelty. Mice treated with drugs acting on endocannabinoid system (ECS (URB597, AM251 or DAergic system (haloperidol were submitted to approach-avoidance conflict tasks with palatable food or novelty. In the same mice, the cannabinoid type-1 (CB1-mediated GABAergic transmission in medium spiny neurons of the dorsomedial striatum was analyzed. The endocannabinoid potentiation by URB597 magnified approach behavior for reward (food and novelty and in parallel inhibited dorsostriatal GABAergic neurotransmission. The decreased activity of CB1 receptor by AM251 (alone or with URB597 or of DAergic D2 receptor by haloperidol had inhibitory effects toward the reward and did not permit the inhibition of dorsostriatal GABAergic transmission. When haloperidol was coadministered with URB597, a restoration effect on reward and reward-dependent motor activity was observed, only if the reward was the palatable food. In parallel, the coadministration led to restoring inhibition of CB1-mediated GABAergic transmission. Thus, in the presence of simultaneous ECS activation and inhibition of DAergic system the response to reward appears to be a stimulus-dependent manner.

  18. The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

    Science.gov (United States)

    Murillo-Rodriguez, Eric; Pastrana-Trejo, Jose Carlos; Salas-Crisóstomo, Mireille; de-la-Cruz, Miriel

    2017-01-01

    Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data

  19. Immune system modulation in the central nervous system: A possible role for endocannabinoids

    International Nuclear Information System (INIS)

    Abd-Allah, Adel R.A.

    2007-01-01

    The immune system is designed to protect the body from infection and tumor formation. To perform this function, cells of the immune system can be dangerous for the survival and function of the neuronal network in the brain under the influence of infection or immune imbalance. An attack of immune cells inside the brain includes the potential for severe neuronal damage or cell death and therefore impairment of the CNS function. To avoid such undesirable action of the immune system, the CNS performs a cascade of cellular and molecular mechanisms enabling strict control of immune reactions i mmune privilege . Under inflammatory and patholological conditions, uncontrolled immune system results in the activation of neuronal damage that is frequently associated with neurological diseases. On the other hand, processes of neuroprotection and neurorepair after neuronal damage depend on a steady and tightly controlled immunesurvelliance. Many immunoprotectants play a role to imbalance the immune reactions in the CNS and other organs which presents an important therapeutic target. It has been reported recently that endocannabinoids are secreted in abundance in the CNS following neuronal insult, probably for its protection. There are at least two types of cannabinoid receptors, CB1 and CB2. Both are coupled to G proteins. CB1 receptors exist primarily on central and peripheral neurons. CB2 receptors are present mainly on immune cells. Endogenous agonists for cannabinoid receptors (endocannabinoids), have been discovered, the most important being arachidonoyl ethanolamide (anandamide), 2-arachidonoyl glycerol (2AG), and 2-archidonyl glyceryl ether. Following their release, endocannabinoids are removed from the extracellular space and then degraded by intracellular enzymic hydrolysis. Therapeutic uses of cannabinoid receptor agonists/antagonists include the management of many disease conditions. They are also involved in immune system suppression and in cell to cell communication

  20. Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

    Science.gov (United States)

    Scheggia, D; Zamberletti, E; Realini, N; Mereu, M; Contarini, G; Ferretti, V; Managò, F; Margiani, G; Brunoro, R; Rubino, T; De Luca, M A; Piomelli, D; Parolaro, D; Papaleo, F

    2018-04-01

    The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

  1. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Science.gov (United States)

    Freundt-Revilla, Jessica; Heinrich, Franciska; Zoerner, Alexander; Gesell, Felix; Beyerbach, Martin; Shamir, Merav; Oevermann, Anna; Baumgärtner, Wolfgang; Tipold, Andrea

    2018-01-01

    Endocannabinoids (ECs) are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS). Activation of cannabinoid type 2 receptors (CB2) is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG) has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA) and Intraspinal Spirocercosis (IS). The two main endocannabinoids, anandamide (AEA) and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A), SRMA under treatment with prednisolone (SRMA Tr), intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC). Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05). Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05). CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular surface of

  2. The endocannabinoid system in canine Steroid-Responsive Meningitis-Arteritis and Intraspinal Spirocercosis.

    Directory of Open Access Journals (Sweden)

    Jessica Freundt-Revilla

    Full Text Available Endocannabinoids (ECs are involved in immunomodulation, neuroprotection and control of inflammation in the central nervous system (CNS. Activation of cannabinoid type 2 receptors (CB2 is known to diminish the release of pro-inflammatory factors and enhance the secretion of anti-inflammatory cytokines. Furthermore, the endocannabinoid 2-arachidonoyl glycerol (2-AG has been proved to induce the migration of eosinophils in a CB2 receptor-dependent manner in peripheral blood and activate neutrophils independent of CB activation in humans. The aim of the current study was to investigate the influence of the endocannabinoid system in two different CNS inflammatory diseases of the dog, i.e. Steroid-Responsive Meningitis-Arteritis (SRMA and Intraspinal Spirocercosis (IS. The two main endocannabinoids, anandamide (AEA and 2-AG, were quantified by mass spectrometry in CSF and serum samples of dogs affected with Steroid- Responsive Meningitis-Arteritis in the acute phase (SRMA A, SRMA under treatment with prednisolone (SRMA Tr, intraspinal Spirocercosis and healthy dogs. Moreover, expression of the CB2 receptor was evaluated in inflammatory lesions of SRMA and IS and compared to healthy controls using immunohistochemistry (IHC. Dogs with SRMA A showed significantly higher concentrations of total AG and AEA in serum in comparison to healthy controls and in CSF compared to SRMA Tr (p<0.05. Furthermore, dogs with IS displayed the highest ECs concentrations in CSF, being significantly higher than in CSF samples of dogs with SRMA A (p<0.05. CSF samples that demonstrated an eosinophilic pleocytosis had the highest levels of ECs, exceeding those with neutrophilic pleocytosis, suggesting that ECs have a major effect on migration of eosinophils in the CSF. Furthermore, CB2 receptor expression was found in glial cells in the spinal cord of healthy dogs, whereas in dogs with SRMA and IS, CB2 was strongly expressed not only in glial cells but also on the cellular

  3. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications

    Directory of Open Access Journals (Sweden)

    Thomas Schwitzer

    2016-01-01

    Full Text Available Cannabis is one of the most prevalent drugs used in industrialized countries. The main effects of Cannabis are mediated by two major exogenous cannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2. Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes. This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system. As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology. This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection. Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases. Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.

  4. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems.

    Science.gov (United States)

    Edwards, Alexander; Abizaid, Alfonso

    2016-07-01

    Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; McGaugh, James L.; Roozendaal, Benno

    2012-01-01

    There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3–3 mg/kg) to male Sprague–Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal β-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212–2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences. PMID:22331883

  6. Effect of blockage of the endocannabinoid system by CB(1) antagonism on cardiovascular risk.

    Science.gov (United States)

    Mach, François; Montecucco, Fabrizio; Steffens, Sabine

    2009-01-01

    The endocannabinoid system is a crucial player in the inflammatory processes underlying atherosclerosis. Recently, basic research studies and animal models have strongly supported the role of the endocannabinoid system not only in the regulation of classical cardiovascular risk factors (including lipid profile and glucose homeostasis), but also in the activation of immune cells and inflammatory mediators. Clinical trials investigating treatment with rimonabant (a selective antagonist of the cannabinoid type 1 receptor) have suggested a beneficial effect of this drug in the management of obesity. Further studies are needed to explore a possible use for rimonabant in treating type 2 diabetes and acute and chronic cardiovascular disease. Despite the slight increase in adverse events (mainly psychiatric), which has led to the recent withdrawal of rimonabant from the market, CB(1) receptor antagonism might represent a very promising therapeutic strategy to reduce the cardiovascular risk. In the present review, we focused on the most important experimental investigations into the role of the endocannabinoid system in atherosclerosis and cardiovascular risk.

  7. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Yuki, E-mail: yukey@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Tomizawa, Motohiro [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502 (Japan); Suzuki, Himiko [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Okamura, Ai [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ohtani, Katsumi [National Institute of Occupational Safety and Health, Kanagawa 214-8585 (Japan); Nunome, Mari; Noro, Yuki [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan); Wang, Dong; Nakajima, Tamie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Kamijima, Michihiro, E-mail: kamijima@med.nagoya-cu.ac.jp [Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601 (Japan)

    2014-09-15

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity.

  8. Fenitrothion action at the endocannabinoid system leading to spermatotoxicity in Wistar rats

    International Nuclear Information System (INIS)

    Ito, Yuki; Tomizawa, Motohiro; Suzuki, Himiko; Okamura, Ai; Ohtani, Katsumi; Nunome, Mari; Noro, Yuki; Wang, Dong; Nakajima, Tamie; Kamijima, Michihiro

    2014-01-01

    Organophosphate (OP) compounds as anticholinesterase agents may secondarily act on diverse serine hydrolase targets, revealing unfavorable physiological effects including male reproductive toxicity. The present investigation proposes that fenitrothion (FNT, a major OP compound) acts on the endocannabinoid signaling system in male reproductive organs, thereby leading to spermatotoxicity (sperm deformity, underdevelopment, and reduced motility) in rats. FNT oxon (bioactive metabolite of FNT) preferentially inhibited the fatty acid amide hydrolase (FAAH), an endocannabinoid anandamide (AEA) hydrolase, in the rat cellular membrane preparation from the testis in vitro. Subsequently, male Wistar rats were treated orally with 5 or 10 mg/kg FNT for 9 weeks and the subchronic exposure unambiguously deteriorated sperm motility and morphology. The activity-based protein profiling analysis with a phosphonofluoridate fluorescent probe revealed that FAAH was selectively inhibited among the FNT-treated cellular membrane proteome in testis. Intriguingly, testicular AEA (endogenous substrate of FAAH) levels were elevated along with the FAAH inhibition caused by the subchronic exposure. More importantly, linear regression analyses for the FNT-elicited spermatotoxicity reveal a good correlation between the testicular FAAH activity and morphological indices or sperm motility. Accordingly, the present study proposes that the FNT-elicited spermatotoxicity appears to be related to inhibition of FAAH leading to overstimulation of the endocannabinoid signaling system, which plays crucial roles in spermatogenesis and sperm motility acquirement. - Highlights: • Subchronic exposure to fenitrothion induces spermatotoxicity in rats. • The fatty acid amide hydrolase is a potential target for the spermatotoxicity. • Overstimulation of the endocannabinoid signal possibly leads to the spermatotoxicity

  9. Dynamic changes to the endocannabinoid system in models of chronic pain

    Science.gov (United States)

    Rani Sagar, Devi; Burston, James J.; Woodhams, Stephen G.; Chapman, Victoria

    2012-01-01

    The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling. PMID:23108548

  10. Endocannabinoid system acts as a regulator of immune homeostasis in the gut.

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    Acharya, Nandini; Penukonda, Sasi; Shcheglova, Tatiana; Hagymasi, Adam T; Basu, Sreyashi; Srivastava, Pramod K

    2017-05-09

    Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1 -/- or CB2 -/- mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

  11. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

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    Coleman, Jonathan R. I.; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L.; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M.; Schneider, Silvia; Silverman, Wendy K.; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H.; Eley, Thalia C.

    2016-01-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27346075

  12. Adipose tissue endocannabinoid system gene expression: depot differences and effects of diet and exercise

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    Yang Rongze

    2011-10-01

    Full Text Available Abstract Background Alterations of endocannabinoid system in adipose tissue play an important role in lipid regulation and metabolic dysfunction associated with obesity. The purpose of this study was to determine whether gene expression levels of cannabinoid type 1 receptor (CB1 and fatty acid amide hydrolase (FAAH are different in subcutaneous abdominal and gluteal adipose tissue, and whether hypocaloric diet and aerobic exercise influence subcutaneous adipose tissue CB1 and FAAH gene expression in obese women. Methods Thirty overweight or obese, middle-aged women (BMI = 34.3 ± 0.8 kg/m2, age = 59 ± 1 years underwent one of three 20-week weight loss interventions: caloric restriction only (CR, N = 9, caloric restriction plus moderate-intensity aerobic exercise (CRM, 45-50% HRR, N = 13, or caloric restriction plus vigorous-intensity aerobic exercise (CRV, 70-75% HRR, N = 8. Subcutaneous abdominal and gluteal adipose tissue samples were collected before and after the interventions to measure CB1 and FAAH gene expression. Results At baseline, FAAH gene expression was higher in abdominal, compared to gluteal adipose tissue (2.08 ± 0.11 vs. 1.78 ± 0.10, expressed as target gene/β-actin mRNA ratio × 10-3, P Conclusions There are depot differences in subcutaneous adipose tissue endocannabinoid system gene expression in obese individuals. Aerobic exercise training may preferentially modulate abdominal adipose tissue endocannabinoid-related gene expression during dietary weight loss. Trial Registration ClinicalTrials.gov: NCT00664729.

  13. Changes in the Peripheral Endocannabinoid System as a Risk Factor for the Development of Eating Disorders.

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    Capasso, Anna; Milano, Walter; Cauli, Omar

    2018-02-12

    Eating Disorder (ED) is characterized by persistently and severely disturbed eating behaviours. They arise from a combination of long-standing behavioural, emotional, psychological, interpersonal, and social factors and result in insufficient nutrient ingestion and/or adsorption. The three main EDs are: anorexia nervosa, bulimia nervosa, and binge eating disorder. We review the role of peripheral endocannabinoids in eating behaviour. The neuronal pathways involved in feeding behaviours are closely related to catecholaminergic, serotoninergic and peptidergic systems. Accordingly, feeding is promoted by serotonin, dopamine, and prostaglandin and inhibited by neuropeptide Y, norepinephrine, GABA, and opioid peptides. The endocannabinoid system plays a role in EDs, and multiple lines of evidence indicate that the cannabinoid signalling system is a key modulatory factor of the activity in the brain areas involved in EDs as well as in reward processes. Besides their central role in controlling food behaviours, peripheral cannabinoids are also involved in regulating adipose tissue and insulin signalling as well as cell metabolism in peripheral tissues such as liver, pancreas, fatty tissue, and skeletal muscle. Altogether, these data indicate that peripheral cannabinoids can provide new therapeutic targets not only for EDs but also for metabolic disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

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    Ahmet Ulugöl

    2014-06-01

    Full Text Available Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MAGL, the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.

  15. Endocannabinoids and the Endocrine System in Health and Disease.

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    Hillard, Cecilia J

    2015-01-01

    Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.

  16. From Fertilisation to Implantation in Mammalian Pregnancy—Modulation of Early Human Reproduction by the Endocannabinoid System

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    Justin C. Konje

    2010-09-01

    Full Text Available There is an increasing recognition that the endocannabinoid system is the crucial cytokine-hormone system regulating early human pregnancy. The synchronous development of the fertilized embryo and the endometrium to ensure timely implantation has been shown to be one of the pivotal steps to successful implantation. This development is thought to be regulated by a finely balanced relationship between various components of the endocannabinoid system in the endometrium, the embryo and the Fallopian tube. In addition, this system has also been shown to be involved in the regulation of the development and maturation of the gametes prior to fertilization. In this review, we will examine the evidence from animal and human studies to support the role of the endocannabinoid system in gametogenesis, fertilization, implantation, early pregnancy maintenance, and in immunomodulation of pregnancy. We will discuss the role of the cannabinoid receptors and the enzymes involved in the synthesis and degradation of the key endocannabinoid ligands (e.g., anandamide and 2-arachinoylglycerol in early reproduction.

  17. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

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    Shenglong Zou

    2018-03-01

    Full Text Available The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R and 2. The CB1R is the prominent subtype in the central nervous system (CNS and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

  18. Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system

    Science.gov (United States)

    Zamberletti, Erica; Piscitelli, Fabiana; De Castro, Valentina; Murru, Elisabetta; Gabaglio, Marina; Colucci, Paola; Fanali, Chiara; Prini, Pamela; Bisogno, Tiziana; Maccarrone, Mauro; Campolongo, Patrizia; Banni, Sebastiano; Rubino, Tiziana; Parolaro, Daniela

    2017-01-01

    Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition. PMID:27903595

  19. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

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    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Toczek, Marek [Department of Experimental Physiology and Pathophysiology Medical University of Bialystok, Mickiewicza 2A, 15-222 Bialystok (Poland); Bielawska, Katarzyna [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland); Skrzydlewska, Elżbieta, E-mail: elzbieta.skrzydlewska@umb.edu.pl [Department of Analytical Chemistry Medical University of Bialystok, Mickiewicza 2D, 15-222 Bialystok (Poland)

    2016-06-15

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB{sub 1} receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB{sub 1} receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the

  20. Crosstalk between liver antioxidant and the endocannabinoid systems after chronic administration of the FAAH inhibitor, URB597, to hypertensive rats

    International Nuclear Information System (INIS)

    Biernacki, Michał; Łuczaj, Wojciech; Gęgotek, Agnieszka; Toczek, Marek; Bielawska, Katarzyna; Skrzydlewska, Elżbieta

    2016-01-01

    Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB 1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB 1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis. - Highlights: • Chronic administration of URB597 to hypertensive rats reduces liver inflammation. • URB597 enhances the redox imbalance in the liver of

  1. The multiple functions of the endocannabinoid system: a focus on the regulation of food intake

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    Tibiriça Eduardo

    2010-01-01

    Full Text Available Abstract Background Cannabis sativa (also known as marijuana has been cultivated by man for more than 5,000 years. However, there was a rise in its use in the 20th century for recreational, religious or spiritual, and medicinal purposes. The main psychoactive constituent of cannabis, whose structure was identified in the 1960's, is Δ9-tetrahydrocannabinol. On the other hand, the discovery of cannabinoid receptors and their endogenous agonists took place only very recently. In fact, the first cannabinoid receptor (CB1 was cloned in 1990, followed 3 years later by the characterization of a second cannabinoid receptor (CB2. Since the 19th century, the use of cannabis has been reported to stimulate appetite and increase the consumption of sweet and tasty food, sometimes resulting in significant weight gain. The recent description of the endocannabinoid system, not only in the central nervous system but also in peripheral tissues, points to its involvement in the regulation of appetite, food intake and energy metabolism. Consequently, the pharmacological modulation of the over-activity of this system could be useful in the treatment of the metabolic syndrome. Conclusions The endocannabinoid system has important physiological functions not only in the central nervous system but also in peripheral tissues. The activation of central CB1 receptors, particularly in hypothalamic nuclei and in the limbic system, is involved in the regulation of feeding behavior, and especially in the control of the intake of palatable food. In the periphery, cannabinoid receptors are present in adipocytes, skeletal muscle, gastrointestinal tract and liver, modulating energy metabolism.

  2. Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

    Science.gov (United States)

    Dyall, Simon C

    2017-11-01

    The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids. The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids. Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.

  3. Neuromodulatory effects of the dorsal hippocampal endocannabinoid system in dextromethorphan/morphine-induced amnesia.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2017-01-05

    Dextromethorphan which is an active ingredient in many cough medicines has been previously shown to potentiate amnesic effect of morphine in rats. However, the effect of dextromethorphan, that is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, in combination with morphine on hippocampus-based long term memory has not been well characterized. The aim of the present study was to assess the possible role of endocannabinoid system of the dorsal hippocampus in dextromethorphan /morphine-induced amnesia. Our results showed that intraperitoneal (i.p.) injection of morphine (5mg/kg) or dextromethorphan (5-15mg/kg) before testing the passive avoidance learning induced amnesia. Combination of ineffective doses of dextromethorphan (7.5mg/kg, i.p.) and morphine (2mg/kg, i.p.) also produced amnesia, suggesting the enhancing effects of the drugs. To assess the effect of the activation or inhibition of the dorsal hippocampal cannabinoid CB 1 receptors on this amnesia, ACPA or AM251 as selective receptor agonists or antagonists were respectively injected into the CA1 regions before systemic injection of dextromethorphan and morphine. Interestingly, intra-CA1 microinjection of ACPA (0.5-1ng/rat) improved the amnesic effect of dextromethorphan /morphine combination. The microinjection of AM251 into the CA1 region enhanced the response of the combination of dextromethorphan /morphine in inducing amnesia. Moreover, Intra-CA1 microinjection of AM251 inhibited the improving effect of ACPA on dextromethorphan /morphine-induced amnesia. It is important to note that intra-CA1 microinjection of the same doses of the agonist or antagonist by itself had no effects on memory formation. Thus, it can be concluded that the dorsal hippocampal endocannabinoid system, via CB 1 receptor-dependent mechanism, may be involved in morphine/dextromethorphan -induced amnesia. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

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    Ibrahim Knani

    2016-12-01

    Full Text Available Objective: Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS. Among numerous metabolic regulators, the endocannabinoid (eCB system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods: We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS. Author Video: Author Video Watch what authors say about their articles Keywords: Endocannabinoids, PWS, Magel2, Peripheral CB1 blockade, Metabolic syndrome

  5. Role of the endocannabinoid system in food intake, energy homeostasis and regulation of the endocrine pancreas.

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    Li, Chen; Jones, Peter M; Persaud, Shanta J

    2011-03-01

    The endocannabinoid system (ECS) is a signalling cascade consisting of CB1 and CB2 receptors, and enzymes for the synthesis and degradation of endogenous ligands for these receptors. Central CB1 receptors have been most widely studied since they play key roles in energy homeostasis and rimonabant, a CB1 receptor antagonist, was used clinically to treat obesity. Less is known about CB2 receptors, but their abundant expression by lymphocytes and macrophages has led to suggestions of their importance in immune and inflammatory reactions. More recently, it has become apparent that both CB1 and CB2 receptors are more widely expressed than originally thought, and the capacity of endocannabinoids to regulate energy balance also occurs through their interactions with cannabinoid receptors on a variety of peripheral tissues. In general, pathological overactivation of the ECS contributes to weight gain, reduced sensitivity to insulin and glucose intolerance, and blockade of CB1 receptors reduces body weight through increased secretion of anorectic signals and improved insulin sensitivity. However, the notion that the ECS per se is detrimental to energy homeostasis is an oversimplification, since activation of cannabinoid receptors expressed by islet cells can stimulate insulin secretion, which is obviously beneficial under conditions of impaired glucose tolerance or type 2 diabetes. We propose that under normal physiological conditions cannabinoid signalling in the endocrine pancreas is a bona fide mechanism of regulating insulin secretion to maintain blood glucose levels, but that energy balance becomes dysregulated with excessive food intake, leading to adipogenesis and fat accumulation through enhanced cannabinoid synthesis. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. Endocannabinoids in the Dentate Gyrus

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    Frazier, Charles J.

    2007-01-01

    Recent years have produced rapid and enormous growth in our understanding of endocannabinoid-mediated signalling in the CNS. While much of the recent progress has focused on other areas of the brain, a significant body of evidence has developed that indicates the presence of a robust system for endocannabinoid-mediated signalling in the dentate gyrus. This chapter will provide an overview of our current understanding of that system based on available anatomical and physiological data.

  7. Astrocytes in endocannabinoid signalling.

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    Navarrete, Marta; Díez, Adolfo; Araque, Alfonso

    2014-10-19

    Astrocytes are emerging as integral functional components of synapses, responding to synaptically released neurotransmitters and regulating synaptic transmission and plasticity. Thus, they functionally interact with neurons establishing tripartite synapses: a functional concept that refers to the existence of communication between astrocytes and neurons and its crucial role in synaptic function. Here, we discuss recent evidence showing that astrocytes are involved in the endocannabinoid (ECB) system, responding to exogenous cannabinoids as well as ECBs through activation of type 1 cannabinoid receptors, which increase intracellular calcium and stimulate the release of glutamate that modulates synaptic transmission and plasticity. We also discuss the consequences of ECB signalling in tripartite synapses on the astrocyte-mediated regulation of synaptic function, which reveal novel properties of synaptic regulation by ECBs, such as the spatially controlled dual effect on synaptic strength and the lateral potentiation of synaptic efficacy. Finally, we discuss the potential implications of ECB signalling for astrocytes in brain pathology and animal behaviour. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  8. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction.

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    Stéphanie eOlière

    2013-09-01

    Full Text Available Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamine. Interestingly, recent accumulating evidence points toward the involvement of the endocannabinoid system (ECBS in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep-insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. The aims of this article are to: 1 review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and 2 evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoid in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

  9. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa

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    Herpertz-Dahlmann Beate

    2008-11-01

    Full Text Available Abstract Background Several lines of evidence indicate that the central cannabinoid receptor 1 (CNR1 as well as the major endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH, N-acylethanolamine-hydrolyzing acid amidase (NAAA and monoglyceride lipase (MGLL are implicated in mediating the orexigenic effects of cannabinoids. The aim of this study was to analyse whether nucleotide sequence variations in the CNR1, FAAH, NAAA and MGLL genes are associated with anorexia nervosa (AN. Methods We analysed the association of a previously described (AATn repeat in the 3' flanking region of CNR1 as well as a total of 15 single nucleotide polymorphisms (SNPs representative of regions with restricted haplotype diversity in CNR1, FAAH, NAAA or MGLL in up to 91 German AN trios (patient with AN and both biological parents using the transmission-disequilibrium-test (TDT. One SNP was additionally analysed in an independent case-control study comprising 113 patients with AN and 178 normal weight controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, ARMS-PCR or using 3730xl capillary sequencers. Results The TDT revealed no evidence for association for any of the SNPs or the (AATn repeat with AN (all two-sided uncorrected p-values > 0.05. The lowest p-value of 0.11 was detected for the A-allele of the CNR1 SNP rs1049353 for which the transmission rate was 59% (95% confidence interval 47%...70%. Further genotyping of rs1049353 in 113 additional independent patients with AN and 178 normal weight controls could not substantiate the initial trend for association (p = 1.00. Conclusion As we found no evidence for an association of genetic variation in CNR1, FAAH, NAAA and MGLL with AN, we conclude that genetic variations in these genes do not play a major role in the etiology of AN in our study groups.

  10. Acylethanolamides and endocannabinoid signaling system in dorsal striatum of rats exposed to perinatal asphyxia.

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    Holubiec, Mariana I; Romero, Juan I; Blanco, Eduardo; Tornatore, Tamara Logica; Suarez, Juan; Rodríguez de Fonseca, Fernando; Galeano, Pablo; Capani, Francisco

    2017-07-13

    Endocannabinoids (eCBs) and acylethanolamides (AEs) have lately received more attention due to their neuroprotective functions in neurological disorders. Here we analyze the alterations induced by perinatal asphyxia (PA) in the main metabolic enzymes and receptors of the eCBs/AEs in the dorsal striatum of rats. To induce PA, we used a model developed by Bjelke et al. (1991). Immunohistochemical techniques were carried out to determine the expression of neuronal and glial markers (NeuN and GFAP), eCBs/AEs synthesis and degradation enzymes (DAGLα, NAPE-PLD and FAAH) and their receptors (CB1 and PPARα). We found a decrease in NAPE-PLD and PPARα expression. Since NAPE-PLD and PPARα take part in the production and reception of biochemical actions of AEs, such as oleoylethanolamide, these results may suggest that PA plays a key role in the regulation of this system. These data agree with previous results obtained in the hippocampus and encourage us to develop further studies using AEs as potential neuroprotective compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Alternative Argets Within the Endocannabinoid System for Future Treatment of Gastrointestinal Diseases

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    Rudolf Schicho

    2011-01-01

    Full Text Available Many beneficial effects of herbal and synthetic cannabinoids on gut motility and inflammation have been demonstrated, suggesting a vast potential for these compounds in the treatment of gastrointestinal disorders. These effects are based on the so-called ‘endocannabinoid system’ (ECS, a cooperating network of molecules that regulate the metabolism of the body’s own and of exogenously administered cannabinoids. The ECS in the gastrointestinal tract quickly responds to homeostatic disturbances by de novo synthesis of its components to maintain homeostasis, thereby offering many potential targets for pharmacological intervention. Of major therapeutic interest are nonpsychoactive cannabinoids or compounds that do not directly target cannabinoid receptors but still possess cannabinoid-like properties. Drugs that inhibit endocannabinoid degradation and raise the level of endocannabinoids are becoming increasingly promising alternative therapeutic tools to manipulate the ECS.

  12. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects

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    Eva M Marco

    2011-10-01

    Full Text Available Public concern on mental health has noticeably increased given the high prevalence of neuropsychiatric disorders. Cognition and emotionality are the most affected functions in neuropsychiatric disorders, i.e. anxiety disorders, depression and schizophrenia. In this review, most relevant literature on the role of the endocannabinoid (eCB system in neuropsychiatric disorders will be presented. Evidence from clinical and animal studies is provided for the participation of CB1 and CB2 receptors (CB1R and CB2R in the above mentioned neuropsychiatric disorders. CBRs are crucial in some of the emotional and cognitive impairments reported, although more research is required to understand the specific role of the eCB system in neuropsychiatric disorders. Cannabidiol (CBD, the main non-psychotropic component of the Cannabis sativa plant, has shown therapeutic potential in several neuropsychiatric disorders. Although further studies are needed, recent studies indicate that CBD therapeutic effects may partially depend on facilitation of eCB-mediated neurotransmission. Last but not least, this review includes recent findings on the role of the eCB system in eating disorders. A deregulation of the eCB system has been proposed to be in the bases of several neuropsychiatric disorders, including eating disorders. Cannabis consumption has been related to the appearance of psychotic symptoms and schizophrenia. In contrast, the pharmacological manipulation of this eCB system has been proposed as a potential strategy for the treatment of anxiety disorders, depression, and anorexia nervosa. In conclusion, the eCB system plays a critical role in psychiatry; however, detrimental consequences of manipulating this endogenous system cannot be underestimated over the potential and promising perspectives of its therapeutic manipulation.

  13. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

    Science.gov (United States)

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. Methods To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. Results GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. Conclusions This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism. PMID:24739187

  14. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages.

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    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-04-17

    Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor (GcMAF), an endogenous glycosylated vitamin D binding protein responsible for macrophage cell activation has demonstrated positive effects in the treatment of autistic children. In this current study, we investigated the in vitro effects of GcMAF treatment on the endocannabinoid system gene expression, as well as cellular activation in blood monocyte-derived macrophages (BMDMs) from autistic patients compared to age-matched healthy developing controls. To achieve these goals, we used biomolecular, biochemical and immunocytochemical methods. GcMAF treatment was able to normalize the observed differences in dysregulated gene expression of the endocannabinoid system of the autism group. GcMAF also down-regulated the over-activation of BMDMs from autistic children. This study presents the first observations of GcMAF effects on the transcriptionomics of the endocannabinoid system and expression of CB2R protein. These data point to a potential nexus between endocannabinoids, vitamin D and its transporter proteins, and the immune dysregulations observed with autism.

  15. Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.

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    Cani, P D; Geurts, L; Matamoros, S; Plovier, H; Duparc, T

    2014-09-01

    The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  16. Dual-acting compounds targeting endocannabinoid and endovanilloid systems — a novel treatment option for chronic pain management.

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    Natalia Malek

    2016-08-01

    Full Text Available Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time and is often resistant to medical treatment. Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments. The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects. Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target. A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain. Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme. Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins. The plasticity of the endocannabinoid system and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated. Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively. Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.

  17. Putative Epigenetic Involvement of the Endocannabinoid System in Anxiety- and Depression-Related Behaviors Caused by Nicotine as a Stressor.

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    Tamaki Hayase

    Full Text Available Like various stressors, the addictive use of nicotine (NC is associated with emotional symptoms such as anxiety and depression, although the underlying mechanisms have not yet been fully elucidated due to the complicated involvement of target neurotransmitter systems. In the elicitation of these emotional symptoms, the fundamental involvement of epigenetic mechanisms such as histone acetylation has recently been suggested. Furthermore, among the interacting neurotransmitter systems implicated in the effects of NC and stressors, the endocannabinoid (ECB system is considered to contribute indispensably to anxiety and depression. In the present study, the epigenetic involvement of histone acetylation induced by histone deacetylase (HDAC inhibitors was investigated in anxiety- and depression-related behavioral alterations caused by NC and/or immobilization stress (IM. Moreover, based on the contributing roles of the ECB system, the interacting influence of ECB ligands on the effects of HDAC inhibitors was evaluated in order to examine epigenetic therapeutic interventions. Anxiety-like (elevated plus-maze test and depression-like (forced swimming test behaviors, which were observed in mice treated with repeated (4 days NC (subcutaneous 0.8 mg/kg and/or IM (10 min, were blocked by the HDAC inhibitors sodium butyrate (SB and valproic acid (VA. The cannabinoid type 1 (CB1 agonist ACPA (arachidonylcyclopropylamide; AC also antagonized these behaviors. Conversely, the CB1 antagonist SR 141716A (SR, which counteracted the effects of AC, attenuated the anxiolytic-like effects of the HDAC inhibitors commonly in the NC and/or IM groups. SR also attenuated the antidepressant-like effects of the HDAC inhibitors, most notably in the IM group. From these results, the combined involvement of histone acetylation and ECB system was shown in anxiety- and depression-related behaviors. In the NC treatment groups, the limited influence of SR against the HDAC inhibitor

  18. Differences in the endocannabinoid system of sperm from fertile and infertile men.

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    Sheena E M Lewis

    Full Text Available Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS, mainly through the action of anandamide (AEA and 2-arachidonoylglycerol (2-AG at cannabinoid (CB(1, CB(2 and vanilloid (TRPV1 receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS, mRNA (through quantitative RT-PCR, protein (through Western Blotting and ELISA expression, and functionality (through activity and binding assays of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG, as well as of their binding receptors CB(1, CB(2 and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1 and CB(2 receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems.

  19. An endocannabinoid hypothesis of drug reward and drug addiction.

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    Onaivi, Emmanuel S

    2008-10-01

    Pharmacologic treatment of drug and alcohol dependency has largely been disappointing, and new therapeutic targets and hypotheses are needed. There is accumulating evidence indicating a central role for the previously unknown but ubiquitous endocannabinoid physiological control system (EPCS) in the regulation of the rewarding effects of abused substances. Thus an endocannabinoid hypothesis of drug reward is postulated. Endocannabinoids mediate retrograde signaling in neuronal tissues and are involved in the regulation of synaptic transmission to suppress neurotransmitter release by the presynaptic cannabinoid receptors (CB-Rs). This powerful modulatory action on synaptic transmission has significant functional implications and interactions with the effects of abused substances. Our data, along with those from other investigators, provide strong new evidence for a role for EPCS modulation in the effects of drugs of abuse, and specifically for involvement of cannabinoid receptors in the neural basis of addiction. Cannabinoids and endocannabinoids appear to be involved in adding to the rewarding effects of addictive substances, including, nicotine, opiates, alcohol, cocaine, and BDZs. The results suggest that the EPCS may be an important natural regulatory mechanism for drug reward and a target for the treatment of addictive disorders.

  20. Lack of effect of chronic pre-treatment with the FAAH inhibitor URB597 on inflammatory pain behaviour: evidence for plastic changes in the endocannabinoid system

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    Okine, Bright N; Norris, Leonie M; Woodhams, Stephen; Burston, James; Patel, Annie; Alexander, Stephen PH; Barrett, David A; Kendall, David A; Bennett, Andrew J; Chapman, Victoria

    2012-01-01

    BACKGROUND AND PURPOSE Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour. EXPERIMENTAL APPROACH Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg−1), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined. KEY RESULTS Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction. CONCLUSION AND IMPLICATIONS Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain. PMID:22595021

  1. The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

    Science.gov (United States)

    Berardi, Andrea; Schelling, Gustav; Campolongo, Patrizia

    2016-09-01

    Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.

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    MacDowell, Karina S; Sayd, Aline; García-Bueno, Borja; Caso, Javier R; Madrigal, José L M; Leza, Juan Carlos

    2017-09-01

    Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.

  3. Role of endocannabinoids in regulating drug dependence

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    Daniela Parolaro

    2007-01-01

    Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

  4. Disruption of social cognition in the sub-chronic PCP rat model of schizophrenia: Possible involvement of the endocannabinoid system.

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    Seillier, Alexandre; Giuffrida, Andrea

    2016-02-01

    Previous studies have shown that social withdrawal in the phencyclidine (PCP) rat model of schizophrenia results from deficient endocannabinoid-induced activation of CB1 receptors. To understand the underlying cognitive mechanisms of the social deficit in PCP-treated rats, we examined the impact of pharmacological manipulation of the endocannabinoid system on sociability (i.e. social approach) and social novelty preference (which relies on social recognition). Control rats showed a clear preference for a "social" cage (i.e. unfamiliar stimulus rat placed under a wire mesh cage) versus an "empty" cage, and spent more time exploring a "novel" cage (i.e. new stimulus rat) versus a "familiar" cage. In contrast, rats receiving PCP (5 mg/kg, b.i.d. for 7 days, followed by a 7 day-washout period) showed intact sociability, but lacked social novelty preference. This PCP-induced deficit was due to increased activity at CB1 receptors as it was reversed by systemic administration of the CB1 antagonist AM251 (1 mg/kg). In agreement with this hypothesis, the cannabinoid agonist CP55,940 (0.003-0.03 mg/kg) dose-dependently suppressed social novelty preference in control animals without affecting sociability. Taken together, these data suggest that PCP-treated rats have a deficit in social cognition, possibly induced by increased stimulation of CB1 receptors. This deficit, however, is distinct from the social withdrawal previously observed in these animals, as the latter is due to deficient, rather than increased, CB1 stimulation. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  5. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages

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    Siniscalco, Dario; Bradstreet, James Jeffrey; Cirillo, Alessandra; Antonucci, Nicola

    2014-01-01

    Background Immune system dysregulation is well-recognized in autism and thought to be part of the etiology of this disorder. The endocannabinoid system is a key regulator of the immune system via the cannabinoid receptor type 2 (CB2R) which is highly expressed on macrophages and microglial cells. We have previously published significant differences in peripheral blood mononuclear cell CB2R gene expression in the autism population. The use of the Gc protein-derived Macrophage Activating Factor...

  6. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System

    Science.gov (United States)

    Gomes, Felipe V.; Silva, Andréia L.; Uliana, Daniela L.; Camargo, Laura H. A.; Guimarães, Francisco S.; Cunha, Fernando Q.; Joca, Sâmia R. L.; Resstel, Leonardo B. M.

    2015-01-01

    Background: Inducible or neuronal nitric oxide synthase gene deletion increases or decreases anxiety-like behavior in mice, respectively. Since nitric oxide and endocannabinoids interact to modulate defensive behavior, the former effect could involve a compensatory increase in basal brain nitric oxide synthase activity and/or changes in the endocannabinoid system. Thus, we investigated the expression and extinction of contextual fear conditioning of inducible nitric oxide knockout mice and possible involvement of endocannabinoids in these responses. Methods: We evaluated the effects of a preferential neuronal nitric oxide synthase inhibitor, 7-nitroindazol, nitric oxide synthase activity, and mRNA changes of nitrergic and endocannabinoid systems components in the medial prefrontal cortex and hippocampus of wild-type and knockout mice. The effects of URB597, an inhibitor of the fatty acid amide hydrolase enzyme, which metabolizes the endocannabinoid anandamide, WIN55,212-2, a nonselective cannabinoid agonist, and AM281, a selective CB1 antagonist, on contextual fear conditioning were also evaluated. Results: Contextual fear conditioning expression was similar in wild-type and knockout mice, but the latter presented extinction deficits and increased basal nitric oxide synthase activity in the medial prefrontal cortex. 7-Nitroindazol decreased fear expression and facilitated extinction in wild-type and knockout mice. URB597 decreased fear expression in wild-type and facilitated extinction in knockout mice, whereas WIN55,212-2 and AM281 increased it in wild-type mice. Nonconditioned knockout mice showed changes in the mRNA expression of nitrergic and endocannabinoid system components in the medial prefrontal cortex and hippocampus that were modified by fear conditioning. Conclusion: These data reinforce the involvement of the nitric oxide and endocannabinoids (anandamide) in stress-related disorders and point to a deregulation of the endocannabinoid system in

  7. Cocaine-induced behavioral sensitization decreases the expression of endocannabinoid signaling-related proteins in the mouse hippocampus.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Palomino, Ana; Pavón, Francisco J; Rivera, Patricia; Serrano, Antonia; Alen, Francisco; Rubio, Leticia; Vargas, Antonio; Castilla-Ortega, Estela; Decara, Juan; Bilbao, Ainhoa; de Fonseca, Fernando Rodríguez; Suárez, Juan

    2016-03-01

    In the reward mesocorticolimbic circuits, the glutamatergic and endocannabinoid systems are implicated in neurobiological mechanisms underlying cocaine addiction. However, the involvement of both systems in the hippocampus, a critical region to process relational information relevant for encoding drug-associated memories, in cocaine-related behaviors remains unknown. In the present work, we studied whether the hippocampal gene/protein expression of relevant glutamate signaling components, including glutamate-synthesizing enzymes and metabotropic and ionotropic receptors, and the hippocampal gene/protein expression of cannabinoid type 1 (CB1) receptor and endocannabinoid metabolic enzymes were altered following acute and/or repeated cocaine administration resulting in conditioned locomotion and locomotor sensitization. Results showed that acute cocaine administration induced an overall down-regulation of glutamate-related gene expression and, specifically, a low phosphorylation level of GluA1. In contrast, locomotor sensitization to cocaine produced an up-regulation of several glutamate receptor-related genes and, specifically, an increased protein expression of the GluN1 receptor subunit. Regarding the endocannabinoid system, acute and repeated cocaine administration were associated with an increased gene/protein expression of CB1 receptors and a decreased gene/protein expression of the endocannabinoid-synthesis enzymes N-acyl phosphatidylethanolamine D (NAPE-PLD) and diacylglycerol lipase alpha (DAGLα). These changes resulted in an overall decrease in endocannabinoid synthesis/degradation ratios, especially NAPE-PLD/fatty acid amide hydrolase and DAGLα/monoacylglycerol lipase, suggesting a reduced endocannabinoid production associated with a compensatory up-regulation of CB1 receptor. Overall, these findings suggest that repeated cocaine administration resulting in locomotor sensitization induces a down-regulation of the endocannabinoid signaling that could

  8. Oxyradical Stress, Endocannabinoids, and Atherosclerosis

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    Anberitha T. Matthews

    2015-12-01

    Full Text Available Atherosclerosis is responsible for most cardiovascular disease (CVD and is caused by several factors including hypertension, hypercholesterolemia, and chronic inflammation. Oxidants and electrophiles have roles in the pathophysiology of atherosclerosis and the concentrations of these reactive molecules are an important factor in disease initiation and progression. Overactive NADPH oxidase (Nox produces excess superoxide resulting in oxidized macromolecules, which is an important factor in atherogenesis. Although superoxide and reactive oxygen species (ROS have obvious toxic properties, they also have fundamental roles in signaling pathways that enable cells to adapt to stress. In addition to inflammation and ROS, the endocannabinoid system (eCB is also important in atherogenesis. Linkages have been postulated between the eCB system, Nox, oxidative stress, and atherosclerosis. For instance, CB2 receptor-evoked signaling has been shown to upregulate anti-inflammatory and anti-oxidative pathways, whereas CB1 signaling appears to induce opposite effects. The second messenger lipid molecule diacylglycerol is implicated in the regulation of Nox activity and diacylglycerol lipase β (DAGLβ is a key biosynthetic enzyme in the biosynthesis eCB ligand 2-arachidonylglycerol (2-AG. Furthermore, Nrf2 is a vital transcription factor that protects against the cytotoxic effects of both oxidant and electrophile stress. This review will highlight the role of reactive oxygen species (ROS in intracellular signaling and the impact of deregulated ROS-mediated signaling in atherogenesis. In addition, there is also emerging knowledge that the eCB system has an important role in atherogenesis. We will attempt to integrate oxidative stress and the eCB system into a conceptual framework that provides insights into this pathology.

  9. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders.

    Science.gov (United States)

    Kolla, Nathan J; Mishra, Achal

    2018-01-01

    Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  10. The Endocannabinoid System, Aggression, and the Violence of Synthetic Cannabinoid Use, Borderline Personality Disorder, Antisocial Personality Disorder, and Other Psychiatric Disorders

    Directory of Open Access Journals (Sweden)

    Nathan J. Kolla

    2018-03-01

    Full Text Available Endogenous and exogenous cannabinoids bind to central cannabinoid receptors to control a multitude of behavioral functions, including aggression. The first main objective of this review is to dissect components of the endocannabinoid system, including cannabinoid 1 and cannabinoid 2 receptors; the endogenous cannabinoids anandamide and 2-arachidonoylglycerol; and the indirect cannabinoid modulators fatty acid amide hydrolase and monoacylglycerol lipase; that have shown abnormalities in basic research studies investigating mechanisms of aggression. While most human research has concluded that the active ingredient of marijuana, Δ9-tetrahydrocannabinol, tends to dampen rather than provoke aggression in acute doses, recent evidence supports a relationship between the ingestion of synthetic cannabinoids and emergence of violent or aggressive behavior. Thus, another objective is to evaluate the emerging clinical data. This paper also discusses the relationship between prenatal and perinatal exposure to cannabis as well as use of cannabis in adolescence on aggressive outcomes. A final objective of the paper is to discuss endocannabinoid abnormalities in psychotic and affective disorders, as well as clinically aggressive populations, such as borderline personality disorder and antisocial personality disorder. With regard to the former condition, decreased anandamide metabolites have been reported in the cerebrospinal fluid, while some preliminary evidence suggests that fatty acid amide hydrolase genetic polymorphisms are linked to antisocial personality disorder and impulsive-antisocial psychopathic traits. To summarize, this paper will draw upon basic and clinical research to explain how the endocannabinoid system may contribute to the genesis of aggressive behavior.

  11. Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue

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    Lucie eGeurts

    2011-07-01

    Full Text Available Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system and gut microbiota-derived compounds, namely lipopolysaccharide (LPS. We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the endocannabinoid system and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the endocannabinoid system and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.

  12. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats.

    Science.gov (United States)

    Blanco, Eduardo; Galeano, Pablo; Holubiec, Mariana I; Romero, Juan I; Logica, Tamara; Rivera, Patricia; Pavón, Francisco J; Suarez, Juan; Capani, Francisco; Rodríguez de Fonseca, Fernando

    2015-01-01

    Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  13. Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

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    Eduardo eBlanco Calvo

    2015-11-01

    Full Text Available Perinatal asphyxia (PA is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory and mood. Endocannabinoids, and other acylethanolamides (AEs without endocannabinoid activity, have recently received growing attention as they have potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals that were delivered spontaneously or by caesarean section were employed as controls. At one month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and GFAP, enzymes responsible for synthesis (DAGLα and NAPE-PLD and degradation (FAAH of ECS/AEs and their receptors (CB1 and PPARα in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

  14. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits.

    Science.gov (United States)

    Lau, Benjamin K; Cota, Daniela; Cristino, Luigia; Borgland, Stephanie L

    2017-09-15

    The endocannabinoid system has emerged as a key player in the control of eating. Endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide (AEA), modulate neuronal activity via cannabinoid 1 receptors (CB1Rs) in multiple nuclei of the hypothalamus to induce or inhibit food intake depending on nutritional and hormonal status, suggesting that endocannabinoids may act in the hypothalamus to integrate different types of signals informing about the animal's energy needs. In the mesocorticolimbic system, (endo)cannabinoids modulate synaptic transmission to promote dopamine release in response to palatable food. In addition, (endo)cannabinoids act within the nucleus accumbens to increase food's hedonic impact; although this effect depends on activation of CB1Rs at excitatory, but not inhibitory inputs in the nucleus accumbens. While hyperactivation of the endocannabinoid system is typically associated with overeating and obesity, much evidence has emerged in recent years suggesting a more complicated system than first thought - endocannabinoids promote or suppress feeding depending on cell and input type, or modulation by various neuronal or hormonal signals. This review presents our latest knowledge of the endocannabinoid system in non-homeostatic and homeostatic feeding circuits. In particular, we discuss the functional role and cellular mechanism of action by endocannabinoids within the hypothalamus and mesocorticolimbic system, and how these are modulated by neuropeptide signals related to feeding. In light of recent advances and complexity in the field, we review cannabinoid-based therapeutic strategies for the treatment of obesity and how peripheral restriction of CB1R antagonists may provide a different mechanism of weight loss without the central adverse effects. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Endocannabinoids as Guardians of Metastasis

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    Irmgard Tegeder

    2016-02-01

    Full Text Available Endocannabinoids including anandamide and 2-arachidonoylglycerol are involved in cancer pathophysiology in several ways, including tumor growth and progression, peritumoral inflammation, nausea and cancer pain. Recently we showed that the endocannabinoid profiles are deranged during cancer to an extent that this manifests in alterations of plasma endocannabinoids in cancer patients, which was mimicked by similar changes in rodent models of local and metastatic cancer. The present topical review summarizes the complexity of endocannabinoid signaling in the context of tumor growth and metastasis.

  16. Modulation of the Endocannabinoids N-Arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG on Executive Functions in Humans.

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    Ana B Fagundo

    Full Text Available Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA and 2-Arachidonoylglycerol (2-AG and executive functions (decision making, response inhibition and cognitive flexibility in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = -.37; p<.05. A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05 and decision making performance (r = .23; P<.05. There was no significant correlation between either 2-AG (r = -.17 or AEA (r = -.08 concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders. Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches.

  17. A Comparative Analysis of the Endocannabinoid System in the Retina of Mice, Tree Shrews, and Monkeys

    DEFF Research Database (Denmark)

    Bouskila, Joseph; Javadi, Pasha; Elkrief, Laurent

    2016-01-01

    is known about the distribution of the enzymes involved in the synthesis and degradation of these eCBs. We therefore examined the expression and localization of the main components of the eCB system in the retina of mice, tree shrews, and monkeys. We found that CB1R and FAAH distributions are well...

  18. Endocannabinoids and the processing of value-related signals

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    Miriam eMelis

    2012-02-01

    Full Text Available Endocannabinoids serve as retrograde signaling molecules at many synapses within the CNS, particularly GABAergic and glutamatergic synapses. Synapses onto midbrain dopamine (DA neurons in the ventral tegmental area (VTA make no exception to this rule. In fact, the effects of cannabinoids on dopamine transmission as well as DA-related behaviors are generally exerted through the modulation of inhibitory and excitatory afferents impinging onto DA neurons. Endocannabinoids, by regulating different forms of synaptic plasticity in the VTA, provide a critical modulation of the DA neuron output and, ultimately, of the systems driving and regulating motivated behaviors. Because DA cells exhibit diverse states of activity, which crucially depend on their intrinsic properties and afferent drive, the understanding of the role played by endocannabinoids in synaptic modulations is critical for their overall functions. Particularly, endocannabinoids by selectively inhibiting afferent activity may alter the functional states of DA neurons and potentiate the responsiveness of the reward system to phasic DA.

  19. The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension

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    Agnieszka Polak

    2018-03-01

    Full Text Available Background/Aims: Recent interest in the use of cannabinoids as therapeutic agents has revealed the involvement of the endogenous cannabinoid system (ECS in the regulation of the cardiovascular system in hypertension. Abnormalities in glucose metabolism and insulin action are commonly detected in hypertensive animals. Thus, potential antihypertensive drugs should be investigated with respect to modulation of glucose homeostasis. Therefore, the aim of the present study was to evaluate the effects of the ECS activation after chronic fatty acid amide hydrolase inhibitor (URB597 administration on plasma glucose and insulin concentrations as well as parameters of myocardial glucose metabolism in the deoxycorticosterone acetate (DOCA-salt hypertensive rats, an animal model of secondary hypertension. Methods: Hypertension was induced by DOCA (25mg/kg injections and addition of 1% NaCl in the drinking water for six weeks. Chronic activation of the ECS was performed by URB597 (1mg/kg injections for two weeks. We examined fasting plasma levels of insulin (ELISA, glucose and intramyocardial glycogen (colorimetric method. Expressions of glucose transporters (GLUT1, 4 and selected proteins engaged in GLUT translocation as well as glucose metabolism were determined using Western blotting. Results: Hypertension induced hypoinsulinemia with concomitant lack of significant changes in glycemia, reduced intramyocardial glycogen content and increased pyruvate dehydrogenase (PDH expression in the cardiac muscle. Importantly, chronic URB597 administration in the hypertensive rats increased insulin concentration, elevated plasmalemmal GLUT1 and GLUT4 expression and concomitantly improved myocardial glycogen storage. Conclusion: Chronic administration of fatty acid amide hydrolase (FAAH inhibitor has potential protective properties on myocardial glucose metabolism in hypertension.

  20. Peripheral endocannabinoids regulate skeletal muscle development and maintenance

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    Dongjiao Zhao

    2010-12-01

    Full Text Available As a principal tissue responsible for insulin-mediated glucose uptake, skeletal muscle is important for whole-body health. The role of peripheral endocannabinoids as regulators of skeletal muscle metabolism has recently gained a lot of interest, as endocannabinoid system disorders could cause peripheral insulin resistance. We investigated the role of the peripheral endocannabinoid system in skeletal muscle development and maintenance. Cultures of C2C12 cells, primary satellite cells and mouse skeletal muscle single fibers were used as model systems for our studies. We found an increase in cannabinoid receptor type 1 (CB1 mRNA and endocannabinoid synthetic enzyme mRNA skeletal muscle cells during differentiation. We also found that activation of CB1 inhibited myoblast differentiation, expanded the number of satellite cells, and stimulated the fast-muscle oxidative phenotype. Our findings contribute to understanding of the role of the endocannabinoid system in skeletal muscle metabolism and muscle oxygen consumption, and also help to explain the effects of the peripheral endocannabinoid system on whole-body energy balance.

  1. ENDOCANNABINOIDS AND EICOSAMOIDS: BIOSYNTHESIS AND INTERACTIONS WITH IMMUNE RESPONSE

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    Yu. K. Karaman

    2013-01-01

    Full Text Available The review is dedicated to modern concepts of arachidonic acid metabolites, i.e., endocannabinoids and eicosanoids, their biosynthetic pathways, cross-talk mechanisms and participation in immune response. New information from literature and own results include data concerning overlapping enzymatic pathways controlling biosynthesis of endocannabinoids and eicosanoids. Impact of synthetic cannabinoid receptor ligands upon production rates of proinflammatory cytokines and eicosanoids is discussed, as like as relationships among immune system reactivity and expression levels of cannabinoid receptors.

  2. Translational Evidence for a Role of Endocannabinoids in the Etiology and Treatment of Posttraumatic Stress Disorder

    Science.gov (United States)

    Neumeister, Alexander; Seidel, Jordan; Ragen, Benjamin J.; Pietrzak, Robert H.

    2014-01-01

    Introduction Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Methods Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. Results There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Conclusion Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. PMID:25456347

  3. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

    Science.gov (United States)

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2016-01-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

  4. The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder

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    Viviana eTrezza

    2013-08-01

    Full Text Available Posttraumatic stress disorder (PTSD is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors.

  5. Individual differences in response to positive and negative stimuli: endocannabinoid-based insight on approach and avoidance behaviors

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    Daniela eLaricchiuta

    2014-12-01

    Full Text Available Approach and avoidance behaviors - the primary responses to the environmental stimuli of danger, novelty and reward - are associated with the brain structures that mediate cognitive functionality, reward sensitivity and emotional expression. Individual differences in approach and avoidance behaviors are modulated by the functioning of amygdaloid-hypothalamic-striatal and striatal-cerebellar networks implicated in action and reaction to salient stimuli. The nodes of these networks are strongly interconnected and by acting on them the endocannabinoid and dopaminergic systems increase the intensity of appetitive or defensive motivation. This review analyzes the approach and avoidance behaviors in humans and rodents, addresses neurobiological and neurochemical aspects of these behaviors, and proposes a possible synaptic plasticity mechanism, related to endocannabinoid-dependent long-term potentiation and depression that allows responding to salient positive and negative stimuli.

  6. Emerging Role of (EndoCannabinoids in Migraine

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    Pinja Leimuranta

    2018-04-01

    Full Text Available In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i the current knowledge on the endocannabinoid system (ECS with emphasis on expression of its components in migraine related structures; (ii distinguishing peripheral from central site of action of cannabinoids, (iii proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v dual (possibly opposing actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components or novel endocannabinoid therapeutics in migraine treatment.

  7. A preliminary study of endocannabinoid system regulation in psychosis: Distinct alterations of CNR1 promoter DNA methylation in patients with schizophrenia.

    Science.gov (United States)

    D'Addario, Claudio; Micale, Vincenzo; Di Bartolomeo, Martina; Stark, Tibor; Pucci, Mariangela; Sulcova, Alexandra; Palazzo, Mariacarlotta; Babinska, Zuzana; Cremaschi, Laura; Drago, Filippo; Carlo Altamura, A; Maccarrone, Mauro; Dell'Osso, Bernardo

    2017-10-01

    Compelling evidence supports the involvement of the endocannabinoid system (ECS) in psychosis vulnerability. We here evaluated the transcriptional regulation of ECS components in human peripheral blood mononuclear cells (PBMCs) obtained from subjects suffering from bipolar disorder, major depressive disorder and schizophrenia, focusing in particular on the effects of DNA methylation. We observed selective alterations of DNA methylation at the promoter of CNR1, the gene coding for the type-1 cannabinoid receptor, in schizophrenic patients (N=25) with no changes in any other disorder. We confirmed the regulation of CNR1 in a well-validated animal model of schizophrenia, induced by prenatal methylazoxymethanol (MAM) acetate exposure (N=7 per group) where we found, in the prefrontal cortex, a significant increase in CNR1 expression and a consistent reduction in DNA methylation at specific CpG sites of gene promoter. Overall, our findings suggest a selective dysregulation of ECS in psychosis, and highlight the evaluation of CNR1 DNA methylation levels in PBMCs as a potential biomarker for schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Endocannabinoid signaling in reward and addiction

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    Parsons, Loren H.; Hurd, Yasmin L.

    2015-01-01

    Brain endocannabinoid signaling influences the motivation for natural rewards (such as palatable food, sexual activity and social interaction) and modulates the rewarding effects of addictive drugs. Pathological forms of natural and drug-induced reward are associated with dysregulated endocannabinoid signaling that may derive from pre-existing genetic factors or from prolonged drug exposure. Impaired endocannabinoid signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, negative emotional states, and craving that propel addiction. Understanding the contributions of endocannabinoid disruptions to behavioral and physiological traits provides insight into the endocannabinoid influence on addiction vulnerability. PMID:26373473

  9. Potential of Endocannabinoids to Control Bladder Pain

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    Dale E. Bjorling

    2018-05-01

    Full Text Available Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority. Endocannabinoids, primarily anandamide (AEA and 2-arachidonoylglycerol (2-AG, are endogenously-produced fatty acid ethanolamides with that induce analgesia. Animal experiments have demonstrated that inhibition of enzymes that degrade AEA or 2-AG have the potential to prevent development of visceral and somatic pain. Although experimental results in animal models have been promising, clinical application of this approach has proven difficult. In addition to fatty acid amide hydrolase (FAAH; degrades AEA and monacylglycerol lipase (MAGL; degrades 2-AG, cyclooxygenase (COX acts to metabolize endocannabinoids. Another potential limitation of this strategy is that AEA activates pro-nociceptive transient receptor potential vanilloid 1 (TRPV1 channels. Dual inhibitors of FAAH and TRPV1 or FAAH and COX have been synthesized and are currently undergoing preclinical testing for efficacy in providing analgesia. Local inhibition of FAAH or MAGL within the bladder may be viable options to reduce pain associated with cystitis with fewer systemic side effects, but this has not been explored. Further investigation is required before manipulation of the endocannabinoid system can be proven as an efficacious alternative for management of bladder pain.

  10. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

    Science.gov (United States)

    Fuss, Johannes; Bindila, Laura; Wiedemann, Klaus; Auer, Matthias K; Briken, Peer; Biedermann, Sarah V

    2017-11-01

    Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. Our data indicate that the

  11. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

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    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; Fornari, Raquel V; Roozendaal, Benno

    2015-05-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

  12. A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice.

    Science.gov (United States)

    Wei, Don; Lee, DaYeon; Li, Dandan; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele

    2016-05-01

    The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140 % of controls, respectively), but unchanged in the medial prefrontal cortex. The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.

  13. Antioxidant status and endocannabinoid concentration in postpartum depressive women

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    Mina Ranjbaran

    2015-02-01

    Conclusion: Women’s Job, husband’s job, wanted or unwanted pregnancy from husbands and marital period are associated to postpartum depression. In postpartum depression, TAC, AEA and 2-AG are reduced. So it can be concluded that both antioxidant system and endocannabinoid concentration involved in the development of postpartum depression.

  14. Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

    Science.gov (United States)

    Grant, Igor; Cahn, B. Rael

    2008-01-01

    The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control. PMID:18806886

  15. Preventive Effects of Resveratrol on Endocannabinoid System and Synaptic Protein Modifications in Rat Cerebral Cortex Challenged by Bilateral Common Carotid Artery Occlusion and Reperfusion

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    Gianfranca Carta

    2018-01-01

    Full Text Available This study aims to evaluate the putative roles of a single acute dose of resveratrol (RVT in preventing cerebral oxidative stress induced by bilateral common carotid artery occlusion, followed by reperfusion (BCCAO/R and to investigate RVT’s ability to preserve the neuronal structural integrity. Frontal and temporal-occipital cortices were examined in two groups of adult Wistar rats, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half the rats were gavage-fed with a single dose of RVT (40 mg/per rat in 300 µL of sunflower oil as the vehicle, while the second half received the vehicle alone. In the frontal cortex, RVT pre-treatment prevented the BCCAO/R-induced increase of lipoperoxides, augmented concentrations of palmitoylethanolamide and docosahexaenoic acid, increased relative levels of the cannabinoid receptors type 1 (CB1 and 2 (CB2, and peroxisome-proliferator-activated-receptor (PPAR-α proteins. Increased expression of CB1/CB2 receptors mirrored that of synaptophysin and post-synaptic density-95 protein. No BCCAO/R-induced changes occurred in the temporal-occipital cortex. Collectively, our results demonstrate that, in the frontal cortex, RVT pre-treatment prevents the BCCAO/R-induced oxidative stress and modulates the endocannabinoid and PPAR-α systems. The increased expression of synaptic structural proteins further suggests the possible efficacy of RVT as a dietary supplement to preserve the nervous tissue metabolism and control the physiological response to the hypoperfusion/reperfusion challenge.

  16. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    Energy Technology Data Exchange (ETDEWEB)

    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  17. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    International Nuclear Information System (INIS)

    Frampton, Gabriel; Coufal, Monique; Li, Huang; Ramirez, Jonathan; DeMorrow, Sharon

    2010-01-01

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the γ-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-γ-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the γ-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  18. Endocannabinoids, Related Compounds and Their Metabolic Routes

    Directory of Open Access Journals (Sweden)

    Filomena Fezza

    2014-10-01

    Full Text Available Endocannabinoids are lipid mediators able to bind to and activate cannabinoid receptors, the primary molecular targets responsible for the pharmacological effects of the Δ9-tetrahydrocannabinol. These bioactive lipids belong mainly to two classes of compounds: N-acylethanolamines and acylesters, being N-arachidonoylethanolamine (AEA and 2-arachidonoylglycerol (2-AG, respectively, their main representatives. During the last twenty years, an ever growing number of fatty acid derivatives (endocannabinoids and endocannabinoid-like compounds have been discovered and their activities biological is the subject of intense investigations. Here, the most recent advances, from a therapeutic point of view, on endocannabinoids, related compounds, and their metabolic routes will be reviewed.

  19. Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification

    Directory of Open Access Journals (Sweden)

    Jantana Keereetaweep

    2016-01-01

    Full Text Available The endocannabinoids N-arachidonoylethanolamide (or anandamide, AEA and 2-arachidonoylglycerol (2-AG belong to the larger groups of N-acylethanolamines (NAEs and monoacylglycerol (MAG lipid classes, respectively. They are biologically active lipid molecules that activate G-protein-coupled cannabinoid receptors found in various organisms. After AEA and 2-AG were discovered in the 1990s, they have been extensively documented to have a broad range of physiological functions. Along with AEA, several NAEs, for example, N-palmitoylethanolamine (PEA, N-stearoylethanolamine (SEA, and N-oleoylethanolamine (OEA are also present in tissues, usually at much larger concentrations than AEA. Any perturbation that involves the endocannabinoid pathway may subsequently alter basal level or metabolism of these lipid mediators. Further, the altered levels of these molecules often reflect pathological conditions associated with tissue damage. Robust and sensitive methodologies to analyze these lipid mediators are essential to understanding how they act as endocannabinoids. The recent advances in mass spectrometry allow researchers to develop lipidomics approaches and several methodologies have been proposed to quantify endocannabinoids in various biological systems.

  20. Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance.

    Science.gov (United States)

    Claeson, Anna-Sara; Gouveia-Figueira, Sandra; Häggström, Jenny; Fowler, Christopher J; Nording, Malin L

    2017-06-01

    Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Effect of biliary cirrhosis on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum: Role of nitric oxide pathway and endocannabinoid system

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    Dehpour A.R.

    2008-06-01

    Full Text Available Background: Relaxation of the corpus cavernosum plays a major role in penile erection. Nitric oxide (NO is known to be the most important factor mediating relaxation of corpus cavernosum, which is mainly derived from nonadrenergic noncholinergic (NANC nerves. The aim of the present study was to investigate the effect of biliary cirrhosis on nonadrenergic noncholinergic (NANC-mediated relaxation of rat corpus cavernosum as well as the possible relevant roles of endocannabinoid and nitric oxide systems.Methods: Corporal strips from sham-operated and biliary cirrhotic rats were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 µM and atropine (1 µM to induce adrenergic and cholinergic blockade. The strips were precontracted with phenylephrine hydrochloride (7.5 µM and electrical field stimulation was applied at different frequencies (2, 5, 10, 15 Hz to obtain NANC-mediated relaxation. In separate precontracted strips of the sham and cirrhotic groups, the concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1mM, as an NO donor, were assessed.  Results: The NANC-mediated relaxation was significantly enhanced in cirrhotic animals (P<0.01. Anandamide potentiated the relaxations in both groups (P<0.05. The cannabinoid CB1 receptor antagonist AM251 (10 µM and the vanilloid receptor antagonist capsazepine (10 µM each significantly prevented the enhanced relaxations in cirrhotic rats (P<0.01. The CB2 receptor antagonist AM630 had no effect on relaxations in the cirrhotic group. In a concentration-dependent manner, L-NAME (30-1000 nM inhibited relaxations in both the sham and cirrhotic groups, although cirrhotic groups were more resistant to the inhibitory effects of L-NAME. The degree of relaxation induced by sodium nitroprusside (10 nM-1 mM was similar in the two groups.Conclusions: Biliary cirrhosis enhances the neurogenic relaxation in rat corpus cavernosum probably via the NO pathway and

  2. Endocannabinoids and Human Sperm Cells

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    Giovanna Zolese

    2010-10-01

    Full Text Available N-acylethanolamides (NAEs are naturally occurring signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. Usually they are present in a very small amounts in many mammalian tissues and cells, including human reproductive tracts and fluids. Recently, the presence of N-arachidonoylethanolamide (anandamide, AEA, the most characterised member of endocannabinoids, and its congeners palmitoylethanolamide (PEA and oleylethanolamide (OEA in seminal plasma, oviductal fluid, and follicular fluids was demonstrated. AEA has been shown to bind not only type-1 (CB1 and type-2 (CB2 cannabinoid receptors, but also type-1 vanilloid receptor (TRPV1, while PEA and OEA are inactive with respect to classical cannabinoid CB1 and CB2 but activate TRPV1 or peroxisome proliferator activate receptors (PPARs. This review concerns the most recent experimental data on PEA and OEA, endocannabinoid-like molecules which appear to exert their action exclusively on sperm cells with altered features, such as membrane characteristics and kinematic parameters. Their beneficial effects on these cells could suggest a possible pharmacological use of PEA and OEA on patients affected by some forms of idiopathic infertility.

  3. Endocannabinoid antagonism: blocking the excess in the treatment of high-risk abdominal obesity.

    Science.gov (United States)

    Duffy, Danielle; Rader, Daniel

    2007-02-01

    Abdominal obesity is a prevalent, worldwide problem linked to cardiometabolic comorbidities and an increased risk of coronary heart disease. First-line therapy to reduce such risk revolves around diet and exercise; however, such changes are often difficult to implement and unsuccessful. Understanding the underlying pathophysiology of underlying metabolic derangements could provide new targets for pharmacologic therapy. One system that has gained recent attention is the endocannabinoid system. The endocannabinoid system has a significant role in central appetite control and peripheral lipogenesis and is up-regulated in diet-induced obesity. Rimonabant is a selective cannabinoid-1 receptor antagonist and is the first compound of its type to test the hypothesis that down-regulating an overactive endocannabinoid system could have therapeutic benefit not only for weight loss but also for the atherogenic dyslipidemia and insulin resistance that cluster with abdominal obesity in particular. Animal models have been critical for elucidating the role of the endocannabinoid system in obesity and in demonstrating that antagonism with rimonabant can induce loss of visceral fat and improve insulin sensitivity. Early human trials with rimonabant have confirmed significant reductions in weight, as well as favorable changes in atherogenic dyslipidemia, insulin resistance, and markers of inflammation. Interestingly, some of these beneficial metabolic effects are partially weight-loss-independent, confirming the importance of peripheral endocannabinoid system effects in addition to central effects.

  4. Safety implications of control systems

    International Nuclear Information System (INIS)

    Smith, O.L.

    1983-01-01

    The Safety Implications of Control Systems Program has three major activities in support of USI-A47. The first task is a failure mode and effects analysis of all plant systems which may potentially induce control system disturbance that have safety implications. This task has made a preliminary study of overfill events and recommended cases for further analysis on the hybrid simulator. Work continues on overcooling and undercooling. A detailed investigation of electric power network is in progress. LERs are providing guidance on important failure modes that will provide initial conditions for further simulator studies. The simulator taks is generating a detailed model of the control system supported by appropriate neutronics, hydraulics, and thermodynamics submodels of all other principal plant components. The simulator is in the last stages of development. Checkout calculations are in progress to establish model stability, robustness, and qualitative credibility. Verification against benchmark codes and plant data will follow

  5. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    International Nuclear Information System (INIS)

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-01-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

  6. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  7. Gestation Related Gene Expression of the Endocannabinoid Pathway in Rat Placenta

    Directory of Open Access Journals (Sweden)

    Kanchan Vaswani

    2015-01-01

    Full Text Available Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglα, and Ptgs2 was studied (cohort 1, microarray. Biological replication of the results was performed by qPCR (cohort 2. Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1, from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.

  8. Essential fatty acids and lipid mediators. Endocannabinoids

    Directory of Open Access Journals (Sweden)

    G. Caramia

    2012-03-01

    hashish and marijuana (--Delta9- tetrahydrocannabinol. They act as true ‘endogenous cannabinoids’ by binding and functionally activating one or both cannabinoid receptor present on nervous and peripheral cell membranes. Enzymes that carry out anandamide oxidation are the same fatty acid oxygenases that are known to act on endogenous arachidonic acid namely, the members of the COX, LOX, and P450 families of enzymes. Recent advances in the biochemistry and pharmacology of the endocannabinoid system, also for its central and peripheral roles in regulating food intake, will offer the development of novel therapeutic agents.

  9. Seeing through the smoke: human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

    Science.gov (United States)

    Silveira, Mason M.; Arnold, Jonathon C.; Laviolette, Steven R.; Hillard, Cecilia J.; Celorrio, Marta; Aymerich, María S.; Adams, Wendy K.

    2016-01-01

    Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications. PMID:27639448

  10. Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

    Science.gov (United States)

    Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

    2016-01-01

    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. PMID:26514583

  11. Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

    Science.gov (United States)

    Di, Shi; Itoga, Christy A; Fisher, Marc O; Solomonow, Jonathan; Roltsch, Emily A; Gilpin, Nicholas W; Tasker, Jeffrey G

    2016-08-10

    Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2-arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid-induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress

  12. The endocannabinoid system and its role in schizophrenia: a systematic review of the literature O sistema endocanabinoide e seu papel na esquizofrenia: uma revisão sistemática da literatura

    Directory of Open Access Journals (Sweden)

    Rodrigo Ferretjans

    2012-10-01

    Full Text Available OBJECTIVE: Schizophrenia is a psychiatric disorder whose mechanisms have remained only partially elucidated. The current proposals regarding its biological basis, such as the dopaminergic hypothesis, do not fully explain the diversity of its symptoms, indicating that other processes may be involved. This paper aims to review evidence supporting the involvement of the endocannabinoid system (ECS, a neurotransmitter group that is the target of Cannabis sativa compounds, in this disorder. METHODS: A systematic review of original papers, published in English, indexed in PubMed up to April, 2012. RESULTS: Most studies employed genetics and histological, neuroimaging or neurochemical methods - either in vivo or post-mortem - to investigate whether components of the ECS are compromised in patients. Overall, the data show changes in cannabinoid receptors in certain brain regions as well as altered levels in endocannabinoid levels in cerebrospinal fluid and/or blood. CONCLUSIONS: Although a dysfunction of the ECS has been described, results are not entirely consistent across studies. Further data are warrant to better define a role of this system in schizophrenia.OBJETIVO: A esquizofrenia é um transtorno psiquiátrico cujos mecanismos permanecem apenas parcialmente elucidados. As atuais propostas relativas à base biológica, tais como a hipótese dopaminérgica, não explicam por completo a diversidade de seus sintomas, o que indica que outros processos podem estar envolvidos. Este artigo tem como objetivo revisar indícios que sustentem o envolvimento do sistema endocanabinoide (SECB, um grupo de neurotransmissoresalvo dos compostos da Cannabis sativa, nesse transtorno. MÉTODOS: Revisão sistemática dos artigos originais, publicados em inglês e indexados no PubMed até abril de 2012. RESULTADOS: A maioria dos estudos empregou métodos neuroquímicos ou de neuroimagem genéticos e histológicos - tanto in vivo quanto post-mortem - para investigar se

  13. Endocannabinoids and cardiovascular prevention: real progress?

    Directory of Open Access Journals (Sweden)

    Livio Dei Cas

    2009-08-01

    Full Text Available ABSTRACT: The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc. Therefore, the antagonism of the endocannabinoid (EC system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1-3. Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a “major modifiable risk factor” for coronary heart disease (4, 5. Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7. (Heart International 2007; 3: 27-34

  14. Exploração farmacológica do sistema endocanabinoide: novas perspectivas para o tratamento de transtornos de ansiedade e depressão? Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?

    Directory of Open Access Journals (Sweden)

    Viviane M. Saito

    2010-05-01

    Full Text Available OBJETIVO: Este artigo revisa o sistema endocanabinoide e as respectivas estratégias de intervenções farmacológicas. MÉTODO: Realizou-se uma revisão da literatura sobre o sistema endocanabinoide e a sua farmacologia, considerando-se artigos originais ou de revisão escritos em inglês. DISCUSSÃO: Canabinoides são um grupo de compostos presentes na Cannabis Sativa (maconha, a exemplo do Δ9-tetraidrocanabinol e seus análogos sintéticos. Estudos sobre o seu perfil farmacológico levaram à descoberta do sistema endocanabinoide do cérebro de mamíferos. Este sistema é composto por pelo menos dois receptores acoplados a uma proteína G, CB1 e CB2, pelos seus ligantes endógenos (endocanabinoides; a exemplo da anandamida e do 2-araquidonoil glicerol e pelas enzimas responsáveis por sintetizá-los e metabolizá-los. Os endocanabinoides representam uma classe de mensageiros neurais que são sintetizados sob demanda e liberados de neurônios pós-sinápticos para restringir a liberação de neurotransmissores clássicos de terminais pré-sinápticos. Esta sinalização retrógrada modula uma diversidade de funções cerebrais, incluindo ansiedade, medo e humor, em que a ativação de receptores CB1 pode exercer efeitos dos tipos ansiolítico e antidepressivo em estudos préclínicos. CONCLUSÃO: Experimentos com modelos animais sugerem que drogas que facilitam a ação dos endocanabinoides podem representar uma nova estratégia para o tratamento de transtornos de ansiedade e depressão.OBJECTIVE: The present review provides a brief introduction into the endocannabinoid system and discusses main strategies of pharmacological interventions. METHOD: We have reviewed the literature relating to the endocannabinoid system and its pharmacology; both original and review articles written in English were considered. DISCUSSION: Cannabinoids are a group of compounds present in Cannabis Sativa (hemp, such as Δ9-tetrahydrocannabinol, and their synthetic

  15. Endocannabinoid Signaling in Motivation, Reward, and Addiction: Influences on Mesocorticolimbic Dopamine Function.

    Science.gov (United States)

    Sagheddu, Claudia; Muntoni, Anna Lisa; Pistis, Marco; Melis, Miriam

    2015-01-01

    Evidence suggests that the endocannabinoid system has been conserved in the animal kingdom for 500 million years, and this system influences many critical behavioral processes including associative learning, reward signaling, goal-directed behavior, motor skill learning, and action-habit transformation. Additionally, the neurotransmitter dopamine has long been recognized to play a critical role in the processing of natural rewards, as well as of motivation that regulates approach and avoidance behavior. This motivational role of dopamine neurons is also based upon the evidence provided by several studies investigating disorders of dopamine pathways such as drug addiction and Parkinson's disease. From an evolutionary point of view, individuals engage in behaviors aimed at maximizing and minimizing positive and aversive consequences, respectively. Accordingly, those with the greatest fitness have a better potential to survival. Hence, deviations from fitness can be viewed as a part of the evolutionary process by means of natural selection. Given the long evolutionary history of both the endocannabinoid and dopaminergic systems, it is plausible that they must serve as fundamental and basic modulators of physiological functions and needs. Notably, endocannabinoids regulate dopamine neuronal activity and its influence on behavioral output. The goal of this chapter is to examine the endocannabinoid influence on dopamine signaling specifically related to (i) those behavioral processes that allow us to successfully adapt to ever-changing environments (i.e., reward signaling and motivational processes) and (ii) derangements from behavioral flexibility that underpin drug addiction. © 2015 Elsevier Inc. All rights reserved.

  16. Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

    2017-11-01

    Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

  17. Classical endocannabinoid-like compounds and their regulation by nutrients

    DEFF Research Database (Denmark)

    Kleberg, Karen; Hassing, Helle A.; Hansen, Harald S.

    2014-01-01

    Endocannabinoid-like compounds are structurally related to the true endocannabinoids but do not contain highly unsaturated fatty acids, and they do not bind the cannabinoid receptors. The classical endocannabinoid-like compounds include N-acylethanolamines and 2-monoacylglycerols......, which are particularly interesting in a nutritional and metabolic context. Exogenously supplied oleoylethanolamide, palmitoylethanolamide, and linoleoylethanolamide have anorexic effects, and the endogenous formation of these N-acylethanolamines in the small intestine may serve an important role...

  18. Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.

    Science.gov (United States)

    Bilgic, Elif; Guzel, Elif; Kose, Sevil; Aydin, Makbule Cisel; Karaismailoglu, Eda; Akar, Irem; Usubutun, Alp; Korkusuz, Petek

    2017-06-01

    Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the down regulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct role in the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 and CB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p=0,001 and p=0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p=0,001, p=0,001, p=0,001 and p=0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p=0,001 and p=0,001). CB1 and CB2 receptor agonist mediated dose dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. Copyright

  19. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes.

    Science.gov (United States)

    Thompson, Zoe; Argueta, Donovan; Garland, Theodore; DiPatrizio, Nicholas

    2017-03-01

    The endocannabinoid system serves many physiological roles, including in the regulation of energy balance, food reward, and voluntary locomotion. Signaling at the cannabinoid type 1 receptor has been specifically implicated in motivation for rodent voluntary exercise on wheels. We studied four replicate lines of high runner (HR) mice that have been selectively bred for 81 generations based on average number of wheel revolutions on days five and six of a six-day period of wheel access. Four additional replicate lines are bred without regard to wheel running, and serve as controls (C) for random genetic effects that may cause divergence among lines. On average, mice from HR lines voluntarily run on wheels three times more than C mice on a daily basis. We tested the general hypothesis that circulating levels of endocannabinoids (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA]) differ between HR and C mice in a sex-specific manner. Fifty male and 50 female mice were allowed access to wheels for six days, while another 50 males and 50 females were kept without access to wheels (half HR, half C for all groups). Blood was collected by cardiac puncture during the time of peak running on the sixth night of wheel access or no wheel access, and later analyzed for 2-AG and AEA content by ultra-performance liquid chromatography coupled to tandem mass spectrometry. We observed a significant three-way interaction among sex, linetype, and wheel access for 2-AG concentrations, with females generally having lower levels than males and wheel access lowering 2-AG levels in some but not all subgroups. The number of wheel revolutions in the minutes or hours immediately prior to sampling did not quantitatively predict plasma 2-AG levels within groups. We also observed a trend for a linetype-by-wheel access interaction for AEA levels, with wheel access lowering plasma concentrations of AEA in HR mice, while raising them in C mice. In addition, females tended to have higher AEA

  20. Fabp1 gene ablation inhibits high-fat diet-induced increase in brain endocannabinoids.

    Science.gov (United States)

    Martin, Gregory G; Landrock, Danilo; Chung, Sarah; Dangott, Lawrence J; Seeger, Drew R; Murphy, Eric J; Golovko, Mikhail Y; Kier, Ann B; Schroeder, Friedhelm

    2017-01-01

    The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet (HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein (FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation (LKO) on the effect of high-fat diet (HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. © 2016 International Society for Neurochemistry.

  1. Endocannabinoids mediate neuron-astrocyte communication.

    Science.gov (United States)

    Navarrete, Marta; Araque, Alfonso

    2008-03-27

    Cannabinoid receptors play key roles in brain function, and cannabinoid effects in brain physiology and drug-related behavior are thought to be mediated by receptors present in neurons. Neuron-astrocyte communication relies on the expression by astrocytes of neurotransmitter receptors. Yet, the expression of cannabinoid receptors by astrocytes in situ and their involvement in the neuron-astrocyte communication remain largely unknown. We show that hippocampal astrocytes express CB1 receptors that upon activation lead to phospholipase C-dependent Ca2+ mobilization from internal stores. These receptors are activated by endocannabinoids released by neurons, increasing astrocyte Ca2+ levels, which stimulate glutamate release that activates NMDA receptors in pyramidal neurons. These results demonstrate the existence of endocannabinoid-mediated neuron-astrocyte communication, revealing that astrocytes are targets of cannabinoids and might therefore participate in the physiology of cannabinoid-related addiction. They also reveal the existence of an endocannabinoid-glutamate signaling pathway where astrocytes serve as a bridge for nonsynaptic interneuronal communication.

  2. TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision

    Directory of Open Access Journals (Sweden)

    Daniel A. Ryskamp

    2014-09-01

    Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.

  3. Endocannabinoids in the rat basolateral amygdala enhance memory consolidation and enable glucocorticoid modulation of memory

    OpenAIRE

    Campolongo, Patrizia; Roozendaal, Benno; Trezza, Viviana; Hauer, Daniela; Schelling, Gustav; McGaugh, James L.; Cuomo, Vincenzo

    2009-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN5...

  4. Don't Worry, Be Happy: Endocannabinoids and Cannabis at the Intersection of Stress and Reward.

    Science.gov (United States)

    Volkow, Nora D; Hampson, Aidan J; Baler, Ruben D

    2017-01-06

    Cannabis enables and enhances the subjective sense of well-being by stimulating the endocannabinoid system (ECS), which plays a key role in modulating the response to stress, reward, and their interactions. However, over time, repeated activation of the ECS by cannabis can trigger neuroadaptations that may impair the sensitivity to stress and reward. This effect, in vulnerable individuals, can lead to addiction and other adverse consequences. The recent shift toward legalization of medical or recreational cannabis has renewed interest in investigating the physiological role of the ECS as well as the potential health effects, both adverse and beneficial, of cannabis. Here we review our current understanding of the ECS and its complex physiological roles. We discuss the implications of this understanding vis-á-vis the ECS's modulation of stress and reward and its relevance to mental disorders in which these processes are disrupted (i.e., addiction, depression, posttraumatic stress disorder, schizophrenia), along with the therapeutic potential of strategies to manipulate the ECS for these conditions.

  5. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

    Directory of Open Access Journals (Sweden)

    Brian C. Shonesy

    2014-12-01

    Full Text Available Summary: Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders. : The role of the primary endogenous cannabinoid 2-AG in mood and anxiety regulation is not well understood. Shonesy et al. show that deletion of a primary 2-AG synthetic enzyme, DAGLα, results in anxiety and sex-specific depressive phenotypes, which can be rapidly reversed by pharmacological normalization of endocannabinoid levels.

  6. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    International Nuclear Information System (INIS)

    Sanson, Benoît; Wang, Tao; Sun, Jing; Wang, Liqun; Kaczocha, Martin; Ojima, Iwao; Deutsch, Dale; Li, Huilin

    2014-01-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels

  7. Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

    Energy Technology Data Exchange (ETDEWEB)

    Sanson, Benoît; Wang, Tao [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Sun, Jing; Wang, Liqun; Kaczocha, Martin [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Ojima, Iwao [Stony Brook University, Stony Brook, NY 1794-3400 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Deutsch, Dale, E-mail: dale.deutsch@stonybrook.edu [Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States); Li, Huilin, E-mail: dale.deutsch@stonybrook.edu [Brookhaven National Laboratory, Upton, NY 11973-5000 (United States); Stony Brook University, Stony Brook, NY 11794-5213 (United States); Stony Brook University, Stony Brook, NY 11794-3400 (United States)

    2014-02-01

    FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5–endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.

  8. Privacy Implications of Surveillance Systems

    DEFF Research Database (Denmark)

    Thommesen, Jacob; Andersen, Henning Boje

    2009-01-01

    This paper presents a model for assessing the privacy „cost‟ of a surveillance system. Surveillance systems collect and provide personal information or observations of people by means of surveillance technologies such as databases, video or location tracking. Such systems can be designed for vari......This paper presents a model for assessing the privacy „cost‟ of a surveillance system. Surveillance systems collect and provide personal information or observations of people by means of surveillance technologies such as databases, video or location tracking. Such systems can be designed...... for various purposes, even as a service for those being observed, but in any case they will to some degree invade their privacy. The model provided here can indicate how invasive any particular system may be – and be used to compare the invasiveness of different systems. Applying a functional approach......, the model is established by first considering the social function of privacy in everyday life, which in turn lets us determine which different domains will be considered as private, and finally identify the different types of privacy invasion. This underlying model (function – domain – invasion) then serves...

  9. Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum.

    Science.gov (United States)

    Liu, Jing; Parsons, Loren; Pope, Carey

    2015-09-01

    Parathion and chlorpyrifos are organophosphorus insecticides (OPs) that elicit acute toxicity by inhibiting acetylcholinesterase (AChE). The endocannabinoids (eCBs, N-arachidonoylethanolamine, AEA; 2-arachidonoylglycerol, 2AG) are endogenous neuromodulators that regulate presynaptic neurotransmitter release in neurons throughout the central and peripheral nervous systems. While substantial information is known about the eCBs, less is known about a number of endocannabinoid-like metabolites (eCBLs, e.g., N-palmitoylethanolamine, PEA; N-oleoylethanolamine, OEA). We report the comparative effects of parathion and chlorpyrifos on AChE and enzymes responsible for inactivation of the eCBs, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and changes in the eCBs AEA and 2AG and eCBLs PEA and OEA, in rat striatum. Adult, male rats were treated with vehicle (peanut oil, 2 ml/kg, sc), parathion (27 mg/kg) or chlorpyrifos (280 mg/kg) 6-7 days after surgical implantation of microdialysis cannulae into the right striatum, followed by microdialysis two or four days later. Additional rats were similarly treated and sacrificed for evaluation of tissue levels of eCBs and eCBLs. Dialysates and tissue extracts were analyzed by LC-MS/MS. AChE and FAAH were extensively inhibited at both time-points (85-96%), while MAGL activity was significantly but lesser affected (37-62% inhibition) by parathion and chlorpyrifos. Signs of toxicity were noted only in parathion-treated rats. In general, chlorpyrifos increased eCB levels while parathion had no or lesser effects. Early changes in extracellular AEA, 2AG and PEA levels were significantly different between parathion and chlorpyrifos exposures. Differential changes in extracellular and/or tissue levels of eCBs and eCBLs could potentially influence a number of signaling pathways and contribute to selective neurological changes following acute OP intoxications. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.

    Science.gov (United States)

    Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E; Cravatt, Benjamin F; Lichtman, Aron H; Kinsey, Steven G

    2015-06-01

    Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.

  11. Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

    Science.gov (United States)

    Cedernaes, Jonathan; Fanelli, Flaminia; Fazzini, Alessia; Pagotto, Uberto; Broman, Jan-Erik; Vogel, Heike; Dickson, Suzanne L; Schiöth, Helgi B; Benedict, Christian

    2016-12-01

    Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, pexercise (+44%, pexercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (pexercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  12. Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

    Directory of Open Access Journals (Sweden)

    Lichtman Aron H

    2011-01-01

    Full Text Available Abstract Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.

  13. Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation.

    Directory of Open Access Journals (Sweden)

    András Iring

    Full Text Available Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1 receptor blockade and inhibition of cannabinoid reuptake, respectively on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H.In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v. failed to influence blood pressure (BP, cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v. induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the

  14. Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.

    Science.gov (United States)

    Smaga, Irena; Bystrowska, Beata; Gawliński, Dawid; Pomierny, Bartosz; Stankowicz, Piotr; Filip, Małgorzata

    2014-08-01

    The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.

  15. Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

    Science.gov (United States)

    Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

    2015-02-01

    A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

  16. Conflicting belief systems: some implications for education

    Directory of Open Access Journals (Sweden)

    E.J. van Niekerk

    1999-03-01

    Full Text Available In this article the conceptions of knowledge and time within Christianity, secular humanism and traditional African religion are juxtaposed. In order to emphasise the vital role o f belief systems in the field of education, some educational implications are inferred from these different conceptions of knowledge and time. The need to create enough space within the South African education system so that parents will be able to send their children to schools where education is conducted according to their particular belief systems is also foregrounded.

  17. Impact of cannabis, cannabinoids and endocannabinoids in the lungs

    Directory of Open Access Journals (Sweden)

    Caroline Turcotte

    2016-09-01

    Full Text Available Since the identification of cannabinoid receptors in the 1990s, a research field has been dedicated to exploring the role of the cannabinoid system in immunity and the inflammatory response in human tissues and animal models. Although the cannabinoid system is present and crucial in many human tissues, studying the impact of cannabinoids on the lungs is particularly relevant because of their contact with exogenous cannabinoids is the context of marijuana consumption. In the past two decades, the scientific community has gathered a large body of evidence supporting that the activation of the cannabinoid system alleviates pain and reduces inflammation. In the context of lung inflammation, exogenous and endogenous cannabinoids have shown therapeutic potential because of their inhibitory effects on immune cell recruitment and functions. On the other hand, cannabinoids were shown to be deleterious to lung function and to impact respiratory pathogen clearance. In this review, we present the existing data on the regulation of lung immunity and inflammation by phytocannabinoids, synthetic cannabinoids and endocannabinoids.

  18. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    Science.gov (United States)

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  19. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes.

    Science.gov (United States)

    Russo, Ethan B

    2016-01-01

    Medicine continues to struggle in its approaches to numerous common subjective pain syndromes that lack objective signs and remain treatment resistant. Foremost among these are migraine, fibromyalgia, and irritable bowel syndrome, disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit. The commonality in symptomatology in these conditions displaying hyperalgesia and central sensitization with possible common underlying pathophysiology suggests that a clinical endocannabinoid deficiency might characterize their origin. Its base hypothesis is that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, anandamide (arachidonylethanolamide), and 2-arachidonoylglycerol, their production, metabolism, and the relative abundance and state of cannabinoid receptors. Its theory is that in certain conditions, whether congenital or acquired, endocannabinoid tone becomes deficient and productive of pathophysiological syndromes. When first proposed in 2001 and subsequently, this theory was based on genetic overlap and comorbidity, patterns of symptomatology that could be mediated by the endocannabinoid system (ECS), and the fact that exogenous cannabinoid treatment frequently provided symptomatic benefit. However, objective proof and formal clinical trial data were lacking. Currently, however, statistically significant differences in cerebrospinal fluid anandamide levels have been documented in migraineurs, and advanced imaging studies have demonstrated ECS hypofunction in post-traumatic stress disorder. Additional studies have provided a firmer foundation for the theory, while clinical data have also produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment and adjunctive lifestyle approaches affecting the ECS.

  20. The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

    Science.gov (United States)

    Seillier, Alexandre; Giuffrida, Andrea

    2018-03-01

    Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Fetal Alcohol Spectrum Disorder: Potential Role of Endocannabinoids Signaling

    Directory of Open Access Journals (Sweden)

    Balapal S. Basavarajappa

    2015-10-01

    Full Text Available One of the unique features of prenatal alcohol exposure in humans is impaired cognitive and behavioral function resulting from damage to the central nervous system (CNS, which leads to a spectrum of impairments referred to as fetal alcohol spectrum disorder (FASD. Human FASD phenotypes can be reproduced in the rodent CNS following prenatal ethanol exposure. Several mechanisms are expected to contribute to the detrimental effects of prenatal alcohol exposure on the developing fetus, particularly in the developing CNS. These mechanisms may act simultaneously or consecutively and differ among a variety of cell types at specific developmental stages in particular brain regions. Studies have identified numerous potential mechanisms through which alcohol can act on the fetus. Among these mechanisms are increased oxidative stress, mitochondrial damage, interference with the activity of growth factors, glia cells, cell adhesion molecules, gene expression during CNS development and impaired function of signaling molecules involved in neuronal communication and circuit formation. These alcohol-induced deficits result in long-lasting abnormalities in neuronal plasticity and learning and memory and can explain many of the neurobehavioral abnormalities found in FASD. In this review, the author discusses the mechanisms that are associated with FASD and provides a current status on the endocannabinoid system in the development of FASD.

  2. Implications of inherent safe nuclear power system

    International Nuclear Information System (INIS)

    Song, Yo-Taik

    1987-01-01

    The safety of present day nuclear power reactors and research reactors depends on a combination of design features of passive and active systems, and the alert judgement of their operators. A few inherently safe designs of nuclear reactors for power plants are currently under development. In these designs, the passive systems are emphasized, and the active systems are minimized. Also efforts are made to eliminate the potential for human failures that initiate the series of accidents. If a major system fails in these designs, the core is flooded automatically with coolants that flow by gravity, not by mechanical pumps or electromagnetic actuators. Depending on the choice of the coolants--water, liquid metal and helium gas--there are three principal types of inherently safe reactors. In this paper, these inherently safe reactor designs are reviewed and their implications are discussed. Further, future perspectives of their acceptance by nuclear industries are discussed. (author)

  3. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity.

    Science.gov (United States)

    Monteleone, A M; Di Marzo, V; Monteleone, P; Dalle Grave, R; Aveta, T; Ghoch, M El; Piscitelli, F; Volpe, U; Calugi, S; Maj, M

    2016-06-01

    Hedonic eating occurs independently from homeostatic needs prompting the ingestion of pleasurable foods that are typically rich in fat, sugar and/or salt content. In normal weight healthy subjects, we found that before hedonic eating, plasma levels of 2-arachidonoylglycerol (2-AG) were higher than before nonhedonic eating, and although they progressively decreased after food ingestion in both eating conditions, they were significantly higher in hedonic eating. Plasma levels of anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), instead, progressively decreased in both eating conditions without significant differences. In this study, we investigated the responses of AEA, 2-AG, OEA and PEA to hedonic eating in obese individuals. Peripheral levels of AEA, 2-AG, OEA and PEA were measured in 14 obese patients after eating favourite (hedonic eating) and non-favourite (nonhedonic eating) foods in conditions of no homeostatic needs. Plasma levels of 2-AG increased after eating the favourite food, whereas they decreased after eating the non-favourite food, with the production of the endocannabinoid being significantly enhanced in hedonic eating. Plasma levels of AEA decreased progressively in nonhedonic eating, whereas they showed a decrease after the exposure to the favourite food followed by a return to baseline values after eating it. No significant differences emerged in plasma OEA and PEA responses to favourite and non-favourite food. Present findings compared with those obtained in our previously studied normal weight healthy subjects suggest deranged responses of endocannabinoids to food-related reward in obesity.

  4. Elevated Levels of Endocannabinoids in Chronic Hepatitis C May Modulate Cellular Immune Response and Hepatic Stellate Cell Activation

    Directory of Open Access Journals (Sweden)

    Eleonora Patsenker

    2015-03-01

    Full Text Available The endocannabinoid (EC system is implicated in many chronic liver diseases, including hepatitis C viral (HCV infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC, however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA and 2-arachidonoyl glycerol (2-AG were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH and monoaclyglycerol lipase (MAGL activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC, ECs inhibited IFN-γ, TNF-α, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects.

  5. Endocannabinoids and Endovanilloids: A Possible Balance in the Regulation of the Testicular GnRH Signalling

    Directory of Open Access Journals (Sweden)

    Rosanna Chianese

    2013-01-01

    Full Text Available Reproductive functions are regulated both at central (brain and gonadal levels. In this respect, the endocannabinoid system (eCS has a very influential role. Interestingly, the characterization of eCS has taken many advantages from the usage of animal models different from mammals. Therefore, this review is oriented to summarize the main pieces of evidence regarding eCS coming from the anuran amphibian Rana esculenta, with particular interest to the morphofunctional relationship between eCS and gonadotropin releasing hormone (GnRH. Furthermore, a novel role for endovanilloids in the regulation of a testicular GnRH system will be also discussed.

  6. Peripheral Endocannabinoid Responses to Hedonic Eating in Binge-Eating Disorder

    Directory of Open Access Journals (Sweden)

    Alessio Maria Monteleone

    2017-12-01

    Full Text Available Reward mechanisms are likely implicated in the pathophysiology of binge-eating behaviour, which is a key symptom of binge-eating disorder (BED. Since endocannabinoids modulate food-related reward, we aimed to investigate the responses of anandamide (AEA and 2-arachidonoylglycerol (2-AG to hedonic eating in patients with BED. Peripheral levels of AEA and 2-AG were measured in 7 obese BED patients before and after eating favorite (hedonic eating and non-favorite (non-hedonic eating foods. We found that plasma levels of AEA progressively decreased after eating the non-favorite food and significantly increased after eating the favorite food, whereas plasma levels of 2-AG did not differ significantly between the two test conditions, although they showed a trend toward significantly different time patterns. The changes in peripheral AEA levels were positively correlated to the subjects’ sensations of the urge to eat and the pleasantness while eating the presented food, while changes in peripheral 2-AG levels were positively correlated to the subjects’ sensation of the pleasantness while eating the presented food and to the amount of food they would eat. These results suggest the occurrence of distinctive responses of endocannabinoids to food-related reward in BED. The relevance of such findings to the pathophysiology of BED remains to be elucidated.

  7. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Frost, M; Nielsen, T L; Wraae, K

    2010-01-01

    Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1...... receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution....

  8. Big Data: Implications for Health System Pharmacy.

    Science.gov (United States)

    Stokes, Laura B; Rogers, Joseph W; Hertig, John B; Weber, Robert J

    2016-07-01

    Big Data refers to datasets that are so large and complex that traditional methods and hardware for collecting, sharing, and analyzing them are not possible. Big Data that is accurate leads to more confident decision making, improved operational efficiency, and reduced costs. The rapid growth of health care information results in Big Data around health services, treatments, and outcomes, and Big Data can be used to analyze the benefit of health system pharmacy services. The goal of this article is to provide a perspective on how Big Data can be applied to health system pharmacy. It will define Big Data, describe the impact of Big Data on population health, review specific implications of Big Data in health system pharmacy, and describe an approach for pharmacy leaders to effectively use Big Data. A few strategies involved in managing Big Data in health system pharmacy include identifying potential opportunities for Big Data, prioritizing those opportunities, protecting privacy concerns, promoting data transparency, and communicating outcomes. As health care information expands in its content and becomes more integrated, Big Data can enhance the development of patient-centered pharmacy services.

  9. Altering endocannabinoid neurotransmission at critical developmental ages: impact on rodent emotionality and cognitive performance

    Directory of Open Access Journals (Sweden)

    Viviana eTrezza

    2012-01-01

    Full Text Available The endocannabinoid system shows functional activity from early stages of brain development: it plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation, thus shaping brain organization during pre- and postnatal life. Cannabis sativa preparations are among the illicit drugs most commonly used by young people, including pregnant women. The developing brain can be therefore exposed to cannabis preparations during two critical periods: first, in offspring of cannabis-using mothers through perinatal and/or prenatal exposure; second, in adolescent cannabis users during neural maturation. In the last decade, it has become clear that the endocannabinoid system critically modulates memory processing and emotional responses. Therefore, it is well possible that developmental exposure to cannabinoid compounds induces enduring changes in behaviors and neural processes belonging to the cognitive and emotional domains. We address this issue by focusing on rodent studies, in order to provide a framework for understanding the impact of cannabinoid exposure on the developing brain.

  10. FEMALE MICE ARE RESISTANT TO Fabp1 GENE ABLATION-INDUCED ALTERATIONS IN BRAIN ENDOCANNABINOID LEVELS

    Science.gov (United States)

    Martin, Gregory G.; Chung, Sarah; Landrock, Danilo; Landrock, Kerstin K.; Dangott, Lawrence J.; Peng, Xiaoxue; Kaczocha, Martin; Murphy, Eric J.; Kier, Ann B.; Schroeder, Friedhelm

    2017-01-01

    Although liver fatty acid binding protein (FABP1, L-FABP) is not detectable in brain, Fabp1 gene ablation (LKO) markedly increases endocannabinoids (EC) in brains of male mice. Since the brain EC system of females differs significantly from that of males, it was important to determine if LKO differently impacted the brain EC system. LKO did not alter brain levels of arachidonic acid (ARA)-containing ECs, i.e arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), but decreased non-ARA-containing N-acylethanolamides (OEA, PEA) and 2-oleoylglycerol (2-OG) that potentiate the actions of AEA and 2-AG. These changes in brain potentiating EC levels were not associated with: i) a net decrease in levels of brain membrane proteins associated with fatty acid uptake and EC synthesis; ii) a net increase in brain protein levels of cytosolic EC chaperones and enzymes in EC degradation; or iii) increased brain protein levels of EC receptors (CB1, TRVP1). Instead, the reduced or opposite responsiveness of female brain EC levels to loss of FABP1 (LKO) correlated with intrinsically lower FABP1 level in livers of WT females than males. These data show that female mouse brain endocannabinoid levels were unchanged (AEA, 2-AG) or decreased (OEA, PEA, 2-OG) by complete loss of FABP1 (LKO). PMID:27450559

  11. Education System Reform in China after 1978: Some Practical Implications

    Science.gov (United States)

    Sun, Miantao

    2010-01-01

    Purpose: This paper aims to provide an overview of education system reform in China since 1978, and its practical implications. Design/methodology/approach: Data were collected from literature review and interview. An overview of education system reform and its practical implications was found through data analysis. Findings: There has been two…

  12. The endocannabinoid anandamide inhibits potassium conductance in rat cortical astrocytes

    Czech Academy of Sciences Publication Activity Database

    Vignali, M.; Benfenati, V.; Caprini, M.; Anděrová, Miroslava; Nobile, M.; Ferroni, S.

    2009-01-01

    Roč. 57, č. 7 (2009), s. 791-806 ISSN 0894-1491 R&D Projects: GA ČR GA305/06/1316; GA ČR GA305/06/1464; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : cortical astroglia * potassium conductance * endocannabinoids Subject RIV: FH - Neurology Impact factor: 4.932, year: 2009

  13. “Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

    Science.gov (United States)

    2012-01-01

    Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203

  14. A Preliminary Model for the Protective Role of the Endocannabinoid 2-Arachydonylglycerol in Neuroinflammation

    Science.gov (United States)

    2015-09-30

    Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy . J Pharmacol Exp Ther, 307:129-137. Zhang M, Chen C. 2008. Endocannabinoid 2... Disorders . Brain Res Rev, 52(2):201-43. Pope C, Mechoulam R, Parsons L. 2010. Endocannabinoid Signaling in Neurotoxicity and Neuroprotection

  15. Circulating endocannabinoids during hematopoietic stem cell transplantation: A pilot study

    Directory of Open Access Journals (Sweden)

    Jennifer M. Knight

    2015-01-01

    Conclusions: The eCB signaling system may have alternative sources and regulatory mechanisms in addition to the immune system. Given the significant associations with inflammatory molecules and depressive symptoms in the peri-transplant period, it is important to better understand this system and its potential implications in the setting of complex and stressful medical procedures such as HCT.

  16. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

    DEFF Research Database (Denmark)

    Nielsen, Morten Frost; Nielsen, T L; Wraae, K

    2010-01-01

    OBJECTIVE: Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants...... of the CB1 receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution. DESIGN AND METHODS: The single nucleotide polymorphisms (SNPs) rs806381, rs......10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20-29 years. RESULTS: The rs806381 polymorphism was significantly associated...

  17. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol.

    Science.gov (United States)

    Hanlon, Erin C; Tasali, Esra; Leproult, Rachel; Stuhr, Kara L; Doncheck, Elizabeth; de Wit, Harriet; Hillard, Cecilia J; Van Cauter, Eve

    2016-03-01

    Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. A commentary on this article appears in this issue on page 495. © 2016 Associated Professional Sleep Societies, LLC.

  18. Coherence of Radial Implicative Fuzzy Systems with Nominal Consequents

    Czech Academy of Sciences Publication Activity Database

    Coufal, David

    -, č. 4 (2006), s. 60-66 ISSN 1509-4553 R&D Projects: GA MŠk 1M0545 Institutional research plan: CEZ:AV0Z10300504 Keywords : implicative fuzzy system * radial fuzzy system * nominal output space * coherence Subject RIV: IN - Informatics, Computer Science

  19. Public perceptions of energy system risks: some policy implications

    International Nuclear Information System (INIS)

    Thomas, K.; Otway, H.J.

    1980-01-01

    The subject is discussed under the headings: introduction; perceptions, beliefs and attitudes; the survey of public perceptions and attitudes towards energy systems; attitudes towards the five energy systems (nuclear, coal, oil, solar and hydro); perceptions of energy systems - the underlying dimensions of belief (economic benefits; environmental risk; psychological and physical risk; indirect risk; technology development); differential analysis of the perceptions of those pro and con nuclear energy; summary of perceptions of energy systems - relevance to the Austrian dilemma; policy implications. (U.K.)

  20. Restricted vs. unrestricted wheel running in mice: Effects on brain, behavior and endocannabinoids.

    Science.gov (United States)

    Biedermann, Sarah V; Auer, Matthias K; Bindila, Laura; Ende, Gabriele; Lutz, Beat; Weber-Fahr, Wolfgang; Gass, Peter; Fuss, Johannes

    2016-11-01

    Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1 H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.

    Directory of Open Access Journals (Sweden)

    Randall G Krug

    Full Text Available The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld, enzymes that degrade (faah, faah2a, faah2b, and receptors that bind (cnr1, cnr2, gpr55-like endocannabinoids are expressed in zebrafish (Danio rerio. These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.

  2. Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

    Science.gov (United States)

    Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

    2017-07-01

    The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Marijuana, the Endocannabinoid System and the Female Reproductive System

    OpenAIRE

    Brents, Lisa K.

    2016-01-01

    Marijuana use among women is highly prevalent, but the societal conversation on marijuana rarely focuses on how marijuana affects female reproduction and endocrinology. This article reviews the current scientific literature regarding marijuana use and hypothalamic-pituitary-ovarian (HPO) axis regulation, ovarian hormone production, the menstrual cycle, and fertility. Evidence suggests that marijuana can reduce female fertility by disrupting hypothalamic release of gonadotropin releasing hormo...

  4. Song-associated reward correlates with endocannabinoid-related gene expression in male European starlings (Sturnus vulgaris).

    Science.gov (United States)

    Hahn, Allison H; Merullo, Devin P; Spool, Jeremy A; Angyal, Caroline S; Stevenson, Sharon A; Riters, Lauren V

    2017-03-27

    Vocal communication is required for successful social interactions in numerous species. During the breeding season, songbirds produce songs that are reinforced by behavioral consequences (e.g., copulation). However, some songbirds also produce songs not obviously directed at other individuals. The consequences maintaining or reinforcing these songs are less obvious and the neural mechanisms associated with undirected communication are not well-understood. Previous studies indicate that undirected singing is intrinsically rewarding and mediated by opioid or dopaminergic systems; however, endocannabinoids are also involved in regulating reward and singing behavior. We used a conditioned place preference paradigm to examine song-associated reward in European starlings and quantitative real-time PCR to measure expression of endocannabinoid-related neural markers (CB 1 , FABP7, FABP5, FAAH, DAGLα), in brain regions involved in social behavior, reward and motivation (ventral tegmental area [VTA], periaqueductal gray [PAG], and medial preoptic nucleus [POM]), and a song control region (Area X). Our results indicate that starlings producing high rates of song developed a conditioned place preference, suggesting that undirected song is associated with a positive affective state. We found a significant positive relationship between song-associated reward and CB 1 receptors in VTA and a significant negative relationship between song-associated reward and CB 1 in PAG. There was a significant positive relationship between reward and the cannabinoid transporter FABP7 in POM and a significant negative relationship between reward and FABP7 in PAG. In Area X, FABP5 and DAGLα correlated positively with singing. These results suggest a role for endocannabinoid signaling in vocal production and reward associated with undirected communication. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Emancipatory Indigenous Knowledge Systems: implications for ...

    African Journals Online (AJOL)

    Erna Kinsey

    Faculty of Education, University of South Africa, P.O. Box 392, Unisa, 0003 South Africa ... Indigenous Knowledge also termed Traditional, Endogenous or Classical .... its civilisation, carries both its indigenous and modern knowledge systems.

  6. Space reflector technology and its system implications

    Science.gov (United States)

    Billman, K. W.; Gilbreath, W. P.; Bowen, S. W.

    1979-01-01

    The technical feasibility of providing nearly continuous solar energy to a world-distributed set of conversion sites by means of a system of orbiting, large-area, low-areal-density reflecting structures is examined. Requisite mirror area to provide a chosen, year-averaged site intensity is shown. A modeled reflector structure, with suitable planarity and ability to meet operational torques and loads, is discussed. Typical spatial and temporal insolation profiles are presented. These determine the sizing of components and the output electric power from a baselined photovoltaic conversion system. Technical and economic challenges which, if met, would allow the system to provide a large fraction of future world energy needs at costs competitive to circa-1995 fossil and nuclear sources are discussed.

  7. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa.

    Science.gov (United States)

    Monteleone, Palmiero; Matias, Isabelle; Martiadis, Vassilis; De Petrocellis, Luciano; Maj, Mario; Di Marzo, Vincenzo

    2005-06-01

    The endocannabinoid system, consisting of two cannabinoid receptors (CB1 and CB2) and the endogenous ligands anandamide (arachidonoylethanolamide (AEA)) and 2-arachidonoylglycerol (2-AG), has been shown to control food intake in both animals and humans, modulating either rewarding or quantitative aspects of the eating behavior. Moreover, hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis. Therefore, alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders, where a deranged leptin signalling has been also reported. In order to verify this hypothesis, we measured plasma levels of AEA, 2-AG, and leptin in 15 women with anorexia nervosa (AN), 12 women with bulimia nervosa (BN), 11 women with binge-eating disorder (BED), and 15 healthy women. Plasma levels of AEA resulted significantly enhanced in both anorexic and BED women, but not in bulimic patients. No significant change occurred in the plasma levels of 2-AG in all the patients' groups. Moreover, circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women. These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED. Although the pathophysiological significance of this alteration awaits further studies to be clarified, it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED.

  8. Adult sex ratio variation : Implications for breeding system evolution

    NARCIS (Netherlands)

    Szekely, T.; Weissing, F. J.; Komdeur, J.

    Adult sex ratio (ASR) exhibits immense variation in nature, although neither the causes nor the implications of this variation are fully understood. According to theory, the ASR is expected to influence sex roles and breeding systems, as the rarer sex in the population has more potential partners to

  9. Human Nature and its Implications for the Legal System | Obioha ...

    African Journals Online (AJOL)

    This paper examines the implications the various conceptions of human nature hold for the legal system. No doubt, there are various and conflicting theories of human nature such that the concept of human nature seems to have remained elusive and pervasive. Some conceive man as nothing but matter pure and simple; ...

  10. Impaired fear memory specificity associated with deficient endocannabinoid-dependent long-term plasticity.

    Science.gov (United States)

    Lovelace, Jonathan W; Vieira, Philip A; Corches, Alex; Mackie, Ken; Korzus, Edward

    2014-06-01

    In addition to its central role in learning and memory, N-methyl D-aspartate receptor (NMDAR)-dependent signaling regulates central glutamatergic synapse maturation and has been implicated in schizophrenia. We have transiently induced NMDAR hypofunction in infant mice during postnatal days 7-11, followed by testing fear memory specificity and presynaptic plasticity in the prefrontal cortex (PFC) in adult mice. We show that transient NMDAR hypofunction during early brain development, coinciding with the maturation of cortical plasticity results in a loss of an endocannabinoid (eCB)-mediated form of long-term depression (eCB-LTD) at adult central glutamatergic synapses, while another form of presynaptic long-term depression mediated by the metabotropic glutamate receptor 2/3 (mGluR2/3-LTD) remains intact. Mice with this selective impairment of presynaptic plasticity also showed deficits in fear memory specificity. The observed deficit in cortical presynaptic plasticity may represent a neural maladaptation contributing to network instability and abnormal cognitive functioning.

  11. Potential role of the endocannabinoid receptor antagonist rimonabant in the management of cardiometabolic risk: a narrative review of available data

    Directory of Open Access Journals (Sweden)

    Kirk A Bronander

    2007-05-01

    Full Text Available Kirk A Bronander1, Michael J Bloch21Division of General Internal Medicine, 2Divisions of Cardiology and General Internal Medicine, Department of Medicine, University of Nevada School of Medicine, Reno, NV, USAAbstract: The endocannabinoid system (ECS is an endogenous physiological system composed of two cannabinoid receptors and several endogenous ligands. The ECS is intimately involved in appetite regulation and energy homeostasis, which makes it an intriguing target for pharmacological treatment of obesity, diabetes, and the metabolic syndrome. Rimonabant is the first cannabinoid receptor (CB-1 antagonist being studied and utilized to treat obesity (it is approved in Europe but is currently under review in the United States. Large randomized trials with rimonabant have demonstrated efficacy in treatment of overweight and obese individuals with weight loss significantly greater than a reduced calorie diet alone. In addition, multiple other cardiometabolic parameters were improved in the treatment groups including increased levels of high density lipoprotein cholesterol, reduced triglycerides, reduced waist circumference, improved insulin sensitivity, decreased insulin levels, and in diabetic patients improvement in glycosylated hemoglobin percentage. There was an increase in the adverse effects of depression, anxiety, irritability, and nausea in rimonabant-treated groups. This novel medication may become an important therapeutic option in the fight to reduce cardiovascular disease worldwide through its unique action on cardiometabolic risk.Keywords: rimonabant, endocannabinoid, metabolic syndrome, obesity

  12. Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

    Directory of Open Access Journals (Sweden)

    Mauro Maccarrone

    2017-05-01

    Full Text Available Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB” was identified as N-arachidonoylethanolamine (or anandamide (AEA, and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.

  13. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study.

    Directory of Open Access Journals (Sweden)

    Jakub Fichna

    Full Text Available AIMS: Irritable bowel syndrome (IBS is a functional gastrointestinal (GI disorder, associated with alterations of bowel function, abdominal pain and other symptoms related to the GI tract. Recently the endogenous cannabinoid system (ECS was shown to be involved in the physiological and pathophysiological control of the GI function. The aim of this pilot study was to investigate whether IBS defining symptoms correlate with changes in endocannabinoids or cannabinoid like fatty acid levels in IBS patients. METHODS: AEA, 2-AG, OEA and PEA plasma levels were determined in diarrhoea-predominant (IBS-D and constipation-predominant (IBS-C patients and were compared to healthy subjects, following the establishment of correlations between biolipid contents and disease symptoms. FAAH mRNA levels were evaluated in colonic biopsies from IBS-D and IBS-C patients and matched controls. RESULTS: Patients with IBS-D had higher levels of 2AG and lower levels of OEA and PEA. In contrast, patients with IBS-C had higher levels of OEA. Multivariate analysis found that lower PEA levels are associated with cramping abdominal pain. FAAH mRNA levels were lower in patients with IBS-C. CONCLUSION: IBS subtypes and their symptoms show distinct alterations of endocannabinoid and endocannabinoid-like fatty acid levels. These changes may partially result from reduced FAAH expression. The here reported changes support the notion that the ECS is involved in the pathophysiology of IBS and the development of IBS symptoms.

  14. Atmospheric environmental implications of propulsion systems

    Science.gov (United States)

    Mcdonald, Allan J.; Bennett, Robert R.

    1995-01-01

    Three independent studies have been conducted for assessing the impact of rocket launches on the earth's environment. These studies have addressed issues of acid rain in the troposphere, ozone depletion in the stratosphere, toxicity of chemical rocket exhaust products, and the potential impact on global warming from carbon dioxide emissions from rocket launches. Local, regional, and global impact assessments were examined and compared with both natural sources and anthropogenic sources of known atmospheric pollutants with the following conclusions: (1) Neither solid nor liquid rocket launches have a significant impact on the earth's global environment, and there is no real significant difference between the two. (2) Regional and local atmospheric impacts are more significant than global impacts, but quickly return to normal background conditions within a few hours after launch. And (3) vastly increased space launch activities equivalent to 50 U.S. Space Shuttles or 50 Russian Energia launches per year would not significantly impact these conclusions. However, these assessments, for the most part, are based upon homogeneous gas phase chemistry analysis; heterogeneous chemistry from exhaust particulates, such as aluminum oxide, ice contrails, soot, etc., and the influence of plume temperature and afterburning of fuel-rich exhaust products, need to be further addressed. It was the consensus of these studies that computer modeling of interactive plume chemistry with the atmosphere needs to be improved and computer models need to be verified with experimental data. Rocket exhaust plume chemistry can be modified with propellant reformulation and changes in operating conditions, but, based upon the current state of knowledge, it does not appear that significant environmental improvements from propellant formulation changes can be made or are warranted. Flight safety, reliability, and cost improvements are paramount for any new rocket system, and these important aspects

  15. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

    Directory of Open Access Journals (Sweden)

    África eFlores

    2013-12-01

    Full Text Available Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signalling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighbouring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describe its potential therapeutic implications.

  16. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far.

    Science.gov (United States)

    Flores, Africa; Maldonado, Rafael; Berrendero, Fernando

    2013-12-20

    Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications.

  17. Energy and environmental implications of novel protein production systems

    Energy Technology Data Exchange (ETDEWEB)

    Edwardson, W; Lewis, C W; Slesser, M

    1981-04-01

    The energy requirements of many novel protein production systems are compared with an examination of the relevant environmental implications of these systems. The prospects for single cell protein, leaf protein, fish farming, fish protein concentrate, algal cultivation, and hydroponic plant growth systems are investigated. Single cell protein from carbohydrate substrates, algal protein, and fish protein seem to hold much promise, as they are technologically feasible for near-term implementation and do not require major energy inputs. (2 diagrams, 1 graph, 47 references, 6 tables)

  18. Practical implications of incentive systems are utilized by dental franchises.

    Science.gov (United States)

    Yavner, S B

    1989-01-01

    The success of any dental practice depends, among other factors, on the critical role of staff employees. In order to encourage desired staff behaviors, incentive systems can be designed for employee dentists, assistants/hygienists and managers. A survey of dental franchises was conducted in 1987 for the purpose of examining their incentive control systems. The specific incentives employed by these dental franchises for their employees are analyzed. The implications of these incentive systems used by dental franchise organizations for all dental practices are then discussed.

  19. Linear systems solvers - recent developments and implications for lattice computations

    International Nuclear Information System (INIS)

    Frommer, A.

    1996-01-01

    We review the numerical analysis' understanding of Krylov subspace methods for solving (non-hermitian) systems of equations and discuss its implications for lattice gauge theory computations using the example of the Wilson fermion matrix. Our thesis is that mature methods like QMR, BiCGStab or restarted GMRES are close to optimal for the Wilson fermion matrix. Consequently, preconditioning appears to be the crucial issue for further improvements. (orig.)

  20. Endocannabinoid and Mood Responses to Exercise in Adults with Varying Activity Levels.

    Science.gov (United States)

    Brellenthin, Angelique G; Crombie, Kevin M; Hillard, Cecilia J; Koltyn, Kelli F

    2017-08-01

    Acute aerobic exercise improves mood and activates the endocannabinoid (eCB) system in physically active individuals; however, both mood and eCB responses to exercise may vary based on habitual levels of physical activity. This study aimed to examine eCB and mood responses to prescribed and preferred exercises among individuals with low, moderate, and high levels of physical activity. Thirty-six healthy adults (21 ± 4 yr) were recruited from low (≤60 min moderate-vigorous physical activity [MVPA] per week), moderate (150-299 min MVPA per week), and high (≥300 MVPA per week) physical activity groups. Participants performed both prescribed (approximately 70%-75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions. Both preferred and prescribed exercise resulted in significant increases (P exercise elicited positive mood improvements compared with preexercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (P mood disturbance in the preferred condition (P mood or eCB outcomes. These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.

  1. The Greek Education System and Implications for the Turkish Education System

    Science.gov (United States)

    Karabulut, Nuriye

    2018-01-01

    The purpose of the current study is to make a detailed introduction to the Greek education system and to compare it with the Turkish education system to come up with some implications for the latter. To this end, the literature was reviewed. A general introduction was made to Greece and its education system was examined considering its goals,…

  2. Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum.

    Science.gov (United States)

    Oleson, Erik B; Beckert, Michael V; Morra, Joshua T; Lansink, Carien S; Cachope, Roger; Abdullah, Rehab A; Loriaux, Amy L; Schetters, Dustin; Pattij, Tommy; Roitman, Mitchell F; Lichtman, Aron H; Cheer, Joseph F

    2012-01-26

    Transient increases in nucleus accumbens (NAc) dopamine concentration are observed when animals are presented with motivationally salient stimuli and are theorized to energize reward seeking. They arise from high-frequency firing of dopamine neurons in the ventral tegmental area (VTA), which also results in the release of endocannabinoids from dopamine cell bodies. In this context, endocannabinoids are thought to regulate reward seeking by modulating dopamine signaling, although a direct link has never been demonstrated. To test this, we pharmacologically manipulated endocannabinoid neurotransmission in the VTA while measuring transient changes in dopamine concentration in the NAc during reward seeking. Disrupting endocannabinoid signaling dramatically reduced, whereas augmenting levels of the endocannabinoid 2-arachidonoylglycerol (2AG) increased, cue-evoked dopamine concentrations and reward seeking. These data suggest that 2AG in the VTA regulates reward seeking by sculpting ethologically relevant patterns of dopamine release during reward-directed behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. State-dependent, bidirectional modulation of neural network activity by endocannabinoids.

    Science.gov (United States)

    Piet, Richard; Garenne, André; Farrugia, Fanny; Le Masson, Gwendal; Marsicano, Giovanni; Chavis, Pascale; Manzoni, Olivier J

    2011-11-16

    The endocannabinoid (eCB) system and the cannabinoid CB1 receptor (CB1R) play key roles in the modulation of brain functions. Although actions of eCBs and CB1Rs are well described at the synaptic level, little is known of their modulation of neural activity at the network level. Using microelectrode arrays, we have examined the role of CB1R activation in the modulation of the electrical activity of rat and mice cortical neural networks in vitro. We find that exogenous activation of CB1Rs expressed on glutamatergic neurons decreases the spontaneous activity of cortical neural networks. Moreover, we observe that the net effect of the CB1R antagonist AM251 inversely correlates with the initial level of activity in the network: blocking CB1Rs increases network activity when basal network activity is low, whereas it depresses spontaneous activity when its initial level is high. Our results reveal a complex role of CB1Rs in shaping spontaneous network activity, and suggest that the outcome of endogenous neuromodulation on network function might be state dependent.

  4. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

    Science.gov (United States)

    Dawson, Alison J; Kilpatrick, Eric S; Coady, Anne-Marie; Elshewehy, Abeer M M; Dakroury, Youssra; Ahmed, Lina; Atkin, Stephen L; Sathyapalan, Thozhukat

    2017-07-14

    Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p weight. There was a significant reduction of weight with orlistat (p weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

  5. Endocannabinoids: Multi-scaled, Global Homeostatic Regulators of Cells and Society

    Science.gov (United States)

    Melamede, Robert

    Living systems are far from equilibrium open systems that exhibit many scales of emergent behavior. They may be abstractly viewed as a complex weave of dissipative structures that maintain organization by passing electrons from reduced hydrocarbons to oxygen. Free radicals are unavoidable byproducts of biological electron flow. Due to their highly reactive chemical properties, free radicals modify all classes of biological molecules (carbohydrates, lipids, nucleic acids, and proteins). As a result, free radicals are destructive. The generally disruptive nature of free radicals makes them the "friction of life." As such, they are believed to be the etiological agents behind age related illnesses such as cardiovascular, immunological, and neurological diseases, cancer, and ageing itself. Free radicals also play a critical constructive role in living systems. From a thermodynamic perspective, life can only exist if a living system takes in sufficient negative entropy from its environment to overcome the obligatory increase in entropy that would result if the system could not appropriately exchange mass, energy and information with its environment. Free radicals are generated in response to perturbations in the relationship between a living system and its environment. However, evolution has selected for biological response systems to free radicals so that the cellular biochemistry can adapt to environmental perturbations by modifying cellular gene expression and biochemistry. Endocannabinoids are marijuana-like compounds that have their origins hundreds of millions of years in the evolutionary past. They serve as fundamental modulators of energy homeostasis in all vertebrates. Their widespread biological activities may often be attributed to their ability to minimize the negative consequences of free radicals.

  6. Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST

    DEFF Research Database (Denmark)

    Karlsson, Rose-Marie; Adermark, Louise; Molander, Anna

    2012-01-01

    mice with a deletion of GLAST to test this prediction. WT and GLAST KO mice were tested for alcohol consumption using two-bottle free-choice drinking. Alcohol reward was evaluated using conditioned place preference (CPP). Sensitivity to depressant alcohol effects was tested using the accelerating...... rotarod, alcohol-induced hypothermia, and loss of righting reflex. Extracellular glutamate was measured using microdialysis, and striatal slice electrophysiology was carried out to examine plasticity of the cortico-striatal pathway as a model system in which adaptations to the constitutive GLAST deletion...... deletion of GLAST unexpectedly results in markedly reduced alcohol consumption and preference, associated with markedly reduced alcohol reward. Endocannabinoid signaling appears to be down-regulated upstream of the CB1 receptor as a result of the GLAST deletion, and is a candidate mechanism behind...

  7. Military Health System Transformation Implications on Health Information Technology Modernization.

    Science.gov (United States)

    Khan, Saad

    2018-03-01

    With the recent passage of the National Defense Authorization Act for Fiscal Year 2017, Congress has triggered groundbreaking Military Health System organizational restructuring with the Defense Health Agency assuming responsibility for managing all hospitals and clinics owned by the Army, Navy, and Air Force. This is a major shift toward a modern value-based managed care system, which will require much greater military-civilian health care delivery integration to be in place by October 2018. Just before the National Defense Authorization Act for Fiscal Year 2017 passage, the Department of Defense had already begun a seismic shift and awarded a contract for the new Military Health System-wide electronic health record system. In this perspective, we discuss the implications of the intersection of two large-scope and large-scale initiatives, health system transformation, and information technology modernization, being rolled out in the largest and most complex federal agency and potential risk mitigating steps. The Military Health System will require an expanded unified clinical leadership to spearhead short-term transformation; furthermore, developing, organizing, and growing a cadre of informatics expertise to expand the use and diffusion of novel solutions such as health information exchanges, data analytics, and others to transcend organizational barriers are still needed to achieve the long-term aim of health system reform as envisioned by the National Defense Authorization Act for Fiscal Year 2017.

  8. Implications of Automotive and Trucking On-Board Information Systems for General Aviation Cockpit Weather Systems

    Science.gov (United States)

    Sireli, Yesim; Kauffmann, Paul; Gupta, Surabhi; Kachroo, Pushkin

    2002-01-01

    In this study, current characteristics and future developments of Intelligent Transportation Systems (ITS) in the automobile and trucking industry are investigated to identify the possible implications of such systems for General Aviation (GA) cockpit weather systems. First, ITS are explained based on tracing their historical development in various countries. Then, current systems and the enabling communication technologies are discussed. Finally, a market analysis for GA is included.

  9. Support mechanisms and risk: Implications on the Nordic electricity system

    DEFF Research Database (Denmark)

    Kitzing, Lena; Ravn, Hans

    2013-01-01

    a stochastic analysis for the Nordic electricity system by conducting simulations with the energy system model Balmorel and by applying the mean-standard deviation approach of modern portfolio theory to quantify risk implications of policy instruments for an exemplary offshore wind park. The analysis reveals......Investments in renewable energy projects, such as offshore wind parks, are very much dependent on financial support. The type of policy instrument chosen for such support determines investors' exposure to market risk, and thus influences which rate of return they expect to achieve. We make...... that the two support policy schemes Feed-in Tariffs and Feed-in Premiums provide different risk-return relationships. In the investigated case, a Feed-in Premium scheme would require a 13% higher support level, because of a 6% higher exposure of investors to market risk. Our findings can help when designing...

  10. Environmental Implications of Eco-Labeling for Rice Farming Systems

    Directory of Open Access Journals (Sweden)

    Solhee Kim

    2018-04-01

    Full Text Available Concerns about climate change have forced countries to strengthen regulations, standards, and certifications related to greenhouse gas emissions. Various policies targeting farm products, such as carbon labeling and the Environmentally-Friendly Agricultural Product Certification (EFAPC for agricultural products, have been implemented in South Korea to reduce greenhouse gas emissions in the agricultural sector. The purpose of this study was to evaluate the implications of the various certification systems for rice farming, including organic farming, non-pesticide farming, and low-pesticide farming. For this study, we constructed a life cycle inventory (LCI of rice farming systems including conventional, low-pesticide, non-pesticide, and organic farming systems in South Korea. Finally, we compared international farming systems in South Korea, the U.S., and the EU. The rice farming systems with eco-labeling certifications have reduced the environmental impacts. The environmental impacts of rice farming by country were highest in the U.S. (100.0, followed by the EU (53.7, and Korea’s conventional (48.6, low-pesticide (35.8, non-pesticide (28.9, and organic (16.7 farming practices. These results may be useful in proliferating and improving the methodology to evaluate eco-labeling and carbon labeling systems.

  11. Adverse social experiences in adolescent rats result in enduring effects on social competence, pain sensitivity and endocannabinoid signaling

    Directory of Open Access Journals (Sweden)

    Peggy Schneider

    2016-10-01

    Full Text Available Social affiliation is essential for many species and gains significant importance during adolescence. Disturbances in social affiliation, in particular social rejection experiences during adolescence, affect an individual’s well-being and are involved in the emergence of psychiatric disorders. The underlying mechanisms are still unknown, partly because of a lack of valid animal models. By using a novel animal model for social peer-rejection, which compromises adolescent rats in their ability to appropriately engage in playful activities, here we report on persistent impairments in social behavior and dysregulations in the endocannabinoid system. From postnatal day (pd 21 to pd 50 adolescent female Wistar rats were either reared with same-strain partners (control or within a group of Fischer 344 rats (inadequate social rearing, ISR, previously shown to serve as inadequate play partners for the Wistar strain. Adult ISR animals showed pronounced deficits in social interaction, social memory, processing of socially transmitted information, and decreased pain sensitivity. Molecular analysis revealed increased CB1 receptor protein levels and CP55,940 stimulated 35SGTPγS binding activity specifically in the amygdala and thalamus in previously peer-rejected rats. Along with these changes, increased levels of the endocannabinoid anandamide and a corresponding decrease of its degrading enzyme fatty acid amide hydrolase were seen in the amygdala. Our data indicate lasting consequences in social behavior and pain sensitivity following peer-rejection in adolescent female rats. These behavioral impairments are accompanied by persistent alterations in CB1 receptor signaling. Finally, we provide a novel translational approach to characterize neurobiological processes underlying social peer-rejection in adolescence.

  12. Distinct roles of the endocannabinoids anandamide and 2-arachidonoylglycerol in social behavior and emotionality at different developmental ages in rats.

    Science.gov (United States)

    Manduca, Antonia; Morena, Maria; Campolongo, Patrizia; Servadio, Michela; Palmery, Maura; Trabace, Luigia; Hill, Matthew N; Vanderschuren, Louk J M J; Cuomo, Vincenzo; Trezza, Viviana

    2015-08-01

    To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  13. Adult sex ratio variation: implications for breeding system evolution.

    Science.gov (United States)

    Székely, T; Weissing, F J; Komdeur, J

    2014-08-01

    Adult sex ratio (ASR) exhibits immense variation in nature, although neither the causes nor the implications of this variation are fully understood. According to theory, the ASR is expected to influence sex roles and breeding systems, as the rarer sex in the population has more potential partners to mate with than the more common sex. Changes in mate choice, mating systems and parental care suggest that the ASR does influence breeding behaviour, although there is a need for more tests, especially experimental ones. In the context of breeding system evolution, the focus is currently on operational sex ratios (OSRs). We argue that the ASR plays a role of similar importance and urge researchers to study the ASR and the OSR side by side. Finally, we plead for a dynamic view of breeding system evolution with feedbacks between mating, parenting, OSR and ASR on both ecological and evolutionary time scales. © 2014 The Authors. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

  14. Clearance systems in the brain—implications for Alzheimer disease

    Science.gov (United States)

    Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J.

    2015-01-01

    Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ. PMID:26195256

  15. Clearance systems in the brain-implications for Alzheimer disease.

    Science.gov (United States)

    Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J

    2015-08-01

    Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

  16. Endocannabinoid receptor 1 gene variations increase risk for obesity and modulate body mass index in European populations

    DEFF Research Database (Denmark)

    Benzinou, Michael; Chèvre, Jean-Claude; Ward, Kirsten J

    2008-01-01

    The therapeutic effects of cannabinoid receptor blockade on obesity-associated phenotypes underline the importance of the endocannabinoid pathway on the energy balance. Using a staged-approach, we examined the contribution of the endocannabinoid receptor 1 gene (CNR1) on obesity and body mass ind...... variations increase the risk for obesity and modulate BMI in our European population. As CB1 is a drug target for obesity, a pharmacogenetic analysis of the endocannabinoid blockade obesity treatment may be of interest to identify best responders....

  17. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes

    NARCIS (Netherlands)

    Eyk, van H.J.; Schinkel, van L.D.; Kantae, V.; Dronkers, C.E.A.; Westenberg, J.J.M.; Roos, de A.; Lamb, H.J.; Jukema, J.W.; Harms, A.C.; Hankemeier, T.; Stelt, van der M.; Jazet, I.M.; Rensen, P.C.N.; Smit, J.W.A.

    2018-01-01

    Background/ObjectivesEndocannabinoids (ECs) are associated with obesity and ectopic fat accumulation, both of which play a role in the development of cardiovascular disease (CVD) in type 2 diabetes (T2D). The effect of prolonged caloric restriction on ECs in relation to fat distribution and cardiac

  18. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation.

    Science.gov (United States)

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals' capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects.

  19. Enhanced/Synthetic Vision Systems - Human factors research and implications for future systems

    Science.gov (United States)

    Foyle, David C.; Ahumada, Albert J.; Larimer, James; Sweet, Barbara T.

    1992-01-01

    This paper reviews recent human factors research studies conducted in the Aerospace Human Factors Research Division at NASA Ames Research Center related to the development and usage of Enhanced or Synthetic Vision Systems. Research discussed includes studies of field of view (FOV), representational differences of infrared (IR) imagery, head-up display (HUD) symbology, HUD advanced concept designs, sensor fusion, and sensor/database fusion and evaluation. Implications for the design and usage of Enhanced or Synthetic Vision Systems are discussed.

  20. Interdependence of the Electricity Generation System and the Natural Gas System and Implications for Energy Security

    Science.gov (United States)

    2013-05-15

    installation of natural gas generation or cogeneration plants to increase their energy security from the typical three days using diesel supplies to weeks-to...better quantify the regional impact of natural gas for energy security. Modeling and simulation could identify those regions and DoD installations that...Interdependence of the Electricity Generation System and the Natural Gas System and Implications for Energy Security N. Judson 15 May 2013 Prepared for the

  1. Exposure to a highly caloric palatable diet during pregestational and gestational periods affects hypothalamic and hippocampal endocannabinoid levels at birth and induces adiposity and anxiety-like behaviors in male rat offspring

    Directory of Open Access Journals (Sweden)

    Maria Teresa eRamírez-López

    2016-01-01

    Full Text Available Exposure to unbalanced diets during pre-gestational and gestational periods may result in long-term alterations in metabolism and behavior. The contribution of the endocannabinoid system to these long-term adaptive responses is unknown. In the present study, we investigated the impact of female rat exposure to a hypercaloric-hypoproteic palatable diet during pre-gestational, gestational and lactational periods on the development of male offspring. In addition, the hypothalamic and hippocampal endocannabinoid contents at birth and the behavioral performance in adulthood were investigated. Exposure to a palatable diet resulted in low weight offspring who exhibited low hypothalamic contents of arachidonic acid and the two major endocannabinoids (anandamide and 2-arachidonoylglycerol at birth. Palmitoylethanolamide, but not oleoylethanolamide, also decreased. Additionally, pups from palatable diet-fed dams displayed lower levels of anandamide and palmitoylethanolamide in the hippocampus. The low-weight male offspring, born from palatable diet exposed mothers, gained less weight during lactation and, although they recovered weight during the post-weaning period, they developed abdominal adiposity in adulthood. These animals exhibited anxiety-like behavior in the elevated plus-maze and open field test and a low preference for a chocolate diet in a food preference test, indicating that maternal exposure to a hypercaloric diet induces long-term behavioral alterations in male offspring. These results suggest that maternal diet alterations in the function of the endogenous cannabinoid system can mediate the observed phenotype of the offspring, since both hypothalamic and hippocampal endocannabinoids regulate feeding, metabolic adaptions to caloric diets, learning, memory and emotions.

  2. Uncoupling of sarcoplasmic reticulum Ca²⁺-ATPase by N-arachidonoyl dopamine. Members of the endocannabinoid family as thermogenic drugs

    DEFF Research Database (Denmark)

    Mahmmoud, Yasser Ahmed; Gaster, Michel

    2013-01-01

    BACKGROUND AND PURPOSE: The sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) plays a role in thermogenesis. The exogenous compound capsaicin increased SERCA-mediated ATP hydrolysis not coupled to Ca²⁺ transport. Here, we have sought to identify endogenous compounds that may function as SERCA uncoupling...... agents. EXPERIMENTAL APPROACH: Using isolated SR vesicles from rabbits, we have screened for endogenous compounds that uncouple SERCA. We have also studied their ability to deplete cytoplasmic ATP from human skeletal muscle cells in culture. KEY RESULTS: Studies on SR vesicles showed that the endogenous......, regardless of the presence of glucose. CONCLUSIONS AND IMPLICATIONS: NADA is an endogenous molecule that may function as SERCA uncoupling agent in vivo. Members of the endocannabinoid family exert concerted actions on several Ca²⁺-handling proteins. Uncoupling of SERCA by exogenous compounds could be a novel...

  3. Energy implications of integrated solid waste management systems. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Little, R.E.; McClain, G.; Becker, M.; Ligon, P.; Shapiro, K.

    1994-07-01

    This study develops estimates of energy use and recovery from managing municipal solid waste (MSW) under various collection, processing, and disposal scenarios. We estimate use and recovery -- or energy balance -- resulting from MSW management activities such as waste collection, transport, processing, and disposal, as well as indirect use and recovery linked to secondary materials manufacturing using recycled materials. In our analysis, secondary materials manufacturing displaces virgin materials manufacturing for 13 representative products. Energy implications are expressed as coefficients that measure the net energy saving (or use) of displacing products made from virgin versus recycled materials. Using data developed for the 1992 New York City Master Plan as a starting point, we apply our method to an analysis of various collection systems and 30 types of facilities to illustrate bow energy balances shift as management systems are modified. In sum, all four scenarios show a positive energy balance indicating the energy and advantage of integrated systems versus reliance on one or few technology options. That is, energy produced or saved exceeds the energy used to operate the solid waste system. The largest energy use impacts are attributable to processing, including materials separation and composting. Collection and transportation energy are relatively minor contributors. The largest two contributors to net energy savings are waste combustion and energy saved by processing recycled versus virgin materials. An accompanying spatial analysis methodology allocates energy use and recovery to New York City, New York State outside the city, the U.S., and outside the U.S. Our analytical approach is embodied in a spreadsheet model that can be used by energy and solid waste analysts to estimate impacts of management scenarios at the state and substate level.

  4. Oral Dysbiotic Communities and Their Implications in Systemic Diseases

    Directory of Open Access Journals (Sweden)

    Preethi Sudhakara

    2018-04-01

    Full Text Available The human body supports the growth of a wide array of microbial communities in various niches such as the oral cavity, gastro-intestinal and urogenital tracts, and on the surface of the skin. These host associated microbial communities include yet-un-cultivable bacteria and are influenced by various factors. Together, these communities of bacteria are referred to as the human microbiome. Human oral microbiome consists of both symbionts and pathobionts. Deviation from symbiosis among the bacterial community leads to “dysbiosis”, a state of community disturbance. Dysbiosis occurs due to many confounding factors that predispose a shift in the composition and relative abundance of microbial communities. Dysbiotic communities have been a major cause for many microbiome related systemic infections. Such dysbiosis is directed by certain important pathogens called the “keystone pathogens”, which can modulate community microbiome variations. One such persistent infection is oral infection, mainly periodontitis, where a wide array of causal organisms have been implied to systemic infections such as cardio vascular disease, diabetes mellitus, rheumatoid arthritis, and Alzheimer’s disease. The keystone pathogens co-occur with many yet-cultivable bacteria and their interactions lead to dysbiosis. This has been the focus of recent research. While immune evasion is one of the major modes that leads to dysbiosis, new processes and new virulence factors of bacteria have been shown to be involved in this important process that determines a disease or health state. This review focuses on such dysbiotic communities, their interactions, and their virulence factors that predispose the host to other systemic implications.

  5. Alternative Fuels and Propulsion Systems: Some Technology trends and Possible Implications for the Future Army

    National Research Council Canada - National Science Library

    Dortmans, Peter

    2004-01-01

    .... For each of these, technological developments are captured and considered in terms of their implications, both on military systems directly, and the broader implications for the future context. The impacts on Land Force core skills within the Army-as-a-system framework of these technologies are discussed.

  6. Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats

    Directory of Open Access Journals (Sweden)

    Valentina Satta

    2018-02-01

    Full Text Available Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED. Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats. For this purpose, brain levels of the endocannabinoids anandamide (AEA and 2-arachidonoyl glycerol (2-AG, as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus. The brain density of cannabinoid type-1 receptors (CB1 was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain. To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD (margarine. Three experimental groups were used, all with ad libitum access to chow: control (CTRL, with no access to margarine; low restriction (LR, with 2 h margarine access 7 days/week; high restriction (HR, with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group. Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both

  7. 21st centuries skill implication on educational system

    Science.gov (United States)

    Wrahatnolo, T.; Munoto

    2018-01-01

    The purpose of this article is to identify skill needed in 21st centuries and its implication on Indonesia’s educational system. This research found that the 21st centuries skill application has more measurable benefits in some sections of life, such as critical thinking and problem solving, initiative, creativity, and entrepreneurship, communication, teamwork, metacognition (change of mindset), digital literature. This study applied qualitative data analysis. The data were taken from different sources and literature. The analysis showed that The 21st centuries education concept’s implementation can be applied in the curriculum of the required subject that is addressed to achieve learning and innovation skills competence and also technology and information media skills competence. While supporting subject group directed to achieve life and career skills competence. All subjects are the derivation from core subject 3R, which are reading, writing, and arithmetic. Based on the description above, it can be concluded that 21st centuries skill needs; (1) a life planning; (2) flexibility and adaptability; (3) initiative and self-management (4) entrepreneurship; (5) social and cultural interaction; (6) productivity and accountability; (7) leadership; (8) critical thinking, (9) problem solving; (10) communication; (11) collaboration and teamwork; (12) lifelong learning; and (13) digital literation.

  8. B cell biology: implications for treatment of systemic lupus erythematosus.

    Science.gov (United States)

    Anolik, J H

    2013-04-01

    B cells are critical players in the orchestration of properly regulated immune responses, normally providing protective immunity without autoimmunity. Balance in the B cell compartment is achieved through the finely regulated participation of multiple B cell populations with different antibody-dependent and independent functions. Both types of functions allow B cells to modulate other components of the innate and adaptive immune system. Autoantibody-independent B cell functions include antigen presentation, T cell activation and polarization, and dendritic cell modulation. Several of these functions are mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization including the development of ectopic tertiary lymphoid tissue. Additionally, the functional versatility of B cells enables them to play either protective or pathogenic roles in autoimmunity. In turn, B cell dysfunction has been critically implicated in the pathophysiology of systemic lupus erythematosus (SLE), a complex disease characterized by the production of autoantibodies and heterogeneous clinical involvement. Thus, the breakdown of B cell tolerance is a defining and early event in the disease process and may occur by multiple pathways, including alterations in factors that affect B cell activation thresholds, B cell longevity, and apoptotic cell processing. Once tolerance is broken, autoantibodies contribute to autoimmunity by multiple mechanisms including immune-complex mediated Type III hypersensitivity reactions, type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines including IFNα, TNF and IL-1. The complexity of B cell functions has been highlighted by the variable success of B cell-targeted therapies in multiple autoimmune diseases, including those conventionally viewed as T cell-mediated conditions. Given the widespread

  9. Ambivalent implications of health care information systems: a study in the Brazilian public health care system

    Directory of Open Access Journals (Sweden)

    João Porto de Albuquerque

    2011-01-01

    Full Text Available This article evaluates social implications of the "SIGA" Health Care Information System (HIS in a public health care organization in the city of São Paulo. The evaluation was performed by means of an in-depth case study with patients and staff of a public health care organization, using qualitative and quantitative data. On the one hand, the system had consequences perceived as positive such as improved convenience and democratization of specialized treatment for patients and improvements in work organization. On the other hand, negative outcomes were reported, like difficulties faced by employees due to little familiarity with IT and an increase in the time needed to schedule appointments. Results show the ambiguity of the implications of HIS in developing countries, emphasizing the need for a more nuanced view of the evaluation of failures and successes and the importance of social contextual factors.

  10. Effects of mood inductions by meal ambiance and moderate alcohol consumption on endocannabinoids and N-acylethanolamines in humans: a randomized crossover trial.

    Directory of Open Access Journals (Sweden)

    Ilse C Schrieks

    Full Text Available The endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG, anandamide (AEA, and some N-acylethanolamine (NAE congeners in humans.Healthy women (n = 28 participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol or alcohol-free sparkling white wine (340 mL; <2 g alcohol as part of a standard evening meal in a room with either a pleasant or an unpleasant ambiance.Plasma concentrations of palmitoylethanolamide (PEA and stearoylethanolamide (SEA increased after 30 min in the unpleasant ambiance, while they decreased in the pleasant ambiance. Changes in ECs and their NAE congeners correlated with mood states, such as happiness and fatigue, but in the pleasant ambiance without alcohol only. ECs and their NAE congeners were correlated with serum free fatty acids and cortisol.This is the first human study to demonstrate that plasma NAEs are responsive to an unpleasant meal ambiance. Furthermore, associations between mood states and ECs and their NAE congeners were observed.Clinicaltrials.gov NCT01426022.

  11. Climate Change: Implications for South African Building Systems and Components

    CSIR Research Space (South Africa)

    Gibberd, Jeremy T

    2017-12-01

    Full Text Available to determine the implications of these changes for buildings. Proposals are made on how buildings may be adapted to climate change and recommendations on further research and development are outlined....

  12. Implications for Effective Child Development System in Africa

    African Journals Online (AJOL)

    Nneka Umera-Okeke

    Child Rights Campaign and the Nigerian Family: Implications for Effective Child .... of socialization like: day-care centres, schools, peer groups, video bars, recreational parks and new social media have taken over this role. The outcome is that ...

  13. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Justin R. Piro

    2012-06-01

    Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

  14. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena

    OpenAIRE

    Solbrig, MV; Adrian, R; Baratta, J; Piomelli, D; Giuffrida, A

    2005-01-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endoca...

  15. A role for endocannabinoids in viral-induced dyskinetic and convulsive phenomena.

    Science.gov (United States)

    Solbrig, Marylou V; Adrian, Russell; Baratta, Janie; Piomelli, Daniele; Giuffrida, Andrea

    2005-08-01

    Dyskinesias and seizures are both medically refractory disorders for which cannabinoid-based treatments have shown early promise as primary or adjunctive therapy. Using the Borna disease (BD) virus rat, an animal model of viral encephalopathy with spontaneous hyperkinetic movements and seizure susceptibility, we identified a key role for endocannabinoids in the maintenance of a balanced tone of activity in extrapyramidal and limbic circuits. BD rats showed significant elevations of the endocannabinoid anandamide in subthalamic nucleus, a relay nucleus compromised in hyperkinetic disorders. While direct and indirect cannabinoid agonists had limited motor effects in BD rats, abrupt reductions of endocannabinoid tone by the CB1 antagonist SR141716A (0.3 mg/kg, i.p.) caused seizures characterized by myoclonic jerks time-locked to periodic spike/sharp wave discharges on hippocampal electroencephalography. The general opiate antagonist naloxone (NLX) (1 mg/kg, s.c.), another pharmacologic treatment with potential efficacy in dyskinesias or L-DOPA motor complications, produced similar seizures. No changes in anandamide levels in hippocampus and amygdala were found in convulsing NLX-treated BD rats. In contrast, NLX significantly increased anandamide levels in the same areas of normal uninfected animals, possibly protecting against seizures. Pretreatment with the anandamide transport blocker AM404 (20 mg/kg, i.p.) prevented NLX-induced seizures. These findings are consistent with an anticonvulsant role for endocannabinoids, counteracting aberrant firing produced by convulsive agents, and with a functional or reciprocal relation between opioid and cannabinoid tone with respect to limbic convulsive phenomena.

  16. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    OpenAIRE

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p.) on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimenta...

  17. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Science.gov (United States)

    Karlsson, Jessica; Fowler, Christopher J

    2014-01-01

    In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  18. Inhibition of endocannabinoid metabolism by the metabolites of ibuprofen and flurbiprofen.

    Directory of Open Access Journals (Sweden)

    Jessica Karlsson

    Full Text Available In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG and anandamide (AEA by cyclooxygenase-2 (COX-2 and fatty acid amide hydrolase (FAAH, respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen.COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1 and arachidonic acid and 2-AG (for COX-2. FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds.It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  19. Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPAR

    Directory of Open Access Journals (Sweden)

    Saoirse E. O'Sullivan

    2009-01-01

    Full Text Available The aim of the present study was to examine whether endocannabinoids cause PPAR-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA, but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours. Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 M, and vasorelaxation to both anandamide and NADA was inhibited by PPAR antagonism (GW9662, 1 M. Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 M inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPAR-mediated vasorelaxation. Activation of PPAR in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation.

  20. Moderate-vigorous physical activity across body mass index in females: moderating effect of endocannabinoids and temperament.

    Directory of Open Access Journals (Sweden)

    Fernando Fernández-Aranda

    Full Text Available Endocannabinoids and temperament traits have been linked to both physical activity and body mass index (BMI however no study has explored how these factors interact in females. The aims of this cross-sectional study were to 1 examine differences among distinct BMI groups on daytime physical activity and time spent in moderate-vigorous physical activity (MVPA, temperament traits and plasma endocannabinoid concentrations; and 2 explore the association and interaction between MVPA, temperament, endocannabinoids and BMI.Physical activity was measured with the wrist-worn accelerometer Actiwatch AW7, in a sample of 189 female participants (43 morbid obese, 30 obese, and 116 healthy-weight controls. The Temperament and Character Inventory-Revised questionnaire was used to assess personality traits. BMI was calculated by bioelectrical impedance analysis via the TANITA digital scale. Blood analyses were conducted to measure levels of endocannabinoids and endocannabinoid-related compounds. Path-analysis was performed to examine the association between predictive variables and MVPA.Obese groups showed lower MVPA and dysfunctional temperament traits compared to healthy-weight controls. Plasma concentrations of 2-arachidonoylglyceryl (2-AG were greater in obese groups. Path-analysis identified a direct effect between greater MVPA and low BMI (b = -0.13, p = .039 and high MVPA levels were associated with elevated anandamide (AEA levels (b = 0.16, p = .049 and N-oleylethanolamide (OEA levels (b = 0.22, p = .004, as well as high Novelty seeking (b = 0.18, p<.001 and low Harm avoidance (b = -0.16, p<.001.Obese individuals showed a distinct temperament profile and circulating endocannabinoids compared to controls. Temperament and endocannabinoids may act as moderators of the low MVPA in obesity.

  1. Platform for systems medicine research and diagnostic applications in psychotic disorders-The METSY project.

    Science.gov (United States)

    Frank, Elisabeth; Maier, Dieter; Pajula, Juha; Suvitaival, Tommi; Borgan, Faith; Butz-Ostendorf, Markus; Fischer, Alexander; Hietala, Jarmo; Howes, Oliver; Hyötyläinen, Tuulia; Janssen, Joost; Laurikainen, Heikki; Moreno, Carmen; Suvisaari, Jaana; Van Gils, Mark; Orešič, Matej

    2018-04-01

    Psychotic disorders are associated with metabolic abnormalities including alterations in glucose and lipid metabolism. A major challenge in the treatment of psychosis is to identify patients with vulnerable metabolic profiles who may be at risk of developing cardiometabolic co-morbidities. It is established that both central and peripheral metabolic organs use lipids to control energy balance and regulate peripheral insulin sensitivity. The endocannabinoid system, implicated in the regulation of glucose and lipid metabolism, has been shown to be dysregulated in psychosis. It is currently unclear how these endocannabinoid abnormalities relate to metabolic changes in psychosis. Here we review recent research in the field of metabolic co-morbidities in psychotic disorders as well as the methods to study them and potential links to the endocannabinoid system. We also describe the bioinformatics platforms developed in the EU project METSY for the investigations of the biological etiology in patients at risk of psychosis and in first episode psychosis patients. The METSY project was established with the aim to identify and evaluate multi-modal peripheral and neuroimaging markers that may be able to predict the onset and prognosis of psychiatric and metabolic symptoms in patients at risk of developing psychosis and first episode psychosis patients. Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines molecular, structural and functional neuroimaging methods with detailed metabolic characterisation and multi-variate network analysis is essential in order to identify how lipid dysregulation may contribute to psychotic disorders. A decision support system, integrating clinical, neuropsychological and neuroimaging data, was also developed in order to aid clinical decision making in psychosis. Knowledge of common and specific mechanisms may aid the etiopathogenic understanding of psychotic and metabolic disorders

  2. THC and endocannabinoids differentially regulate neuronal activity in the prefrontal cortex and hippocampus in the subchronic PCP model of schizophrenia.

    Science.gov (United States)

    Aguilar, David D; Giuffrida, Andrea; Lodge, Daniel J

    2016-02-01

    Cannabis use has been associated with an increased risk to develop schizophrenia as well as symptom exacerbation in patients. In contrast, clinical studies have revealed an inverse relationship between the cerebrospinal fluid levels of the endocannabinoid anandamide and symptom severity, suggesting a therapeutic potential for endocannabinoid-enhancing drugs. Indeed, preclinical studies have shown that these drugs can reverse distinct behavioral deficits in a rodent model of schizophrenia. The mechanisms underlying the differences between exogenous and endogenous cannabinoid administration are currently unknown. Using the phencyclidine (PCP) rat model of schizophrenia, we compared the effects on neuronal activity of systematic administration of delta-9-tetrahydrocannabinol (THC) with the fatty acid amide hydrolase inhibitor URB597. Specifically, we found that the inhibitory response in the prefrontal cortex to THC administration was absent in PCP-treated rats. In contrast, an augmented response to endocannabinoid upregulation was observed in the prefrontal cortex of PCP-treated rats. Interestingly, differential effects were also observed at the neuronal population level, as endocannabinoid upregulation induced opposite effects on coordinated activity when compared with THC. Such information is important for understanding why marijuana and synthetic cannabinoid use may be contraindicated in schizophrenia patients while endocannabinoid enhancement may provide a novel therapeutic approach. © The Author(s) 2015.

  3. The mirror-neuron system and observational learning: Implications for the effectiveness of dynamic visualizations.

    OpenAIRE

    Van Gog, Tamara; Paas, Fred; Marcus, Nadine; Ayres, Paul; Sweller, John

    2009-01-01

    Van Gog, T., Paas, F., Marcus, N., Ayres, P., & Sweller, J. (2009). The mirror-neuron system and observational learning: Implications for the effectiveness of dynamic visualizations. Educational Psychology Review, 21, 21-30.

  4. Understanding the implication of investing in biodiesel production in South Africa: a system dynamics approach

    CSIR Research Space (South Africa)

    Musango, JK

    2010-07-01

    Full Text Available This paper presents a Bioenergy Systems Sustainability Assessment and Management (BIOSSAM) model. The BIOSSAM model was developed as a means to provide insights into the implications of expanding bioenergy programmes in South Africa, which is deemed...

  5. Environmental Implications of Eco-Labeling for Rice Farming Systems

    OpenAIRE

    Solhee Kim; Taegon Kim; Timothy M. Smith; Kyo Suh

    2018-01-01

    Concerns about climate change have forced countries to strengthen regulations, standards, and certifications related to greenhouse gas emissions. Various policies targeting farm products, such as carbon labeling and the Environmentally-Friendly Agricultural Product Certification (EFAPC) for agricultural products, have been implemented in South Korea to reduce greenhouse gas emissions in the agricultural sector. The purpose of this study was to evaluate the implications of the various certific...

  6. Endocannabinoids in Alzheimer's disease and their impact on normative cognitive performance: a case-control and cohort study

    Directory of Open Access Journals (Sweden)

    Christen Erica

    2009-01-01

    Full Text Available Abstract Background Neuropathological, animal, and cell culture studies point to a role for the body's own endogenous cannabinoids (eCBs system in Alzheimer's disease (AD pathology and treatment. To date, no published studies have investigated the potential utility of circulating eCBs as diagnostic biomarkers for AD or the impact of central eCBs on cognition. Results In comparison with healthy controls, there were no significant differences in measured eCB concentrations in plasma samples from patients with AD. Detectable eCBs in cerebrospinal fluid (CSF had no relationship to cognitive performance in healthy controls at risk for AD. In pooled plasma samples, an inverse correlation was observed between plasma levels of the eCB 2-AG (2-arachidonoylglycerol and TNF-α (r = -0.41, p Conclusion These results suggest that circulating endocannabinoids do not have utility as diagnostic biomarkers for AD and do not have a robust correlation with cognitive performance. Circulating levels of 2-AG may downregulate TNF-α production.

  7. Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Elphick Maurice R

    2009-07-01

    Full Text Available Abstract Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG, and the related compound N-palmitoylethanolamine (PEA, in neuropathic spinal cord. Selective spinal nerve ligation (SNL in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30 mg/kg, ip for 14 days significantly reduced the development of mechanical allodynia at days 5, 10 and 14 post-SNL surgery, compared to vehicle-treated SNL rats (P P P P P

  8. Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

    Science.gov (United States)

    Monteleone, Alessio Maria; Di Marzo, Vincenzo; Aveta, Teresa; Piscitelli, Fabiana; Dalle Grave, Riccardo; Scognamiglio, Pasquale; El Ghoch, Marwan; Calugi, Simona; Monteleone, Palmiero; Maj, Mario

    2015-02-01

    A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy

  9. Tourist activated networks: Implications for dynamic packaging systems in tourism

    DEFF Research Database (Denmark)

    Zach, Florian; Gretzel, Ulrike; Fesenmaier, Daniel R.

    2008-01-01

    This paper discusses tourist activated networks as a concept to inform technological applications supporting dynamic bundling and en-route recommendations. Empirical data was collected from travellers who visited a regional destination in the US and then analyzed with respect to its network...... structure. The results indicate that the tourist activated network for the destination is rather sparse and that there are clearly differences in core and peripheral nodes. The findings illustrate the structure of a tourist activated network and provide implications for technology design and tourism...

  10. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats

    Science.gov (United States)

    Vázquez, Mariam; Sánchez, Laura; Rivera, Patricia; Gavito, Ana; Mela, Virginia; Alén, Francisco; Decara, Juan; Suárez, Juan; Giné, Elena; López-Moreno, José Antonio; Chowen, Julie; Rodríguez-de-Fonseca, Fernando; Serrano, Antonia; Viveros, María Paz

    2016-01-01

    Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats

  11. Effects of Adolescent Intermittent Alcohol Exposure on the Expression of Endocannabinoid Signaling-Related Proteins in the Spleen of Young Adult Rats.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Pavón

    Full Text Available Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS, which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in

  12. A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition.

    Directory of Open Access Journals (Sweden)

    Margarita Zachariou

    Full Text Available Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI, a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of

  13. Safety implications of electronic driving support systems : an orientation.

    OpenAIRE

    Gundy, C.M. Steyvers, F.J.J.M. & Kaptein, N.A.

    1995-01-01

    This report focuses on traffic safety aspects of driving support systems. The report consists of two parts. First of all, the report discusses a number of topics, relevant for the implementation and evaluation of driving support systems. These topics include: (1) safety research into driving support systems: (2) the importance of research into driver models and the driving task; (3) horizontal integration of driving support systems; (4) vertical integration of driving support systems; (5) tas...

  14. Complexity, flow, and antifragile healthcare systems: implications for nurse executives.

    Science.gov (United States)

    Clancy, Thomas R

    2015-04-01

    As systems evolve over time, their natural tendency is to become increasingly more complex. Studies in the field of complex systems have generated new perspectives on the application of management strategies in health systems. Much of this research appears as a natural extension of the cross-disciplinary field of systems theory. In this article, I further discuss the concept of fragility, its impact on system behavior, and ways to reduce it.

  15. Implications of science and technology on the radiological protection system

    International Nuclear Information System (INIS)

    Metivier, H.; LAZO, T.

    2006-01-01

    Full text of publication follows: The mission of the Nuclear Energy Agency (Nea) Committee on Radiation Protection and Public Health (C.R.P.P.H.) includes providing member -country governments with insight into evolving or emerging issues that could affect radiation protection policy, regulation or application. Although it can not be currently said that the scientific understanding of radiological risks has significantly changed recently, ongoing radio-biological and epidemiological research could challenge the conventional paradigm in the mid -term future. The C.R.P.P.H. finalized in March 2006 finalize a study of possible challenges and their implications. This study includes two principle areas: challenges arising from scientific developments; and, challenges to the implementation of radiation protection. This report updates the earlier C.R.P.P.H. report, 'Developments in Radiation Health Sciences and their Impact on Radiation Protection' (Nea 1998). Broadly speaking, ongoing radiation biology studies present the possibility that our current practice of summing various type s of exposures into a single value of effective dose is not scientifically supported because of significantly differing dose/response relationships (chronic vs. acute, internal vs. external, high Let versus low Let, etc.). In addition, non-targeted effects, and the possibility of individual hyper-sensitivity to radiation further challenge our current notion of the relationship between detriment and dose. Although there is no conclusive evidence for this at this time, the possible implications of such changes will be investigated to better prepare governments and the radiation protection community should sound scientific evidence emerge. In addition to these possible scientific challenges, the applications and events that would require radiological protection input are also evolving. In particular, the use of radiation in medicine, with new techniques and the spread of existing technologies

  16. The activity of the endocannabinoid metabolising enzyme fatty acid amide hydrolase in subcutaneous adipocytes correlates with BMI in metabolically healthy humans

    Directory of Open Access Journals (Sweden)

    Alexander Stephen PH

    2011-08-01

    Full Text Available Abstract Background The endocannabinoid system (ECS is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA and 2-arachidonoylglcyerol (2-AG, and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MGL. Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI, or other markers of adiposity and metabolism. Methods Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs. Results MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose or serum adipokine levels (adiponectin, leptin or resistin. In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels. Conclusions In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently.

  17. Influences of Vestibular System on Sympathetic Nervous System. Implications for countermeasures.

    Science.gov (United States)

    Denise, Pr Pierre

    As gravity is a direct and permanent stress on body fluids, muscles and bones, it is not surpris-ing that weightlessness has important effects on cardiovascular and musculo-skeletal systems. However, these harmful effects do not totally result from the removal of the direct stress of gravity on these organs, but are also partially and indirectly mediated by the vestibular sys-tem. Besides its well known crucial role in spatial orientation and postural equilibrium, it is now clear that the vestibular system is also involved in the regulation of other important physi-ological systems: respiratory and cardiovascular systems, circadian regulation, food intake and even bone mineralization. The neuroanatomical substrate for these vestibular-mediated reg-ulations is still poorly defined, but there is much evidence that vestibular system has strong impacts not only on brainstem autonomic centers but on many hypothalamic nuclei as well. As autonomic nervous system controls almost all body organs, bringing into play the vestibular system by hypergravity or microgravity could virtually affects all major physiological func-tions. There is experimental evidence that weightlessness as well as vestibular lesion induce sympathetic activation thus participating in space related physiological alterations. The fact that some effects of weightlessness on biological systems are mediated by the vestibular system has an important implication for using artificial gravity as a countermeasure: artificial gravity should load not only bones and the cardiovascular system but the vestibular system as well. In short-arm centrifuges, the g load at the head level is low because the head is near the axis of rotation. If the vestibular system is involved in cardiovascular deconditioning and bone loss during weightlessness, it would be more effective to significantly stimulate it and thus it would be necessary to place the head off-axis. Moreover, as the otolithic organs are non longer stimu-lated in

  18. Productivity Implications of Employee Performance Appraisal System : A Critical Survey.

    OpenAIRE

    Dr. VSR Subramaniam

    2004-01-01

    The Productivity of any organisation is directly correlated to the Effectiveness of the Employee Performance Appraisal System, subject to the Effectiveness of the Support Systems, depending upon the type of organizational business. INFERENCE : Technology, Systems and Manpower are linked in an inter- related circle focusing towards Productivity =============================================================== DOCTORAL (Ph.D) RESEARCH WORK OF DR.VSR.SUBRAMANIAM IN JAMNALAL BAJAJ INSTITUTE OF MANA...

  19. System justification: A motivational process with implications for social conflict

    NARCIS (Netherlands)

    Jost, J. T.; Liviatan, I.; van der Toorn, J.; Ledgerwood, A.; Mandisodza, A.; Nosek, B. A.

    2012-01-01

    According to system justification theory, people are motivated to defend and legitimize the social systems that affect them. In this chapter, we review 15 years of theory and empirical research demonstrating the motivational underpinnings of system justification processes. We begin by explaining why

  20. LISA Pathfinder drag-free control and system implications

    International Nuclear Information System (INIS)

    Fichter, Walter; Gath, Peter; Vitale, Stefano; Bortoluzzi, Daniele

    2005-01-01

    The top-level requirement of the LISA Pathfinder mission is the verification of pure relative free fall between two test masses with an accuracy of about 3 x 10 -14 m s -2 Hz -1/2 in a measurement bandwidth between 1 mHz and 30 mHz. The drag-free control system is one of the key technology elements that shall be verified. Its design is strongly connected to the overall system and experimental design, in particular, via the following issues: the differential test mass motion and thus the science measurements depend on the control system; design constraints, such as negative stiffness of test masses and electrostatic actuation cross-talk, have an impact on science and control system performance; derived requirements for control system components, in particular, the micro-propulsion system, must be within reasonable and feasible limits. In this paper, the control design approach is outlined and the system-related issues are addressed

  1. Effects of acute versus repeated cocaine exposure on the expression of endocannabinoid signaling-related proteins in the mouse cerebellum

    Directory of Open Access Journals (Sweden)

    Ana ePalomino

    2014-03-01

    Full Text Available Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression (CB1 receptors and enzymes that produce (DAGLα/β and NAPE-PLD and degrade (MAGL and FAAH eCB were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system (glutamate synthesizing enzymes LGA and KGA, mGluR3/5 metabotropic receptors, and NR1/2A/2B/2C-NMDA and GluR1/2/3/4-AMPA ionotropic receptor subunits and the gene expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-AG production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that

  2. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.

    Science.gov (United States)

    Scavone, J L; Sterling, R C; Van Bockstaele, E J

    2013-09-17

    Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. The geopolitics of renewables; exploring the political implications of renewable energy systems

    NARCIS (Netherlands)

    Scholten, D.J.; Bosman, Rick

    2016-01-01

    This paper explores the potential political implications of the geographic and technical characteristics of renewable energy systems. This is done through a thought experiment that imagines a purely renewable based energy system, keeping all else equal. We start by noting that all countries have

  4. Cost Implications of an Interim Storage Facility in the Waste Management System

    Energy Technology Data Exchange (ETDEWEB)

    Jarrell, Joshua J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Joseph, III, Robert Anthony [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Howard, Rob L [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Petersen, Gordon M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Nutt, Mark [Argonne National Lab. (ANL), Argonne, IL (United States); Carter, Joe [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Cotton, Thomas [Complex Systems Group, Bozeman, MT (United States)

    2016-09-01

    This report provides an evaluation of the cost implications of incorporating a consolidated interim storage facility (ISF) into the waste management system (WMS). Specifically, the impacts of the timing of opening an ISF relative to opening a repository were analyzed to understand the potential effects on total system costs.

  5. Regulation of vitamin D homeostasis: implications for the immune system.

    Science.gov (United States)

    van Etten, Evelyne; Stoffels, Katinka; Gysemans, Conny; Mathieu, Chantal; Overbergh, Lut

    2008-10-01

    Vitamin D homeostasis in the immune system is the focus of this review. The production of both the activating (25- and 1alpha-hydroxylase) and the metabolizing (24-hydroxylase) enzymes by cells of the immune system itself, indicates that 1,25(OH)(2)D(3) can be produced locally in immune reaction sites. Moreover, the strict regulation of these enzymes by immune signals is highly suggestive for an autocrine/paracrine role in the immune system, and opens new treatment possibilities.

  6. Enterprises as Inquiring Systems with Implications for Information Warfare

    Science.gov (United States)

    2014-06-01

    and reductionist, but applied in almost all decisions because it is considered “objective” and logic is “better” than intuition. 2.3 Kantian Model...The Kantian system is something of a mixture of Leibnizian and Lockian. The system is open, like that of Lockian. It generates hypotheses on the...basis of inputs received. The unique feature of the Kantian system is that the theoretic aspect allows an input to be interpreted in different ways

  7. The endocannabinoid anandamide regulates the peristaltic reflex by reducing neuro-neuronal and neuro-muscular neurotransmission in ascending myenteric reflex pathways in rats.

    Science.gov (United States)

    Sibaev, Andrei; Yuece, Birol; Allescher, Hans Dieter; Saur, Dieter; Storr, Martin; Kurjak, Manfred

    2014-04-01

    Endocannabinoids (EC) and the cannabinoid-1 (CB1) receptor are involved in the regulation of motility in the gastrointestinal (GI) tract. However, the underlying physiological mechanisms are not completely resolved. The purpose of this work was to study the physiological influence of the endocannabinoid anandamide, the putative endogenous CB1 active cannabinoid, and of the CB1 receptor on ascending peristaltic activity and to identify the involved neuro-neuronal, neuro-muscular and electrophysiological mechanisms. The effects of anandamide and the CB1 receptor antagonist SR141716A were investigated on contractions of the circular smooth muscle of rat ileum and in longitudinal rat ileum segments where the ascending myenteric part of the peristaltic reflex was studied in a newly designed organ bath. Additionally intracellular recordings were performed in ileum and colon. Anandamide significantly reduced cholinergic twitch contractions of ileum smooth muscle whereas SR141716A caused an increase. Anandamide reduced the ascending peristaltic contraction by affecting neuro-neuronal and neuro-muscular neurotransmission. SR141716A showed opposite effects and all anandamide effects were antagonized by SR141716A (1 μM). Anandamide reduced excitatory junction potentials (EJP) and inhibitory junction potentials (IJP), whereas intestinal slow waves were not affected. CB1 receptors regulate force and timing of the intestinal peristaltic reflex and these actions involve interneurons and motor-neurons. The endogenous cannabinoid anandamide mediates these effects by activation of CB1 receptors. The endogenous cannabinoid system is permanently active, suggesting the CB1 receptor being a possible target for the treatment of motility related disorders. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Implications of the behavioural immune system for social behaviour and human health in the modern world.

    Science.gov (United States)

    Schaller, Mark; Murray, Damian R; Bangerter, Adrian

    2015-05-26

    The 'behavioural immune system' is composed of mechanisms that evolved as a means of facilitating behaviours that minimized infection risk and enhanced fitness. Recent empirical research on human populations suggests that these mechanisms have unique consequences for many aspects of human sociality--including sexual attitudes, gregariousness, xenophobia, conformity to majority opinion and conservative sociopolitical attitudes. Throughout much of human evolutionary history, these consequences may have had beneficial health implications; but health implications in modern human societies remain unclear. This article summarizes pertinent ways in which modern human societies are similar to and different from the ecologies within which the behavioural immune system evolved. By attending to these similarities and differences, we identify a set of plausible implications-both positive and negative-that the behavioural immune system may have on health outcomes in contemporary human contexts. We discuss both individual-level infection risk and population-level epidemiological outcomes. We also discuss a variety of additional implications, including compliance with public health policies, the adoption of novel therapeutic interventions and actual immunological functioning. Research on the behavioural immune system, and its implications in contemporary human societies, can provide unique insights into relationships between fitness, sociality and health. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  9. Design implications for a community-based social recipe system

    NARCIS (Netherlands)

    Lim, V.; Yalvac, F.; Funk, M.; Hu, J.; Rauterberg, G.W.M.; Regazzoni, C.S.; Marcenaro, L.

    2014-01-01

    We introduced the concept of a community-based social recipe system which suggests recipes to groups of users based on available ingredients from these users (i.e. who can be from the same household or different households). In this paper we discuss the relevance and desirability of such a system

  10. Safety implications of electronic driving support systems : an orientation.

    NARCIS (Netherlands)

    Gundy, C.M. Steyvers, F.J.J.M. & Kaptein, N.A.

    1995-01-01

    This report focuses on traffic safety aspects of driving support systems. The report consists of two parts. First of all, the report discusses a number of topics, relevant for the implementation and evaluation of driving support systems. These topics include: (1) safety research into driving support

  11. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation.

    Science.gov (United States)

    Gouveia-Figueira, Sandra; Späth, Jana; Zivkovic, Angela M; Nording, Malin L

    2015-01-01

    Bioactive lipids, including oxylipins, endocannabinoids, and related compounds may function as specific biochemical markers of certain aspects of inflammation. However, the postprandial responsiveness of these compounds is largely unknown; therefore, changes in the circulating oxylipin and endocannabinoid metabolome in response to a challenge meal were investigated at six occasions in a subject who freely modified her usual diet. The dietary change, and especially the challenge meal itself, represented a modification of precursor fatty acid status, with expectedly subtle effects on bioactive lipid levels. To detect even the slightest alteration, highly sensitive ultra-performance liquid chromatography (UPLC) coupled to electrospray ionization (ESI) tandem mass spectrometry (MS/MS) methods for bioactive lipid profiling was employed. A previously validated UPLC-ESI-MS/MS method for profiling the endocannabinoid metabolome was used, while validation of an UPLC-ESI-MS/MS method for oxylipin analysis was performed with acceptable outcomes for a majority of the parameters according to the US Food and Drug Administration guidelines for linearity (0.9938 metabolome, caused by changes in diet and ii) responsiveness to a challenge meal for a subset of the oxylipin and endocannabinoid metabolome. To summarize, we have shown proof-of-concept of our UPLC-ESI-MS/MS bioactive lipid protocols for the purpose of monitoring subtle shifts, and thereby useful to address lipid-mediated postprandial inflammation.

  12. Policy implications in developing a land use management information systems

    Science.gov (United States)

    Landini, A. J.

    1975-01-01

    The current land use map for the city of Los Angeles was developed by the guesstimation process and provides single stage information for each level in the critical geographical hierarchy for land use planning management. Processing and incorporation of LANDSAT data in the land use information system requires special funding; however, computergraphic maps are able to provide a viable information system for city planning and management.

  13. Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

    Directory of Open Access Journals (Sweden)

    Belém Sampaio-Marques

    2015-05-01

    Full Text Available Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies.

  14. Energy and air emission implications of a decentralized wastewater system

    International Nuclear Information System (INIS)

    Shehabi, Arman; Stokes, Jennifer R; Horvath, Arpad

    2012-01-01

    Both centralized and decentralized wastewater systems have distinct engineering, financial and societal benefits. This paper presents a framework for analyzing the environmental effects of decentralized wastewater systems and an evaluation of the environmental impacts associated with two currently operating systems in California, one centralized and one decentralized. A comparison of energy use, greenhouse gas emissions and criteria air pollutants from the systems shows that the scale economies of the centralized plant help lower the environmental burden to less than a fifth of that of the decentralized utility for the same volume treated. The energy and emission burdens of the decentralized plant are reduced when accounting for high-yield wastewater reuse if it supplants an energy-intensive water supply like a desalination one. The centralized facility also reduces greenhouse gases by flaring methane generated during the treatment process, while methane is directly emitted from the decentralized system. The results are compelling enough to indicate that the life-cycle environmental impacts of decentralized designs should be carefully evaluated as part of the design process. (letter)

  15. Product Configuration Systems - Implications for Product Innovation and Development

    DEFF Research Database (Denmark)

    Edwards, Kasper; Pedersen, Jørgen Lindgaard

    2004-01-01

    configurations. However, costs are but one parameter on which firms compete and firms must continually innovate new and develop existing products. This paper presents original empirical insights on implementation and use of product configuration systems in a number of Danish industrial firms. The paper discusses...... the organisational changes associated with PCS and how this affects product innovation and development. The paper begins by introducing product configuration systems, which are then placed in context to the firm as a process technology which coordinate different processes: product development, order acquisition......Product Configuration Systems (PCS) is a step in the direction of mass customization in the sense that PCS allows a firm to significantly lower the unit cost of configuration. Thus PCS is a valuable technology for lowering operating costs while retaining a high number of possible product...

  16. Configuration and technology implications of potential nuclear hydrogen system applications.

    Energy Technology Data Exchange (ETDEWEB)

    Conzelmann, G.; Petri, M.; Forsberg, C.; Yildiz, B.; ORNL

    2005-11-05

    Nuclear technologies have important distinctions and potential advantages for large-scale generation of hydrogen for U.S. energy services. Nuclear hydrogen requires no imported fossil fuels, results in lower greenhouse-gas emissions and other pollutants, lends itself to large-scale production, and is sustainable. The technical uncertainties in nuclear hydrogen processes and the reactor technologies needed to enable these processes, as well waste, proliferation, and economic issues must be successfully addressed before nuclear energy can be a major contributor to the nation's energy future. In order to address technical issues in the time frame needed to provide optimized hydrogen production choices, the Nuclear Hydrogen Initiative (NHI) must examine a wide range of new technologies, make the best use of research funding, and make early decisions on which technology options to pursue. For these reasons, it is important that system integration studies be performed to help guide the decisions made in the NHI. In framing the scope of system integration analyses, there is a hierarchy of questions that should be addressed: What hydrogen markets will exist and what are their characteristics? Which markets are most consistent with nuclear hydrogen? What nuclear power and production process configurations are optimal? What requirements are placed on the nuclear hydrogen system? The intent of the NHI system studies is to gain a better understanding of nuclear power's potential role in a hydrogen economy and what hydrogen production technologies show the most promise. This work couples with system studies sponsored by DOE-EE and other agencies that provide a basis for evaluating and selecting future hydrogen production technologies. This assessment includes identifying commercial hydrogen applications and their requirements, comparing the characteristics of nuclear hydrogen systems to those market requirements, evaluating nuclear hydrogen configuration options

  17. Environmental and natural resource implications of sustainable urban infrastructure systems

    Science.gov (United States)

    Bergesen, Joseph D.; Suh, Sangwon; Baynes, Timothy M.; Kaviti Musango, Josephine

    2017-12-01

    As cities grow, their environmental and natural resource footprints also tend to grow to keep up with the increasing demand on essential urban services such as passenger transportation, commercial space, and thermal comfort. The urban infrastructure systems, or socio-technical systems providing these services are the major conduits through which natural resources are consumed and environmental impacts are generated. This paper aims to gauge the potential reductions in environmental and resources footprints through urban transformation, including the deployment of resource-efficient socio-technical systems and strategic densification. Using hybrid life cycle assessment approach combined with scenarios, we analyzed the greenhouse gas (GHG) emissions, water use, metal consumption and land use of selected socio-technical systems in 84 cities from the present to 2050. The socio-technical systems analyzed are: (1) bus rapid transit with electric buses, (2) green commercial buildings, and (3) district energy. We developed a baseline model for each city considering gross domestic product, population density, and climate conditions. Then, we overlaid three scenarios on top of the baseline model: (1) decarbonization of electricity, (2) aggressive deployment of resource-efficient socio-technical systems, and (3) strategic urban densification scenarios to each city and quantified their potentials in reducing the environmental and resource impacts of cities by 2050. The results show that, under the baseline scenario, the environmental and natural resource footprints of all 84 cities combined would increase 58%-116% by 2050. The resource-efficient scenario along with strategic densification, however, has the potential to curve down GHG emissions to 17% below the 2010 level in 2050. Such transformation can also limit the increase in all resource footprints to less than 23% relative to 2010. This analysis suggests that resource-efficient urban infrastructure and decarbonization of

  18. Quality and safety implications of emergency department information systems.

    Science.gov (United States)

    Farley, Heather L; Baumlin, Kevin M; Hamedani, Azita G; Cheung, Dickson S; Edwards, Michael R; Fuller, Drew C; Genes, Nicholas; Griffey, Richard T; Kelly, John J; McClay, James C; Nielson, Jeff; Phelan, Michael P; Shapiro, Jason S; Stone-Griffith, Suzanne; Pines, Jesse M

    2013-10-01

    The Health Information Technology for Economic and Clinical Health Act of 2009 and the Centers for Medicare & Medicaid Services "meaningful use" incentive programs, in tandem with the boundless additional requirements for detailed reporting of quality metrics, have galvanized hospital efforts to implement hospital-based electronic health records. As such, emergency department information systems (EDISs) are an important and unique component of most hospitals' electronic health records. System functionality varies greatly and affects physician decisionmaking, clinician workflow, communication, and, ultimately, the overall quality of care and patient safety. This article is a joint effort by members of the Quality Improvement and Patient Safety Section and the Informatics Section of the American College of Emergency Physicians. The aim of this effort is to examine the benefits and potential threats to quality and patient safety that could result from the choice of a particular EDIS, its implementation and optimization, and the hospital's or physician group's approach to continuous improvement of the EDIS. Specifically, we explored the following areas of potential EDIS safety concerns: communication failure, wrong order-wrong patient errors, poor data display, and alert fatigue. Case studies are presented that illustrate the potential harm that could befall patients from an inferior EDIS product or suboptimal execution of such a product in the clinical environment. The authors have developed 7 recommendations to improve patient safety with respect to the deployment of EDISs. These include ensuring that emergency providers actively participate in selection of the EDIS product, in the design of processes related to EDIS implementation and optimization, and in the monitoring of the system's ongoing success or failure. Our recommendations apply to emergency departments using any type of EDIS: custom-developed systems, best-of-breed vendor systems, or enterprise systems

  19. Emerging applications for traceability systems and implications for consumers

    NARCIS (Netherlands)

    Frewer, L.J.; Davies, O.H.; Rijswijk, W. van; Luijckx, N.L.; Ward, S.

    2008-01-01

    The modified European Food Law (General Food Law) has been emphasizing on the need to increase consumer confidence through implementation of regulatory measures focused on increased traceability in food chain. The implementation of effective traceability systems can provide the basis of

  20. Security and confidentiality of health information systems: implications for physicians.

    Science.gov (United States)

    Dorodny, V S

    1998-01-01

    Adopting and developing the new generation of information systems will be essential to remain competitive in a quality conscious health care environment. These systems enable physicians to document patient encounters and aggregate the information from the population they treat, while capturing detailed data on chronic medical conditions, medications, treatment plans, risk factors, severity of conditions, and health care resource utilization and management. Today, the knowledge-based information systems should offer instant, around-the-clock access for the provider, support simple order entry, facilitate data capture and retrieval, and provide eligibility verification, electronic authentication, prescription writing, security, and reporting that benchmarks outcomes management based upon clinical/financial decisions and treatment plans. It is an integral part of any information system to incorporate and integrate transactional (financial/administrative) information, as well as analytical (clinical/medical) data in a user-friendly, readily accessible, and secure form. This article explores the technical, financial, logistical, and behavioral obstacles on the way to the Promised Land.

  1. Focusing on Ciona intestinalis (Tunicata) innate immune system. Evolutionary implications

    OpenAIRE

    N Parrinello

    2009-01-01

    Phylogenetic analyses based on molecular data provide compelling evidence that ascidians are of critical importance for studying chordate immune system evolution. The Ciona intestinalis draft genome sequence allows searches for phylogenetic relationships, gene cloning and expression of immunorelevant molecules. Acidians lack of the pivotal components of the vertebrate recombinatory adaptive immunity, i.e., MHC, TCRs and dimeric immunoglobulins. However, bioinformatic sequence analyses recogni...

  2. Cosmological implications of the redshift distribution of QSO absorption systems

    International Nuclear Information System (INIS)

    Khare-Joshi, P.; Perry, J.J.

    1982-01-01

    We have used the observational data on QSO absorption redshifts, as compiled by Perry, Burbidge and Burbidge (1978) (hereafter PB 2 ), Drew (1978) and Weyman et al. (1979) (hereafter W 2 PT), to study various selection effects likely to affect the distribution of absorption redshifts and, then to determine the probable number distribution of absorbers per redshift interval of 0.1, as a function of z. The distribution obtained, assuming all the observed absorption to be intervening, is found to be statistically incompatible with the redshift distribution of galaxies with constant cross-section for any Friedman cosmology with zero cosmological constant and q 0 >= 0. Therefore, in order to eliminate the absorption systems which are plausibly intrinsic, we have applied the criterion suggested by W 2 PT and by the analysis of the distribution of absorption systems as a function of the relative velocity between the emitting and the absorbing gas, for the PB 2 data set; to wit, we have analysed the distributions obtained by assuming that those systems with relative velocity greater than 0.02 c, 0.02 c but not equal to 0.1 c to 0.11 c and 0.06 c respectively, or those systems without O VI and N V lines, are produced by the intervening galaxies. The results are discussed. (author)

  3. System-wide emissions implications of increased wind power penetration.

    Science.gov (United States)

    Valentino, Lauren; Valenzuela, Viviana; Botterud, Audun; Zhou, Zhi; Conzelmann, Guenter

    2012-04-03

    This paper discusses the environmental effects of incorporating wind energy into the electric power system. We present a detailed emissions analysis based on comprehensive modeling of power system operations with unit commitment and economic dispatch for different wind penetration levels. First, by minimizing cost, the unit commitment model decides which thermal power plants will be utilized based on a wind power forecast, and then, the economic dispatch model dictates the level of production for each unit as a function of the realized wind power generation. Finally, knowing the power production from each power plant, the emissions are calculated. The emissions model incorporates the effects of both cycling and start-ups of thermal power plants in analyzing emissions from an electric power system with increasing levels of wind power. Our results for the power system in the state of Illinois show significant emissions effects from increased cycling and particularly start-ups of thermal power plants. However, we conclude that as the wind power penetration increases, pollutant emissions decrease overall due to the replacement of fossil fuels.

  4. Effect of Climate Change on the Food Supply System: Implications ...

    African Journals Online (AJOL)

    Climate change has become an issue of great concern in recent years due to its effect on every aspect of life. The ecosystem, agriculture, industry, households and human well-being are all intertwined with climate change issues. The food supply system worldwide has been affected and is also contributing to climate ...

  5. Research teams as complex systems: implications for knowledge management

    NARCIS (Netherlands)

    Vasileiadou, E.

    2012-01-01

    The recent increase in research collaboration creates the need to better understand the interaction between individual researchers and the collaborative team. The paper elaborates the conceptualisation of research teams as complex systems which emerge out of the local interactions of individual

  6. Crowds As Complex Adaptive Systems: Strategic Implications For Law Enforcement

    Science.gov (United States)

    2016-03-01

    spread by word -of- mouth , news outlets, and social media .186 According to David Karpf, an assistant professor at George Washington University, the...71 6. A Word about Social Media ...such as the police. 6. A Word about Social Media The burgeoning role of social media is a significant development in crowd system dynamics. Social

  7. Implications of climate change (global warming) for the healthcare system.

    Science.gov (United States)

    Raffa, R B; Eltoukhy, N S; Raffa, K F

    2012-10-01

    Temperature-sensitive pathogenic species and their vectors and hosts are emerging in previously colder regions as a consequence of several factors, including global warming. As a result, an increasing number of people will be exposed to pathogens against which they have not previously needed defences. We illustrate this with a specific example of recent emergence of Cryptococcus gattii infections in more temperate climates. The outbreaks in more temperate climates of the highly virulent--but usually tropically restricted--C. gattii is illustrative of an anticipated growing challenge for the healthcare system. There is a need for preparedness by healthcare professionals in anticipation and for management of such outbreaks, including other infections whose recent increased prevalence in temperate climates can be at least partly associated with global warming. (Re)emergence of temperature-sensitive pathogenic species in more temperate climates will present new challenges for healthcare systems. Preparation for outbreaks should precede their occurrence. © 2012 Blackwell Publishing Ltd.

  8. The implications of an increasingly decentralised energy system

    International Nuclear Information System (INIS)

    Wolfe, Philip

    2008-01-01

    The UK government has signalled that the increasing use of decentralised energy forms part of its plan to achieve the UK's contribution to the EU's sustainable energy targets. Much of the technology for decentralised energy already exists, although it is not widely used in the UK. There will be need for new developments in onsite energy production, and in the delivery, integration and regulatory infrastructure to support it. Other State of Science reviews for this project describe particular energy technologies, but this paper highlights selected developments in thermal technologies and in biological processes which offer the potential for breakthroughs in converting biomass to energy. The effectiveness and deployment of decentralised energy can be enhanced by systems and infrastructure technology, not just for electricity but also in heat and biogas networks. Such systems are expected to be a focus of rapid development over the next two decades. Opportunities exist particularly in active networks, smart metering and intelligent tariff-interactive load management. Substantial regulatory and policy reform will be required to optimise the potential for onsite energy generation and effective two-way interchanges with centralised energy systems. There will be need for a regulatory system for heat networks and appropriate incentives for active networks. The development of an energy services business model in the industry will not progress until the compensation model changes to make it viable. The strength of the drivers for a trend towards decentralised energy, coupled with a wide range of scientific developments, should make this a very dynamic sector and present a host of new opportunities for British technology

  9. Lunar South Pole Illumination: Review, Reassessment, and Power System Implications

    Science.gov (United States)

    Fincannon, James

    2007-01-01

    This paper reviews past analyses and research related to lunar south pole illumination and presents results of independent illumination analyses using an analytical tool and a radar digital elevation model. The analysis tool enables assessment at most locations near the lunar poles for any time and any year. Average illumination fraction, energy storage duration, solar/horizon terrain elevation profiles and illumination fraction profiles are presented for various highly illuminated sites which have been identified for manned or unmanned operations. The format of the data can be used by power system designers to develop mass optimized solar and energy storage systems. Data are presented for the worse case lunar day (a critical power planning bottleneck) as well as three lunar days during lunar south pole winter. The main site under consideration by present lunar mission planners (on the Crater Shackleton rim) is shown to have, for the worse case lunar day, a 0.71 average illumination fraction and 73 to 117 hours required for energy storage (depending on power system type). Linking other sites and including towers at either site are shown to not completely eliminate the need for energy storage.

  10. Interactions of nanomaterials and biological systems: implications to personalized nanomedicine☆

    Science.gov (United States)

    Zhang, Xue-Qing; Xu, Xiaoyang; Bertrand, Nicolas; Pridgen, Eric; Swami, Archana; Farokhzad, Omid C.

    2012-01-01

    The application of nanotechnology to personalized medicine provides an unprecedented opportunity to improve the treatment of many diseases. Nanomaterials offer several advantages as therapeutic and diagnostic tools due to design flexibility, small sizes, large surface-to-volume ratio, and ease of surface modification with multivalent ligands to increase avidity for target molecules. Nanomaterials can be engineered to interact with specific biological components, allowing them to benefit from the insights provided by personalized medicine techniques. To tailor these interactions, a comprehensive knowledge of how nanomaterials interact with biological systems is critical. Herein, we discuss how the interactions of nanomaterials with biological systems can guide their design for diagnostic, imaging and drug delivery purposes. A general overview of nanomaterials under investigation is provided with an emphasis on systems that have reached clinical trials. Finally, considerations for the development of personalized nanomedicines are summarized such as the potential toxicity, scientific and technical challenges in fabricating them, and regulatory and ethical issues raised by the utilization of nanomaterials. PMID:22917779

  11. Cratering record in the inner solar system: Implications for earth

    International Nuclear Information System (INIS)

    Barlow, N.G.

    1988-01-01

    Internal and external processes have reworked the Earth's surface throughout its history. In particular, the effect of meteorite impacts on the early history of the earth is lost due to fluvial, aeolian, volcanic and plate tectonic action. The cratering record on other inner solar system bodies often provides the only clue to the relative cratering rates and intensities that the earth has experienced throughout its history. Of the five major bodies within the inner solar system, Mercury, Mars, and the Moon retain scars of an early episode of high impact rates. The heavily cratered regions on Mercury, Mars, and the Moon show crater size-frequency distribution curves similar in shape and crater density, whereas the lightly cratered plains on the Moon and Mars show distribution curves which, although similar to each other, are statistically different in shape and density from the more heavily cratered units. The similarities among crater size-frequency distribution curves for the Moon, Mercury, and Mars suggest that the entire inner solar system was subjected to the two populations of impacting objects but Earth and Venus have lost their record of heavy bombardment impactors. Thus, based on the cratering record on the Moon, Mercury, and Mars, it can be inferred that the Earth experienced a period of high crater rates and basin formation prior to about 3.8 BY ago. Recent studies have linked mass extinctions to large terrestrial impacts, so life forms were unable to establish themselves until impact rates decreased substantially and terrestrial conditions became more benign. The possible periodicity of mass extinctions has led to the theory of fluctuating impact rates due to comet showers in the post heavy bombardment period. The active erosional environment on the Earth complicates attempts to verify these showers by erasing geological evidence of older impact craters

  12. A zero-sum monetary system, interest rates, and implications

    OpenAIRE

    Hanley, Brian P.

    2015-01-01

    To the knowledge of the author, this is the first time it has been shown that interest rates that are extremely high by modern standards (100% and higher) are necessary within a zero-sum monetary system, and not just driven by greed. Extreme interest rates that appeared in various places and times reinforce the idea that hard money may have contributed to high rates of interest. Here a model is presented that examines the interest rate required to succeed as an investor in a zero-sum fixed qu...

  13. A Study of Search Intermediary Working Notes: Implications for IR System Design.

    Science.gov (United States)

    Spink, Amanda; Goodrum, Abby

    1996-01-01

    Reports findings from an exploratory study investigating working notes created during encoding and external storage (EES) processes by human search intermediaries (librarians at the University of North Texas) using a Boolean information retrieval (IR) system. Implications for the design of IR interfaces and further research is discussed.…

  14. A balancing act? The implications of mixed strategies for performance measurement system design

    NARCIS (Netherlands)

    Dekker, H.C.; Groot, T.L.C.M.; Schoute, M.

    2013-01-01

    This paper examines how firms design performance measurement systems (PMSs) to support the pursuit of mixed strategies. In particular, we examine the implications of firms' joint strategic emphasis on both low cost and differentiation for their use of performance measurement and incentive

  15. Future earth orbit transportation systems/technology implications

    Science.gov (United States)

    Henry, B. Z.; Decker, J. P.

    1976-01-01

    Assuming Space Shuttle technology to be state-of-the-art, projected technological advances to improve the capabilities of single-stage-to-orbit (SSTO) derivatives are examined. An increase of about 30% in payload performance can be expected from upgrading the present Shuttle system through weight and drag reductions and improvements in the propellants and engines. The ODINEX (Optimal Design Integration Executive Computer Program) program has been used to explore design options. An advanced technology SSTO baseline system derived from ODINEX analysis has a conventional wing-body configuration using LOX/LH engines, three with two-position nozzles with expansion ratios of 40 and 200 and four with fixed nozzles with an expansion ratio of 40. Two assisted-takeoff approaches are under consideration in addition to a concept in which the orbital vehicle takes off empty using airbreathing propulsion and carries out a rendezvous with two large cryogenic tankers carrying propellant at an altitude of 6100 m. Further approaches under examination for propulsion, aerothermodynamic design, and design integration are described.

  16. Tumor target amplification: Implications for nano drug delivery systems.

    Science.gov (United States)

    Seidi, Khaled; Neubauer, Heidi A; Moriggl, Richard; Jahanban-Esfahlan, Rana; Javaheri, Tahereh

    2018-04-10

    Tumor cells overexpress surface markers which are absent from normal cells. These tumor-restricted antigenic signatures are a fundamental basis for distinguishing on-target from off-target cells for ligand-directed targeting of cancer cells. Unfortunately, tumor heterogeneity impedes the establishment of a solid expression pattern for a given target marker, leading to drastic changes in quality (availability) and quantity (number) of the target. Consequently, a subset of cancer cells remains untargeted during the course of treatment, which subsequently promotes drug-resistance and cancer relapse. Since target inefficiency is only problematic for cancer treatment and not for treatment of other pathological conditions such as viral/bacterial infections, target amplification or the generation of novel targets is key to providing eligible antigenic markers for effective targeted therapy. This review summarizes the limitations of current ligand-directed targeting strategies and provides a comprehensive overview of tumor target amplification strategies, including self-amplifying systems, dual targeting, artificial markers and peptide modification. We also discuss the therapeutic and diagnostic potential of these approaches, the underlying mechanism(s) and established methodologies, mostly in the context of different nanodelivery systems, to facilitate more effective ligand-directed cancer cell monitoring and targeting. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Implications for a Wireless, External Device System to Study Electrocorticography

    Directory of Open Access Journals (Sweden)

    David Rotermund

    2017-04-01

    Full Text Available Implantable neuronal interfaces to the brain are an important keystone for future medical applications. However, entering this field of research is difficult since such an implant requires components from many different areas of technology. Since the complete avoidance of wires is important due to the risk of infections and other long-term problems, means for wirelessly transmitting data and energy are a necessity which adds to the requirements. In recent literature, many high-tech components for such implants are presented with remarkable properties. However, these components are typically not freely available for such a system. Every group needs to re-develop their own solution. This raises the question if it is possible to create a reusable design for an implant and its external base-station, such that it allows other groups to use it as a starting point. In this article, we try to answer this question by presenting a design based exclusively on commercial off-the-shelf components and studying the properties of the resulting system. Following this idea, we present a fully wireless neuronal implant for simultaneously measuring electrocorticography signals at 128 locations from the surface of the brain. All design files are available as open source.

  18. The dopamine motive system: implications for drug and food addiction.

    Science.gov (United States)

    Volkow, Nora D; Wise, Roy A; Baler, Ruben

    2017-11-16

    Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

  19. Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

    Science.gov (United States)

    Speed, Haley E; Masiulis, Irene; Gibson, Jay R; Powell, Craig M

    2015-01-01

    A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons

  20. Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

    Directory of Open Access Journals (Sweden)

    Haley E Speed

    Full Text Available A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C of Neuroligin 3 (NLGN3R451C is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs from parvalbumin-positive (PV or somatostatin-positive (SOM interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at

  1. The safety implications of control systems program at ORNL

    International Nuclear Information System (INIS)

    Smith, O.L.

    1987-01-01

    Simulations of two pressurized water reactors (PWRs) point to several conclusions that bear on the principle interests of Unresolved Safety Issue A-47: (1) the simulated control systems of both plants exhibit considerable ability to respond to the investigated classes of off-normal disturbances; (2) overfill of the steam generators usually produced only minor cooling of the primary side; (3) despite protective features, substantial amounts of water could be injected into the steam lines because of low steam quality or high water level, but further analysis is needed to determine whether this creates the potential for water-hammer damage or other mass or momentum effects; and (4) potential core-uncovery scenarios explored steam generator tube rupture and other small breaks that might lead to loss of primary inventory without actuation of high pressure injection. The results indicated situations in which automatic actuation of high pressure injection would terminate the leak and others in which operator intervention appeared necessary

  2. Steroid-binding receptors in fungi: implication for systemic mycoses

    Directory of Open Access Journals (Sweden)

    Mostafa chadeganipour

    2015-03-01

    Full Text Available It has been shown that some of the mycotic infections especially systemic mycoses show increased male susceptibility and some steroids have been known to influence the immune response. Researchers found that some fungi including yeasts use "message molecules" including hormones to elicit certain responses, especially in the sexual cycle, but until recently no evidence was available to link specific hormonal evidence to this pronounced sex ratio. More evidence needed to demonstrate that a steroid (s might in some manner influence the pathogenicity of the fungus in vivo. Therefore, the aim of this review paper is to shed some light on this subject along with effort to make mycologists more aware of this research as a stimulus for the explore of new ideas and design further research in this area of medical mycology.

  3. Economic implications of fusion-fission energy systems

    International Nuclear Information System (INIS)

    Deonigi, D.E.; Schulte, S.C.

    1979-04-01

    The principal conclusions that can be made based on the estimated costs reported in this paper are twofold. First, hybrid reactors operating symbiotically with conventional fission reactors are a potentially attractive supply alternative. Estimated hybrid energy system costs are slightly greater than estimated costs of the most attractive alternatives. However, given the technological, economic, and institutional uncertainties associated with future energy supply, differences of such magnitude are of little significance. Second, to be economically viable, hybrid reactors must be both fuel producers and electricity producers. A data point representing each hybrid reactor driver-blanket concept is plotted as a function of net electrical production efficiency and annual fuel production. The plots illustrate that the most economically viable reactor concepts are those that produce both fuel and electricity

  4. Implication of coumarins towards central nervous system disorders.

    Science.gov (United States)

    Skalicka-Woźniak, Krystyna; Orhan, Ilkay Erdogan; Cordell, Geoffrey A; Nabavi, Seyed Mohammad; Budzyńska, Barbara

    2016-01-01

    Coumarins are widely distributed, plant-derived, 2H-1-benzopyran-2-one derivatives which have attracted intense interest in recent years as a result of their diverse and potent pharmacological properties. Particularly, their effects on the central nervous system (CNS) have been established. The present review discusses the most important pharmacological effects of natural and synthetic coumarins on the CNS, including their interactions with benzodiazepine receptors, their dopaminergic and serotonergic affinity, and their ability to inhibit cholinesterases and monoamine oxidases. The structure-activity relationships pertaining to these effects are also discussed. This review posits that natural or synthetic coumarins have the potential for development in the therapy of psychiatric and neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, schizophrenia, anxiety, epilepsy, and depression. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Reforming the health care system: implications for health care marketers.

    Science.gov (United States)

    Petrochuk, M A; Javalgi, R G

    1996-01-01

    Health care reform has become the dominant domestic policy issue in the United States. President Clinton, and the Democratic leaders in the House and Senate have all proposed legislation to reform the system. Regardless of the plan which is ultimately enacted, health care delivery will be radically changed. Health care marketers, given their perspective, have a unique opportunity to ensure their own institutions' success. Organizational, managerial, and marketing strategies can be employed to deal with the changes which will occur. Marketers can utilize personal strategies to remain proactive and successful during an era of health care reform. As outlined in this article, responding to the health care reform changes requires strategic urgency and action. However, the strategies proposed are practical regardless of the version of health care reform legislation which is ultimately enacted.

  6. The safety implications of control systems program at ORNL

    International Nuclear Information System (INIS)

    Smith, O.L.

    1987-01-01

    Simulations of two pressurized water reactors (PWRs) point to several conclusions that bear on the principle interests of Unresolved Safety Issue A-47: the simulated control systems of both plants exhibit considerable ability to respond to the investigated classes of off-normal disturbances; overfill of the steam generators usually produced only minor cooling of the primary side; despite protective features, substantial amounts of water could be injected into the steam lines because of low steam quality or high water level, but further analysis is needed to determine whether this creates the potential for water-hammer damage or other mass or momentum effects; and potential core-uncovery scenarios explored steam generator tube rupture and other small breaks that might lead to loss of primary inventory without actuation of high pressure injection. The results indicated situations in which automatic actuation of high pressure injection would terminate the leak and others in which operator intervention appeared necessary

  7. Carbon dioxide in magmas and implications for hydrothermal systems

    Science.gov (United States)

    Lowenstern, J. B.

    2001-01-01

    This review focuses on the solubility, origin, abundance, and degassing of carbon dioxide (CO2) in magma-hydrothermal systems, with applications for those workers interested in intrusion-related deposits of gold and other metals. The solubility of CO2 increases with pressure and magma alkalinity. Its solubility is low relative to that of H2O, so that fluids exsolved deep in the crust tend to have high CO2/H2O compared with fluids evolved closer to the surface. Similarly, CO2/H2O will typically decrease during progressive decompression- or crystallization-induced degassing. The temperature dependence of solubility is a function of the speciation of CO2, which dissolves in molecular form in rhyolites (retrograde temperature solubility), but exists as dissolved carbonate groups in basalts (prograde). Magnesite and dolomite are stable under a relatively wide range of mantle conditions, but melt just above the solidus, thereby contributing CO2 to mantle magmas. Graphite, diamond, and a free CO2-bearing fluid may be the primary carbon-bearing phases in other mantle source regions. Growing evidence suggests that most CO2 is contributed to arc magmas via recycling of subducted oceanic crust and its overlying sediment blanket. Additional carbon can be added to magmas during magma-wallrock interactions in the crust. Studies of fluid and melt inclusions from intrusive and extrusive igneous rocks yield ample evidence that many magmas are vapor saturated as deep as the mid crust (10-15 km) and that CO2 is an appreciable part of the exsolved vapor. Such is the case in both basaltic and some silicic magmas. Under most conditions, the presence of a CO2-bearing vapor does not hinder, and in fact may promote, the ascent and eruption of the host magma. Carbonic fluids are poorly miscible with aqueous fluids, particularly at high temperature and low pressure, so that the presence of CO2 can induce immiscibility both within the magmatic volatile phase and in hydrothermal systems

  8. The implications of risk management information systems for the organization of financial firms

    OpenAIRE

    Michael S. Gibson

    1998-01-01

    Financial dealer firms have invested heavily in recent years to develop information systems for risk measurement. I take it as given that technological progress is likely to continue at a rapid pace, making it less expensive for financial firms to assemble risk information. I look beyond questions of risk measurement methodology to investigate the implications of risk management information systems. By examining several theoretical models of the firm in the presence of asymmetric information,...

  9. Towards 5G communication systems: Are there health implications?

    Science.gov (United States)

    Di Ciaula, Agostino

    2018-04-01

    The spread of radiofrequency electromagnetic fields (RF-EMF) is rising and health effects are still under investigation. RF-EMF promote oxidative stress, a condition involved in cancer onset, in several acute and chronic diseases and in vascular homeostasis. Although some evidences are still controversial, the WHO IARC classified RF-EMF as "possible carcinogenic to humans", and more recent studies suggested reproductive, metabolic and neurologic effects of RF-EMF, which are also able to alter bacterial antibiotic resistance. In this evolving scenario, although the biological effects of 5G communication systems are very scarcely investigated, an international action plan for the development of 5G networks has started, with a forthcoming increment in devices and density of small cells, and with the future use of millimeter waves (MMW). Preliminary observations showed that MMW increase skin temperature, alter gene expression, promote cellular proliferation and synthesis of proteins linked with oxidative stress, inflammatory and metabolic processes, could generate ocular damages, affect neuro-muscular dynamics. Further studies are needed to better and independently explore the health effects of RF-EMF in general and of MMW in particular. However, available findings seem sufficient to demonstrate the existence of biomedical effects, to invoke the precautionary principle, to define exposed subjects as potentially vulnerable and to revise existing limits. An adequate knowledge of pathophysiological mechanisms linking RF-EMF exposure to health risk should also be useful in the current clinical practice, in particular in consideration of evidences pointing to extrinsic factors as heavy contributors to cancer risk and to the progressive epidemiological growth of noncommunicable diseases. Copyright © 2018 Elsevier GmbH. All rights reserved.

  10. Differential Regulation of Eicosanoid and Endocannabinoid Production by Inflammatory Mediators in Human Choriodecidua.

    Directory of Open Access Journals (Sweden)

    M D Mitchell

    Full Text Available An increase in intrauterine prostaglandin production is critical for the onset and progression of labor in women and indeed all mammalian species studied. Endocannabinoids can act as substrates for enzymes of the prostaglandin biosynthetic pathways and can be utilized to generate other related compounds such as prostamides. The end products are indistinguishable by radioimmunoassay. We have separated such compounds by mass spectrometry. We now show that inflammatory stimuli such as LPS and proinflammatory cytokines act differentially on these pathways in human choriodecidua and preferentially create drive through to prostaglandin end products. These findings create doubt about the interpretation of data on prostaglandin biosynthesis in intrauterine tissues from pregnant women especially in the presence of an infection. The possibility is raised that separation of these products might reduce variability in results and lead to potential uses for their measurement in the diagnosis of preterm labor.

  11. The use of prime implicants in dependability analysis of software controlled systems

    Energy Technology Data Exchange (ETDEWEB)

    Yau, Michael; Apostolakis, George; Guarro, Sergio

    1998-11-01

    The behavior of software controlled systems is usually non-binary and dynamic. It is, thus, convenient to employ multi-valued logic to model these systems. Multi-valued logic functions can be used to represent the functional and temporal relationships between the software and hardware components. The resulting multi-valued logic model can be analyzed deductively, i.e. by tracking causality in reverse from undesirable 'top' events to identify faults that may be present in the system. The result of this deductive analysis is a set of prime implicants for a user-defined system top event. The prime implicants represent all the combinations of basic component conditions and software input conditions that may result in the top event; they are the extension to multi-valued logic of the concept of minimal cut sets that is used routinely in the analysis of binary fault trees. This paper discusses why prime implicants are needed in the dependability analysis of software controlled systems, how they are generated, and how they are used to identify faults in a software controlled system.

  12. The use of prime implicants in dependability analysis of software controlled systems

    International Nuclear Information System (INIS)

    Yau, Michael; Apostolakis, George; Guarro, Sergio

    1998-01-01

    The behavior of software controlled systems is usually non-binary and dynamic. It is, thus, convenient to employ multi-valued logic to model these systems. Multi-valued logic functions can be used to represent the functional and temporal relationships between the software and hardware components. The resulting multi-valued logic model can be analyzed deductively, i.e. by tracking causality in reverse from undesirable 'top' events to identify faults that may be present in the system. The result of this deductive analysis is a set of prime implicants for a user-defined system top event. The prime implicants represent all the combinations of basic component conditions and software input conditions that may result in the top event; they are the extension to multi-valued logic of the concept of minimal cut sets that is used routinely in the analysis of binary fault trees. This paper discusses why prime implicants are needed in the dependability analysis of software controlled systems, how they are generated, and how they are used to identify faults in a software controlled system

  13. Implications of a Non-Unified Command System and the Need for a Unified Command System in Zambia

    Science.gov (United States)

    2015-06-12

    aspects. It has been found that Zambia’s two attempts to unify its system happened during the one party participatory democracy era. Since the coming...and its Implication for Democracy ,” in Ourselves to Know: Civil Military Relations and Defence Transformation in Southern Africa, eds. Rocky Williams...adopted a multiparty system of government under the Movement for Multi-Party Democracy (MMD) which decided to revert to independent commands. As

  14. Processing cardiovascular information in the vlPAG during electroacupuncture in rats: roles of endocannabinoids and GABA

    Science.gov (United States)

    Tjen-A-Looi, Stephanie C.; Li, Peng; Longhurst, John C.

    2009-01-01

    A long-loop pathway, involving the hypothalamic arcuate nucleus (ARC), ventrolateral periaqueductal gray (vlPAG), and the rostral ventrolateral medulla (rVLM), is essential in electroacupuncture (EA) attenuation of sympathoexcitatory cardiovascular reflex responses. The ARC provides excitatory input to the vlPAG, which, in turn, inhibits neuronal activity in the rVLM. Although previous studies have shown that endocannabinoid CB1 receptor activation modulates γ-aminobutyric acid (GABA)-ergic and glutamatergic neurotransmission in the dorsolateral PAG in stress-induced analgesia, an important role for endocannabinoids in the vlPAG has not yet been observed. We recently have shown (Fu LW, Longhurst JC. J Appl Physiol; doi:10.1152/japplphysiol.91648.2008) that EA reduces the local vlPAG concentration of GABA, but not glutamate, as measured with high-performance liquid chromatography from extracellular samples collected by microdialysis. We, therefore, hypothesized that, during EA, endocannabinoids, acting through CB1 receptors, presynaptically inhibit GABA release to disinhibit the vlPAG and ultimately modulate excitatory reflex blood pressure responses. Rats were anesthetized, ventilated, and instrumented to measure heart rate and blood pressure. Gastric distention-induced blood pressure responses of 18 ± 5 mmHg were reduced to 6 ± 1 mmHg by 30 min of low-current, low-frequency EA applied bilaterally at pericardial P 5–6 acupoints overlying the median nerves. Like EA, microinjection of the fatty acid amide hydrolase inhibitor URB597 (0.1 nmol, 50 nl) into the vlPAG to increase endocannabinoids locally reduced the gastric distention cardiovascular reflex response from 21 ± 5 to 3 ± 4 mmHg. This inhibition was reversed by pretreatment with the GABAA antagonist gabazine (27 mM, 50 nl), suggesting that endocannabinoids exert their action through a GABAergic receptor mechanism in the vlPAG. The EA-related inhibition from 18 ± 3 to 8 ± 2 mmHg was reversed to 14

  15. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    Directory of Open Access Journals (Sweden)

    Patrizia eCampolongo

    2012-03-01

    Full Text Available Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p. on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal and Low Arousal conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the Low Arousal condition spent more time in the centre of the arena than vehicle-treated rats exposed to the High Arousal context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution.AM404 administration did not alter the locomotor activity of the animals exposed to both environmental conditions. Interestingly, AM404 administration increased the emotional reactivity of rats exposed to the High Arousal condition but did not influence emotionality of rats exposed to the Low Arousal condition. Moreover, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the High Arousal condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the Low Arousal condition.These findings suggest that drugs which enhance the endocannabinoid signalling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions.

  16. Circulating Endocannabinoids and Insulin Resistance in Patients with Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Xiaoya Wang

    2016-01-01

    Full Text Available Objectives. The purpose of this study is to investigate the relationship between plasma endocannabinoids and insulin resistance (IR in patients with obstructive sleep apnea (OSA. Methods. A population of 64 with OSA and 24 control subjects was recruited. Body mass index (BMI, waist circumference, lipids, blood glucose and insulin, homeostasis model of assessment for insulin resistance index (HOMA-IR, anandamide (AEA, 1/2-arachidonoylglycerol (1/2-AG, and apnea-hypopnea index (AHI were analyzed. Results. Fasting blood insulin (22.9 ± 7.8 mIU/L versus 18.5 ± 7.2 mIU/L, P<0.05, HOMA-IR (2.9 ± 1.0 versus 2.4 ± 0.9, P<0.01, AEA (3.2 ± 0.7 nmol/L versus 2.5 ± 0.6 nmol/L, P<0.01, and 1/2-AG (40.8 ± 5.7 nmol/L versus 34.3 ± 7.7 nmol/L, P<0.01 were higher in OSA group than those in control group. In OSA group, AEA, 1/2-AG, and HOMA-IR increase with the OSA severity. The correlation analysis showed significant positive correlation between HOMA-IR and AHI (r=0.44, P<0.01, AEA and AHI (r=0.52, P<0.01, AEA and HOMA-IR (r=0.62, P<0.01, and 1/2-AG and HOMA-IR (r=0.33, P<0.01. Further analysis showed that only AEA was significantly correlated with AHI and HOMA-IR after adjusting for confounding factors. Conclusions. The present study indicated that plasma endocannabinoids levels, especially AEA, were associated with IR and AHI in patients with OSA.

  17. Implications of complex adaptive systems theory for interpreting research about health care organizations.

    Science.gov (United States)

    Jordon, Michelle; Lanham, Holly Jordan; Anderson, Ruth A; McDaniel, Reuben R

    2010-02-01

    Data about health care organizations (HCOs) are not useful until they are interpreted. Such interpretations are influenced by the theoretical lenses used by the researcher. Our purpose was to suggest the usefulness of theories of complex adaptive systems (CASs) in guiding research interpretation. Specifically, we addressed two questions: (1) What are the implications for interpreting research observations in HCOs of the fact that we are observing relationships among diverse agents? (2) What are the implications for interpreting research observations in HCOs of the fact that we are observing relationships among agents that learn? We defined diversity and learning and the implications of the non-linear relationships among agents from a CAS perspective. We then identified some common analytical practices that were problematic and may lead to conceptual and methodological errors. Then we described strategies for interpreting the results of research observations. We suggest that the task of interpreting research observations of HCOs could be improved if researchers take into account that the systems they study are CASs with non-linear relationships among diverse, learning agents. Our analysis points out how interpretation of research results might be shaped by the fact that HCOs are CASs. We described how learning is, in fact, the result of interactions among diverse agents and that learning can, by itself, reduce or increase agent diversity. We encouraged researchers to be persistent in their attempts to reason about complex systems and learn to attend not only to structures, but also to processes and functions of complex systems.

  18. Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

    Science.gov (United States)

    Achterberg, E J Marijke; van Swieten, Maaike M H; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

    2016-08-01

    Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.

    Science.gov (United States)

    Monteleone, P; Bifulco, M; Di Filippo, C; Gazzerro, P; Canestrelli, B; Monteleone, F; Proto, M C; Di Genio, M; Grimaldi, C; Maj, M

    2009-10-01

    Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.

  20. Public Health Perspectives of Preeclampsia in Developing Countries: Implication for Health System Strengthening

    OpenAIRE

    Kayode O. Osungbade; Olusimbo K. Ige

    2011-01-01

    Objectives. Review of public health perspectives of preeclampsia in developing countries and implications for health system strengthening. Methods. Literature from Pubmed (MEDLINE), AJOL, Google Scholar, and Cochrane database were reviewed. Results. The prevalence of preeclampsia in developing countries ranges from 1.8% to 16.7%. Many challenges exist in the prediction, prevention, and management of preeclampsia. Promising prophylactic measures like low-dose aspirin and calcium supplem...

  1. Number pronunciation in a multilingual environment and implications for an ASR system

    CSIR Research Space (South Africa)

    Molapo, R

    2014-11-01

    Full Text Available . Mbogho, “Web-based corpus acquisition for Swahili language modelling,” in 3rd workshop on Spoken Languages Technolo- gies for Under-resourced languages, 2012, pp. 42–47. [8] T. Schlippe, C. Zhu, J. Gebhardt, and T. Schultz, “Text normalization based... multilingual environment and implications for an ASR system Raymond Molapo Human Language Technologies Research Group Meraka Institute CSIR, South Africa Multilingual Speech Technologies Group North-West University Vanderbijlpark South Africa Email: rmolapo...

  2. Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli.

    Science.gov (United States)

    Rea, Kieran; Olango, Weredeselam M; Okine, Bright N; Madasu, Manish K; McGuire, Iseult C; Coyle, Kathleen; Harhen, Brendan; Roche, Michelle; Finn, David P

    2014-01-01

    Pain is both a sensory and an emotional experience, and is subject to modulation by a number of factors including genetic background modulating stress/affect. The Wistar-Kyoto (WKY) rat exhibits a stress-hyper-responsive and depressive-like phenotype and increased sensitivity to noxious stimuli, compared with other rat strains. Here, we show that this genotype-dependent hyperalgesia is associated with impaired pain-related mobilisation of endocannabinoids and transcription of their synthesising enzymes in the rostral ventromedial medulla (RVM). Pharmacological blockade of the Cannabinoid1 (CB1) receptor potentiates the hyperalgesia in WKY rats, whereas inhibition of the endocannabinoid catabolising enzyme, fatty acid amide hydrolase, attenuates the hyperalgesia. The latter effect is mediated by CB1 receptors in the RVM. Together, these behavioural, neurochemical, and molecular data indicate that impaired endocannabinoid signalling in the RVM underpins hyper-responsivity to noxious stimuli in a genetic background prone to heightened stress/affect. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  3. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients

    Directory of Open Access Journals (Sweden)

    Verde Roberta

    2010-04-01

    Full Text Available Abstract Background The endocannabinoids, anandamide and 2-AG, are produced by adipocytes, where they stimulate lipogenesis via cannabinoid CB1 receptors and are under the negative control of leptin and insulin. Endocannabinoid levels are elevated in the blood of obese individuals and nonobese type 2 diabetes patients. To date, no study has evaluated endocannabinoid levels in subcutaneous adipose tissue (SAT of subjects with both obesity and type 2 diabetes (OBT2D, characterised by similar adiposity and whole body insulin resistance and lower plasma leptin levels as compared to non-diabetic obese subjects (OB. Design and Methods The levels of anandamide and 2-AG, and of the anandamide-related PPARα ligands, oleoylethanolamide (OEA and palmitoylethanolamide (PEA, in the SAT obtained by abdominal needle biopsy in 10 OBT2D, 11 OB, and 8 non-diabetic normal-weight (NW subjects, were measured by liquid chromatography-mass spectrometry. All subjects underwent a hyperinsulinaemic euglycaemic clamp. Results As compared to NW, anandamide, OEA and PEA levels in the SAT were 2-4.4-fold elevated (p Conclusions The observed alterations emphasize, for the first time in humans, the potential different role and regulation of adipose tissue anandamide (and its congeners and 2-AG in obesity and type 2 diabetes.

  4. Medical tourism and policy implications for health systems: a conceptual framework from a comparative study of Thailand, Singapore and Malaysia

    OpenAIRE

    Pocock, Nicola S; Phua, Kai Hong

    2011-01-01

    Abstract Medical tourism is a growing phenomenon with policy implications for health systems, particularly of destination countries. Private actors and governments in Southeast Asia are promoting the medical tourist industry, but the potential impact on health systems, particularly in terms of equity in access and availability for local consumers, is unclear. This article presents a conceptual framework that outlines the policy implications of medical tourism's growth for health systems, draw...

  5. Developmental programming of somatic growth, behavior and endocannabinoid metabolism by variation of early postnatal nutrition in a cross-fostering mouse model.

    Science.gov (United States)

    Schreiner, Felix; Ackermann, Merle; Michalik, Michael; Hucklenbruch-Rother, Eva; Bilkei-Gorzo, Andras; Racz, Ildiko; Bindila, Laura; Lutz, Beat; Dötsch, Jörg; Zimmer, Andreas; Woelfle, Joachim

    2017-01-01

    Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer-assisted videotracking. Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p6>10 (DAGLα p6>10 (FAAH pOpen-field social behavior testing revealed significant group differences, with formerly underfed mice turning out to be the most sociable animals (p<0.01). Locomotor activity did not differ. Our data indicate a developmental plasticity of somatic growth, behavior and parameters of the eCB system, with long-lasting impact of early postnatal nutrition. Developmental programming of the eCB system in metabolically active tissues, as shown here for liver and fat, may play a role in the formation of the adult cardiometabolic risk profile following perinatal malnutrition in humans.

  6. We Don’t Want to Be Officially Certified! Reasons and Implications of the Participatory Guarantee Systems

    Directory of Open Access Journals (Sweden)

    Mamen Cuéllar-Padilla

    2018-04-01

    Full Text Available Official organic regulation in Europe is based on the third-party certification system to guarantee organic products. Many critics and dissatisfactions have motivated the emergence of other guarantee systems, based on an intense implication of producers and, in some cases, consumers and other local actors, involved in localised agri-food systems. They are called Participatory Guarantee Systems (PGS, and are not recognised as valid guarantee systems by the official organic regulation. In the present paper, we analyse the main differences between the PGS and the third party certification system, deepening on their differentiated social and political implications. We conclude that the procedures behind PGS generate numerous positive impacts in the territories related to local producers (and consumers empowerment and localised agri-food systems drive, while their implications make them not considered as a substitute to third party certification system, unless certain conditions of social consolidated groups and agroecological and food sovereignty perspective of food system take place.

  7. Implications of an emerging EHR monoculture for hospitals and healthcare systems.

    Science.gov (United States)

    Koppel, Ross; Lehmann, Christoph U

    2015-03-01

    In many hospitals and health systems, a 'new' electronic health record means a shift to one vendor: Epic, a vendor that dominates in large and medium hospital markets and continues its success with smaller institutions and ambulatory practices. Our paper examines the implications of this emerging monoculture: its advantages and disadvantages for physicians and hospitals and its role in innovation, professional autonomy, implementation difficulties, workflow, flexibility, cost, data standards, interoperability, and interactions with other information technology (IT) systems. © The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. ORGANISATIONAL DETERMINANTS INFLUENCING INFORMATION SYSTEMS REIMPLEMENTATION: SOME IMPLICATIONS TO THE DEVELOPING COUNTRIES

    Directory of Open Access Journals (Sweden)

    Sayyen Teoh

    2010-01-01

    Full Text Available This article presents an in-depth study of global Web-based Marketing Decision Support System reimplementation, in a British-based Fast Moving Consumer Goods (FMCG manufacturer. The paper shows that the success of a system implementation can still be marginal even if the organisation understands the key organisational determinants of success and has influence over them. The paper concludes with a discussion of how implementation planning, user need analysis and communication problems could be overcomed and also some implications to the companies in the developing nations.

  9. Antitrust implications of utility participation in the market for remote photovoltaic systems

    International Nuclear Information System (INIS)

    Starrs, T.J.

    1994-01-01

    Remote photovoltaic systems are an important niche market in the development of a viable photovoltaics industry. Electric utilities in the US have started offering remote photovoltaic service. Utilities have the potential to use their monopoly power in regulated markets to unfair competitive advantage in competitive markets. Therefore, utility participation in remote photovoltaic markets raises potentially significant issues of antitrust law and policy. This paper describes some of the legal and factual criteria that US courts and regulatory agencies are likely to use in assessing the antitrust implications of utility participation in the market for remote photovoltaic systems

  10. Dose-response effects of systemic anandamide administration in mice sequentially submitted to the open field and elevated plus-maze tests

    OpenAIRE

    Ribeiro,A.; Ferraz-de-Paula,V.; Pinheiro,M.L.; Palermo-Neto,J.

    2009-01-01

    The endocannabinoid system is involved in the control of many physiological functions, including the control of emotional states. In rodents, previous exposure to an open field increases the anxiety-like behavior in the elevated plus-maze. Anxiolytic-like effects of pharmacological compounds that increase endocannabinoid levels have been well documented. However, these effects are more evident in animals with high anxiety levels. Several studies have described characteristic inverted U-shaped...

  11. Nutritional status-dependent endocannabinoid signalling regulates the integration of rat visceral information.

    Science.gov (United States)

    Khlaifia, Abdessattar; Matias, Isabelle; Cota, Daniela; Tell, Fabien

    2017-06-01

    Vagal sensory inputs transmit information from the viscera to brainstem neurones located in the nucleus tractus solitarii to set physiological parameters. These excitatory synapses exhibit a CB1 endocannabinoid-induced long-term depression (LTD) triggered by vagal fibre stimulation. We investigated the impact of nutritional status on long-term changes in this long-term synaptic plasticity. Food deprivation prevents LTD induction by disrupting CB1 receptor signalling. Short-term refeeding restores the capacity of vagal synapses to express LTD. Ghrelin and cholecystokinin, respectively released during fasting and refeeding, play a key role in the control of LTD via the activation of energy sensing pathways such as AMPK and the mTOR and ERK pathways. Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarii, a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB)-induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reversed by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding, restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and

  12. Systems scale assessment of the sustainability implications of emerging green initiatives

    International Nuclear Information System (INIS)

    Tiwary, Abhishek; Namdeo, Anil; Fuentes, Jose; Dore, Anthony; Hu, Xiao-Ming; Bell, Margaret

    2013-01-01

    This paper demonstrates a systems framework for assessment of environmental impacts from ‘green initiatives’, through a case study of meso-scale, anthropogenic–biogenic interactions. The following cross-sectoral green initiatives, combining the emerging trends in the North East region of the United Kingdom, have been considered – increasing the vegetation cover; decarbonising road transport; decentralising energy production through biomass plants. Two future scenarios are assessed – Baseline 2 020 (projected emissions from realisation of policy instruments); Aggressive 2 020 (additional emissions from realisation of green initiatives). Resulting trends from the Aggressive 2 020 scenario suggest an increase in emissions of pollutant precursors, including biogenic volatile organic compounds and nitrogen dioxide over the base case by up to 20% and 5% respectively. This has implications for enhanced daytime ozone and secondary aerosols formation by up to 15% and over 5% respectively. Associated land cover changes show marginal decrease of ambient temperature but modest reductions in ammonia and ambient particulates. -- Highlights: • A systems scale assessment framework for emerging green initiatives is proposed. • Interactions between urban greenspace, greener vehicles and bioenergy system examined. • Altering future emissions profile enhances synthesis of photochemical precursors. • Incorporating whole-system evaluation deemed vital for well-rounded sustainability. -- Systems scale implication for air pollution was assessed across three sectors of emerging green initiatives-energy, transport and ecosystem

  13. Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Hai-Jing Sun

    2017-01-01

    Full Text Available Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA and 2-arachidonoylglycerol (2-AG detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS, malonaldehyde (MDA, and MPO (myeloperoxidase and increased superoxide dismutase (SOD production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.

  14. A Biological Security Motivation System for Potential Threats: Are There Implications for Policy-Making?

    Directory of Open Access Journals (Sweden)

    Erik Z Woody

    2013-09-01

    Full Text Available Research indicates that there is a specially adapted, hard-wired brain circuit, the security motivation system, which evolved to manage potential threats, such as the possibility of contamination or predation. The existence of this system may have important implications for policy-making related to security. The system is sensitive to partial, uncertain cues of potential danger, detection of which activates a persistent, potent motivational state of wariness or anxiety. This state motivates behaviours to probe the potential danger, such as checking, and to correct for it, such as washing. Engagement in these behaviours serves as the terminating feedback for the activation of the system. Because security motivation theory makes predictions about what kinds of stimuli activate security motivation and what conditions terminate it, the theory may have applications both in understanding how policy-makers can best influence others, such as the public, and also in understanding the behavior of policy-makers themselves.

  15. Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Jakub Mlost

    2018-01-01

    Full Text Available Osteoarthritis (OA is a joint disease in which cartilage degenerates as a result of mechanical and biochemical changes. The main OA symptom is chronic pain involving both peripheral and central mechanisms of nociceptive processing. Our previous studies have implicated the benefits of dual- over single-acting compounds interacting with the endocannabinoid system (ECS in OA treatment. In the present study, we focused on the specific molecular alterations associated with pharmacological treatment. OA was induced in Wistar rats by intra-articular injection of 3 mg of monoiodoacetate (MIA. Single target compounds (URB597, an FAAH inhibitor, and SB366791, a TRPV1 antagonist and a dual-acting compound OMDM198 (FAAH inhibitor/TRPV1 antagonist were used in the present study. At day 21 post-MIA injection, rats were sacrificed 1 h after i.p. treatment, and changes in mRNA expression were evaluated in the lumbar spinal cord by RT-qPCR. Following MIA administration, we observed 2-4-fold increase in mRNA expression of targeted receptors (Cnr1, Cnr2, and Trpv1, endocannabinoid degradation enzymes (Faah, Ptgs2, and Alox12, and TRPV1 sensitizing kinases (Mapk3, Mapk14, Prkcg, and Prkaca. OMDM198 treatment reversed some of the MIA effects on the spinal cord towards intact levels (Alox12, Mapk14, and Prkcg. Apparent regulation of ECS and TRPV1 in response to pharmacological intervention is a strong justification for novel ECS-based multi-target drug treatment in OA.

  16. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  17. The administration of endocannabinoid uptake inhibitors OMDM-2 or VDM-11 promotes sleep and decreases extracellular levels of dopamine in rats.

    Science.gov (United States)

    Murillo-Rodríguez, Eric; Palomero-Rivero, Marcela; Millán-Aldaco, Diana; Di Marzo, Vincenzo

    2013-01-17

    The family of the endocannabinoid system comprises endogenous lipids (such as anandamide [ANA]), receptors (CB(1)/CB(2) cannabinoid receptors), metabolic enzymes (fatty acid amide hydrolase [FAAH]) and a putative membrane transporter (anandamide membrane transporter [AMT]). Although the role of ANA, FAAH or the CB(1) cannabinoid receptor in sleep modulation has been reported, the effects of the inhibition of AMT on sleep remain unclear. In the present study, we show that microdialysis perfusion in rats of AMT inhibitors, (9Z)-N-[1-((R)-4-hydroxbenzyl)-2-hydroxyethyl]-9-octadecenamide (OMDM-2) or N-(4-hydroxy-2-methylphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (VDM-11; 10, 20 or 30 μM; each compound) delivered into the paraventricular thalamic nucleus (PVA) increased sleep and decreased waking. In addition, the infusion of compounds reduced the extracellular levels of dopamine collected from nucleus accumbens. Taken together, these findings illustrate a critical role of AMT in sleep modulation. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. The Development of Innovation System Research: Towards meaningful implications for innovation policy?

    DEFF Research Database (Denmark)

    Rakas, Marija; Hain, Daniel

    and private organizations. This proposition has stimulated discussions across academic disciplines and been applied in various fields of study, such as innovation management, economic geography, growth economics, and the study of socio-technological transitions. While the general idea of “system thinking......” nowadays can be considered as pervasive across academic traditions associated with the broader field of innovation studies, we observe significant heterogeneity with respect to the building blocks of the NIS concept emphasized as well as the problems tackled and implications provided. Yet, this diversity...

  19. The population dynamical implications of male-biased parasitism in different mating systems.

    Directory of Open Access Journals (Sweden)

    Martin R Miller

    2007-07-01

    Full Text Available Although there is growing evidence that males tend to suffer higher levels of parasitism than females, the implications of this for the population dynamics of the host population are not yet understood. Here we build on an established 'two-sex' model and investigate how increased susceptibility to infection in males affects the dynamics, under different mating systems. We investigate the effect of pathogenic disease at different case mortalities, under both monogamous and polygynous mating systems. If the case mortality is low, then male-biased parasitism appears similar to unbiased parasitism in terms of its effect on the population dynamics. At higher case mortalities, we identified significant differences between male-biased and unbiased parasitism. A host population may therefore be differentially affected by male-biased and unbiased parasitism. The dynamical outcome is likely to depend on a complex interaction between the host's mating system and demography, and the parasite virulence.

  20. HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists.

    Science.gov (United States)

    Fusco, Nicola; Bosari, Silvano

    2016-09-21

    Management of cancers of the digestive system has progressed rapidly into the molecular era. Despite the significant recent achievements in the diagnosis and treatment of these patients, the number of deaths for these tumors has currently plateaued. Many investigations have assessed the role of HER2 in tumors of the digestive system in both prognostic and therapeutic settings, with heterogeneous results. Novel testing and treatment guidelines are emerging, in particular in gastric and colorectal cancers. However, further advances are needed. In this review we provide a comprehensive overview of the current state-of-knowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.

  1. Private investments in hospitals : a comparison of three healthcare systems and possible implications for real estate strategies

    NARCIS (Netherlands)

    van der Zwart, J.; van der Voordt, Theo; de Jonge, H.

    2010-01-01

    Objectives: This article explores lessons to be learned from three different healthcare systems and the possible implications for the management of healthcare real estate, in particular in connection to the Dutch system. It discusses similarities and differences among the different systems, in

  2. Dynamics of quadruple systems composed of two binaries: stars, white dwarfs, and implications for Ia supernovae

    Science.gov (United States)

    Fang, Xiao; Thompson, Todd A.; Hirata, Christopher M.

    2018-05-01

    We investigate the long-term secular dynamics and Lidov-Kozai (LK) eccentricity oscillations of quadruple systems composed of two binaries at quadrupole and octupole orders in the perturbing Hamiltonian. We show that the fraction of systems reaching high eccentricities is enhanced relative to triple systems, over a broader range of parameter space. We show that this fraction grows with time, unlike triple systems evolved at quadrupole order. This is fundamentally because with their additional degrees of freedom, quadruple systems do not have a maximal set of commuting constants of the motion, even in secular theory at quadrupole order. We discuss these results in the context of star-star and white dwarf-white dwarf (WD) binaries, with emphasis on WD-WD mergers and collisions relevant to the Type Ia supernova problem. For star-star systems, we find that more than 30 per cent of systems reach high eccentricity within a Hubble time, potentially forming triple systems via stellar mergers or close binaries. For WD-WD systems, taking into account general relativistic and tidal precession and dissipation, we show that the merger rate is enhanced in quadruple systems relative to triple systems by a factor of 3.5-10, and that the long-term evolution of quadruple systems leads to a delay-time distribution ˜1/t for mergers and collisions. In gravitational wave-driven mergers of compact objects, we classify the mergers by their evolutionary patterns in phase space and identify a regime in about 8 per cent of orbital shrinking mergers, where eccentricity oscillations occur on the general relativistic precession time-scale, rather than the much longer LK time-scale. Finally, we generalize previous treatments of oscillations in the inner binary eccentricity (evection) to eccentric mutual orbits. We assess the merger rate in quadruple and triple systems and the implications for their viability as progenitors of stellar mergers and Type Ia supernovae.

  3. Nuclear whistleblower protection system in U.S. and its implication to Japanese regulatory system

    International Nuclear Information System (INIS)

    Tanabe, Tomoyuki; Suzuki, Tatsujiro

    2003-01-01

    The nuclear whistleblower protection system in U.S.A consists of two programs: 1) allegation program and 2) whistleblower protection system. The former is explained by basic act, definition of allegation, anonymous allegation, direct allegation to NRC (Nuclear Regulatory Commission), number of allegation from 1997 to 2001, procedure and period of investigation and notice of allegation to licensees. The latter is explained by basis act, outline of the system, enforcement by NRC and DOL (Department of Labor), number of discrimination compliant and anxiety of licensees. The system is good conditions in U.S.A depend on 1) prevent of illegal act and increase, 2) preparation of procedure and its transparency and 3) enforcement system. However, a hostile act to licensees is found in the whistleblower protection system. There are many problems in Japanese regulatory system. The improvement points of Japanese system are proposed. (S.Y.)

  4. Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

    Science.gov (United States)

    Iball, Jonathan; Ali, Afia B.

    2011-01-01

    Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization. PMID

  5. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids.

    Science.gov (United States)

    Pataky, Zoltan; Carrard, Isabelle; Gay, Valerie; Thomas, Aurélien; Carpentier, Anne; Bobbioni-Harsch, Elisabetta; Golay, Alain

    2018-04-10

    To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Among completers (n = 87), body weight decreased in 35 patients (-9.1 ± 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL. © 2018 The Author(s) Published by S. Karger GmbH, Freiburg.

  6. Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids?

    Directory of Open Access Journals (Sweden)

    Zoltan Pataky

    2018-04-01

    Full Text Available Objective: To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED as well as quality of life (QoL and to elucidate the role of endocannabinoids in metabolic syndrome (MS. Methods: In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. Results: Among completers (n = 87, body weight decreased in 35 patients (-9.1 ± 8.6 kg, remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg. 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08, fasting glucose (p 2 = 0.12, total cholesterol (p = 0.001, R2 = 0.11, triglycerides (p = 0.001, R2 = 0.11, LDL-cholesterol (p = 0.03, R2 = 0.05 as well as depression score (p = 0.002, R2 = 0.29. Conclusion: Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL.

  7. Endocannabinoid release modulates electrical coupling between CCK cells connected via chemical and electrical synapses in CA1

    Directory of Open Access Journals (Sweden)

    Jonathan eIball

    2011-11-01

    Full Text Available Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholesystokinin (CCK interneurons which co-express cannbinoid type-1 (CB1 receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labelling in acute slices of rat hippocampus at P18-20 days. CA1 stratum radiatum CCK Schaffer collateral associated (SCA cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released IPSPs that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5M resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI, maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.

  8. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids

    Science.gov (United States)

    Covey, Dan P.; Bunner, Kendra D.; Schuweiler, Douglas R.; Cheer, Joseph F.; Garris, Paul A.

    2018-01-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  9. Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

    Science.gov (United States)

    Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R; Cheer, Joseph F; Garris, Paul A

    2016-06-01

    The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement

  10. Models of governance in multihospital systems. Implications for hospital and system-level decision-making.

    Science.gov (United States)

    Morlock, L L; Alexander, J A

    1986-12-01

    This study utilizes data from a national survey of 159 multihospital systems in order to describe the types of governance structures currently being utilized, and to compare the policy making process for various types of decisions in systems with different approaches to governance. Survey results indicate that multihospital systems most often use one of three governance models. Forty-one percent of the systems (including 33% of system hospitals) use a parent holding company model in which there is a system-wide corporate governing board and separate governing boards for each member hospital. Twenty-two percent of systems in the sample (but 47% of all system hospitals) utilize what we have termed a modified parent holding company model in which there is one system-wide governing board, but advisory boards are substituted for governing boards at the local hospital level. Twenty-three percent of the sampled systems (including 11% of system hospitals) use a corporate model in which there is one system-wide governing board but no other governing or advisory boards at either the divisional, regional or local hospital levels. A comparison of systems using these three governance approaches found significant variation in terms of system size, ownership and the geographic proximity of member hospitals. In order to examine the relationship between alternative approaches to governance and patterns of decision-making, the three model types were compared with respect to the percentages of systems reporting that local boards, corporate management and/or system-wide corporate boards have responsibility for decision-making in a number of specific issue areas. Study results indicate that, regardless of model type, corporate boards are most likely to have responsibility for decisions regarding the transfer, pledging and sale of assets; the formation of new companies; purchase of assets greater than $100,000; changes in hospital bylaws; and the appointment of local board members. In

  11. Physician practice management companies: implications for hospital-based integrated delivery systems.

    Science.gov (United States)

    Burns, L R; Robinson, J C

    1997-01-01

    Physician practice management companies (PPMCs) are one of the most visible entrants into the industry of managing physician practices, and anywhere from 100-150 are already in operation. Although PPMCs and hospital-based integrated delivery systems (IDSs) differ from each other in many ways, they share a number of common features, including the pursuit of capitation contracts from payors. As a result, PPMCs pose a growing, direct threat to hospital systems in competing for managed care contracts that cover physician service. PPMCs also provide an alternative to hospital-based IDSs at the local market level for physician group consolidation. This article looks at the structure, operation, and strategy of PPMCs and examines what implications their growth will have for hospital-based IDSs.

  12. Optimal use of video for teaching the practical implications of studying business information systems

    DEFF Research Database (Denmark)

    Fog, Benedikte; Ulfkjær, Jacob Kanneworff Stigsen; Schlichter, Bjarne Rerup

    that video should be introduced early during a course to prevent students’ misconceptions of working with business information systems, as well as to increase motivation and comprehension within the academic area. It is also considered of importance to have a trustworthy person explaining the practical......The study of business information systems has become increasingly important in the Digital Economy. However, it has been found that students have difficulties understanding the practical implications thereof and this leads to a motivational decreases. This study aims to investigate how to optimize...... not sufficiently reflect the theoretical recommendations of using video optimally in a management education. It did not comply with the video learning sequence as introduced by Marx and Frost (1998). However, it questions if the level of cognitive orientation activities can become too extensive. It finds...

  13. Distribution Grid Integration of Photovoltaic Systems in Germany – Implications on Grid Planning and Grid Operation

    International Nuclear Information System (INIS)

    Stetz, Thomas

    2017-01-01

    Photovoltaic is the most dispersed renewable energy source in Germany, typically interconnected to low and medium voltage systems. In recent years, cost-intensive grid reinforcements had to be undertaken all across Germany’s distribution grids in order to increase their hosting capacity for these photovoltaic installations. This paper presents an overview on research results which show that photovoltaic itself can provide ancillary services to reduce its cost of interconnection. Especially the provision of reactive power turned out to be a technically effective and economically efficient method to increase a grid’s hosting capacity for photovoltaic capacity. Different reactive power control methods were investigated, revealing significant differences with regards to their grid operation implications. Business cases for residential-scale photovoltaic applications have shifted from feed-in-tariff based active power feed-in to self-consumption. However, increasing the photovoltaic self-consumption by additional battery-storage systems is still not economically reliable in Germany. (author)

  14. Ecological network analysis for economic systems: growth and development and implications for sustainable development.

    Science.gov (United States)

    Huang, Jiali; Ulanowicz, Robert E

    2014-01-01

    The quantification of growth and development is an important issue in economics, because these phenomena are closely related to sustainability. We address growth and development from a network perspective in which economic systems are represented as flow networks and analyzed using ecological network analysis (ENA). The Beijing economic system is used as a case study and 11 input-output (I-O) tables for 1985-2010 are converted into currency networks. ENA is used to calculate system-level indices to quantify the growth and development of Beijing. The contributions of each direct flow toward growth and development in 2010 are calculated and their implications for sustainable development are discussed. The results show that during 1985-2010, growth was the main attribute of the Beijing economic system. Although the system grew exponentially, its development fluctuated within only a small range. The results suggest that system ascendency should be increased in order to favor more sustainable development. Ascendency can be augmented in two ways: (1) strengthen those pathways with positive contributions to increasing ascendency and (2) weaken those with negative effects.

  15. Classification systems in nursing : Formalizing nursing knowledge and implications for nursing information systems

    NARCIS (Netherlands)

    Goossen, WTF; Epping, PJMM; Abraham, IL

    The development of nursing information systems (NIS) is often hampered by the fact that nursing lacks a unified nursing terminology and classification system. Currently there exist various initiatives in this area. We address the question as to how current initiatives in the development of nursing

  16. Relationships between Conceptual Knowledge and Reasoning about Systems: Implications for Fostering Systems Thinking in Secondary Science

    Science.gov (United States)

    Lyons, Cheryl

    2014-01-01

    Reasoning about systems is necessary for understanding many modern issues that face society and is important for future scientists and all citizens. Systems thinking may allow students to make connections and identify common themes between seemingly different situations and phenomena, and is relevant to the focus on cross-cutting concepts in…

  17. Polarized cellular patterns of endocannabinoid production and detection shape cannabinoid signaling in neurons

    Directory of Open Access Journals (Sweden)

    Delphine eLadarre

    2015-01-01

    Full Text Available Neurons display important differences in plasma membrane composition between somatodendritic and axonal compartments, potentially leading to currently unexplored consequences in G-protein-coupled-receptor signaling. Here, by using highly-resolved biosensor imaging to measure local changes in basal levels of key signaling components, we explored features of type-1 cannabinoid receptor (CB1R signaling in individual axons and dendrites of cultured rat hippocampal neurons. Activation of endogenous CB1Rs led to rapid, Gi/o-protein- and cAMP-mediated decrease of cyclic-AMP-dependent protein kinase (PKA activity in the somatodendritic compartment. In axons, PKA inhibition was significantly stronger, in line with axonally-polarized distribution of CB1Rs. Conversely, inverse agonist AM281 produced marked rapid increase of basal PKA activation in somata and dendrites, but not in axons, removing constitutive activation of CB1Rs generated by local production of the endocannabinoid 2-arachidonoylglycerol (2-AG. Interestingly, somatodendritic 2-AG levels differently modified signaling responses to CB1R activation by Δ9-THC, the psychoactive compound of marijuana, and by the synthetic cannabinoids WIN55,212-2 and CP55,940. These highly contrasted differences in sub-neuronal signaling responses warrant caution in extrapolating pharmacological profiles, which are typically obtained in non-polarized cells, to predict in vivo responses of axonal (i.e. presynaptic GPCRs. Therefore, our results suggest that enhanced comprehension of GPCR signaling constraints imposed by neuronal cell biology may improve the understanding of neuropharmacological action.

  18. Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats.

    Science.gov (United States)

    Zubrzycki, Marek; Janecka, Anna; Liebold, Andreas; Ziegler, Mechthild; Zubrzycka, Maria

    2017-11-01

    Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia. The specific effects of these compounds within the orofacial region are largely unknown. In this study, we tried to determine whether an increase in cannabinoid and opioid concentration in the CSF affects impulse transmission between the motor centres localized in the vicinity of the third and fourth cerebral ventricles. The study objectives were realized on rats using a method that allows the recording of the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation. The amplitude of ETJ was a measure of the effect of neurotransmitters on neural structures. Perfusion of cerebral ventricles with anandamide (AEA), endomorphin-2 (EM-2), URB597, an inhibitor of fatty acid amide hydrolase (FAAH) and JZL195, a dual inhibitor of FAAH and monoacylglycerol lipase (MAGL) reduced the ETJ amplitude. The antinociceptive effect of AEA, EM-2, URB597 and JZL195 was blocked by CB 1 receptor antagonist, AM251 and by μ receptor-antagonist, β-funaltrexamine. In contrast to AEA, 2-arachidonoylglycerol alone did not decrease ETJ amplitude. We demonstrated that in the orofacial area, analgesic activity is modulated by AEA and that EM-2-induced antinociception was mediated by μ and CB 1 receptors. The action of AEA and EM-2 is tightly regulated by FAAH and FAAH/MAGL, by preventing the breakdown of endogenous cannabinoids in regions where they are produced on demand. Therefore, the current findings support the therapeutic potential of FAAH and FAAH/MAGL inhibitors as novel pharmacotherapeutic agents for orofacial pain. © 2017 The British Pharmacological Society.

  19. Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.

    Directory of Open Access Journals (Sweden)

    Gonzalo E Yévenes

    Full Text Available Glycine receptors (GlyRs are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA are positive modulators of α(1, α(2 and α(3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly potentiate α(1 GlyRs but inhibit α(2 and α(3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM region 2 and intracellular lysine 385 determine the positive modulation of α(1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α(2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α(1 GlyRs, without affecting inhibition of α(2 and α(3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.

  20. Reclaimed water as a reservoir of antibiotic resistance genes: distribution system and irrigation implications

    Directory of Open Access Journals (Sweden)

    Nicole L Fahrenfeld

    2013-05-01

    Full Text Available Treated wastewater is increasingly being reused to achieve sustainable water management in arid regions. The objective of this study was to quantify the distribution of antibiotic resistance genes (ARGs in recycled water, particularly after it has passed through the distribution system, and to consider point-of-use implications for soil irrigation. Three separate reclaimed wastewater distribution systems in the western U.S. were examined. Quantitative polymerase chain reaction (qPCR was used to quantify ARGs corresponding to resistance to sulfonamides (sul1, sul2, macrolides (ermF, tetracycline (tet(A, tet(O, glycopeptides (vanA, and methicillin (mecA, in addition to genes present in waterborne pathogens Legionella pneumophila (Lmip, Escherichia coli (gadAB, and Pseudomonas aeruginosa (ecfx, gyrB. In a parallel lab study, the effect of irrigating an agricultural soil with secondary, chlorinated, or dechlorinated wastewater effluent was examined in batch microcosms. A broader range of ARGs were detected after the reclaimed water passed through the distribution systems, highlighting the importance of considering bacterial re-growth and the overall water quality at the point of use. Screening for pathogens with qPCR indicated presence of Lmip and gadAB genes, but not ecfx or gyrB. In the lab study, chlorination was observed to reduce 16S rRNA and sul2 gene copies in the wastewater effluent, while dechlorination had no apparent effect. ARGs levels did not change with time in soil slurries incubated after a single irrigation event with any of the effluents. However, when irrigated repeatedly with secondary wastewater effluent (not chlorinated or dechlorinated, elevated levels of sul1 and sul2 were observed. This study suggests that reclaimed water may be an important reservoir of ARGs, especially at the point of use, and that attention should be directed towards the fate of ARGs in irrigation water and the implications for human health.

  1. Implications of the 'Energide' concept for communication and information handling in the central nervous system.

    Science.gov (United States)

    Agnati, L F; Fuxe, K; Baluska, F; Guidolin, D

    2009-08-01

    Recently a revision of the cell theory has been proposed, which has several implications both for physiology and pathology. This revision is founded on adapting the old Julius von Sach's proposal (1892) of the Energide as the fundamental universal unit of eukaryotic life. This view maintains that, in most instances, the living unit is the symbiotic assemblage of the cell periphery complex organized around the plasma membrane, some peripheral semi-autonomous cytosol organelles (as mitochondria and plastids, which may be or not be present), and of the Energide (formed by the nucleus, microtubules, and other satellite structures). A fundamental aspect is the proposal that the Energide plays a pivotal and organizing role of the entire symbiotic assemblage (see Appendix 1). The present paper discusses how the Energide paradigm implies a revision of the concept of the internal milieu. As a matter of fact, the Energide interacts with the cytoplasm that, in turn, interacts with the interstitial fluid, and hence with the medium that has been, classically, known as the internal milieu. Some implications of this aspect have been also presented with the help of a computational model in a mathematical Appendix 2 to the paper. Finally, relevances of the Energide concept for the information handling in the central nervous system are discussed especially in relation to the inter-Energide exchange of information.

  2. The Future of Killing: Ethical and Legal Implications of Fully Autonomous Weapon Systems

    Directory of Open Access Journals (Sweden)

    Martin Lark

    2017-03-01

    Full Text Available Warfare is moving towards full weapon autonomy. Already, there are weapons in service that replace a human at the point of engagement. The remote pilot must adhere to the law and consider the moral and ethical implications of using lethal force. Future fully autonomous weapons will be able to search for, identify and engage targets without human intervention, raising the question of who is responsible for the moral and ethical considerations of using such weapons. In the chaos of war, people are fallible, but they can apply judgement and discretion and identify subtle signals. For example, humans can identify when an enemy wants to surrender, are burying their dead, or are assisting non-combatants. An autonomous weapon may not be so discerning and may not be capable of being programmed to apply discretion, compassion, or mercy, nor can it adapt commanders’ intent or apply initiative. Before fully autonomous weapons use lethal force, it is argued that there needs to be assurances that the ethical implications are understood and that control mechanisms are in place to ensure that oversight of the system is able to prevent incidents that could amount to breaches of the laws of armed conflict.

  3. Health Systems Research in a Complex and Rapidly Changing Context: Ethical Implications of Major Health Systems Change at Scale.

    Science.gov (United States)

    MacGregor, Hayley; Bloom, Gerald

    2016-12-01

    This paper discusses health policy and systems research in complex and rapidly changing contexts. It focuses on ethical issues at stake for researchers working with government policy makers to provide evidence to inform major health systems change at scale, particularly when the dynamic nature of the context and ongoing challenges to the health system can result in unpredictable outcomes. We focus on situations where 'country ownership' of HSR is relatively well established and where there is significant involvement of local researchers and close ties and relationships with policy makers are often present. We frame our discussion around two country case studies with which we are familiar, namely China and South Africa and discuss the implications for conducting 'embedded' research. We suggest that reflexivity is an important concept for health system researchers who need to think carefully about positionality and their normative stance and to use such reflection to ensure that they can negotiate to retain autonomy, whilst also contributing evidence for health system change. A research process informed by the notion of reflexive practice and iterative learning will require a longitudinal review at key points in the research timeline. Such review should include the convening of a deliberative process and should involve a range of stakeholders, including those most likely to be affected by the intended and unintended consequences of change. © 2016 The Authors Developing World Bioethics Published by John Wiley & Sons Ltd.

  4. Nonequilibrium thermodynamics and maximum entropy production in the Earth system: applications and implications.

    Science.gov (United States)

    Kleidon, Axel

    2009-06-01

    The Earth system is maintained in a unique state far from thermodynamic equilibrium, as, for instance, reflected in the high concentration of reactive oxygen in the atmosphere. The myriad of processes that transform energy, that result in the motion of mass in the atmosphere, in oceans, and on land, processes that drive the global water, carbon, and other biogeochemical cycles, all have in common that they are irreversible in their nature. Entropy production is a general consequence of these processes and measures their degree of irreversibility. The proposed principle of maximum entropy production (MEP) states that systems are driven to steady states in which they produce entropy at the maximum possible rate given the prevailing constraints. In this review, the basics of nonequilibrium thermodynamics are described, as well as how these apply to Earth system processes. Applications of the MEP principle are discussed, ranging from the strength of the atmospheric circulation, the hydrological cycle, and biogeochemical cycles to the role that life plays in these processes. Nonequilibrium thermodynamics and the MEP principle have potentially wide-ranging implications for our understanding of Earth system functioning, how it has evolved in the past, and why it is habitable. Entropy production allows us to quantify an objective direction of Earth system change (closer to vs further away from thermodynamic equilibrium, or, equivalently, towards a state of MEP). When a maximum in entropy production is reached, MEP implies that the Earth system reacts to perturbations primarily with negative feedbacks. In conclusion, this nonequilibrium thermodynamic view of the Earth system shows great promise to establish a holistic description of the Earth as one system. This perspective is likely to allow us to better understand and predict its function as one entity, how it has evolved in the past, and how it is modified by human activities in the future.

  5. Queueing in a spent fuel transportation system - preliminary analysis of implications for system design

    International Nuclear Information System (INIS)

    Cashwell, J.W.; Wood, T.W.

    1985-01-01

    Compliance with the Nuclear Waste Policy Act of 1982 (PL 97-425) will require the transportation of large volumes of spent fuel to a central receiving facility (either a geologic repository or a monitored retrievable storage facility). Decisions on the transport mode and technology will evolve over the next several years, in anticipation of the deployment of a receiving facility in the late 1990s. Regardless of the particular transportation mode or modes and the details of cask technology, the transport system from many diverse sources to a single point will generate an essentially random arrival pattern. This random arrival pattern will lead to the formation of queues at the receiving facility. As is normal in any queueing system, the waiting time distribution caused by this queueing will depend on the receiving facility input processing rate and the characteristics of the traffic. Since this is a cyclic system, there is also a reverse effect in which (for a given size cask fleet) average wait time affects traffic intensity. Both effects must be accounted for to properly represent the system. This paper develops a simple analytic queueing model which accounts for both of these effects simultaneously. Since both effects are determined by receiving facility input rates and cask fleet size and characteristics, two major sets of system design parameters are linked by the queueing process. The model is used with estimated traffic and service parameters to predict the severity of queueing under plausible reference system conditions, and to establish shadow prices for the trade off between larger cask fleets and more efficient receiving facilities. Since many of the parameter values used in this estimation are quite preliminary, these results are presented primarily in the context of demonstrating the utility of the queueing model for future trade off studies

  6. Queueing in a spent fuel transportation system: a preliminary analysis of implications for system design

    International Nuclear Information System (INIS)

    Cashwell, J.W.; Wood, T.W.

    1985-03-01

    Compliance with the Nuclear Waste Policy Act of 1982 (PL 97-425) will require the transportation of large volumes of spent fuel to a central receiving facility (Either a geologic repository or a monitored retrievable storage facility). Decisions on the transport mode and technology will evolve over the next several years, in anticipation of the deployment of a receiving facility in the late 1990s. Regardless of the particular transportation mode or modes and the details of cask technology, the transport system from many diverse sources to a single point will generate an essentially random arrival pattern. This random arrival pattern will lead to the formation of queues at the receiving facility. As is normal in any queueing system, the waiting time distribution caused by this queueing will depend on the receiving facility input processing rate and the characteristics of the traffic. Since this is a cyclic system, there is also a reverse effect in which (for a given size cask fleet) average wait time affects traffic intensity. Both effects must be accounted for to properly represent the system. This paper develops a simple analytic queueing model which accounts for both of these effects simultaneously. Since both effects are determined by receiving facility input and cask fleet size characteristics, two major sets of system design parameters are linked by the queueing process. The model is used with estimated traffic and service parameters to predict the severity of queueing under plausible reference system conditions, and to establish ''shadow prices'' for the trade off between larger cask fleets and more efficient receiving facilities. Since many of the parameter values used in this estimation are quite preliminary, these results are presented primarily in the context of demonstrating the utility of the queueing model for future trade off studies. 5 refs., 5 figs., 2 tabs

  7. Plasma endocannabinoid levels in lean, overweight and obese humans: relationships with intestinal permeability markers, inflammation and incretin secretion.

    Science.gov (United States)

    Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V; Argueta, Donovan A; Rayner, Christopher K; Feinle-Bisset, Christine; Young, Richard L

    2018-02-13

    Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation, however little is known of these effects in humans. This study aimed to: (i) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl-sn-glycerol (2-AG) and OEA in humans, and (ii) examine relationships with intestinal permeability, inflammation markers and incretin hormone secretion. 20 lean, 18 overweight and 19 obese participants underwent intraduodenal Intralipid® infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumour necrosis factor-α (TNF-α), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and toll-like receptor-4 (TLR4) (RT-PCR), were assessed. Fasting plasma AEA was increased in obese, compared with lean and overweight (Plean (Plean and overweight. The relationships between plasma AEA with duodenal ZO-1 and IAP, and GIP, suggest that altered endocannabinoid signalling may contribute to changes in intestinal permeability, inflammation and incretin release in human obesity.

  8. Information Systems Security Job Advertisement Analysis: Skills Review and Implications for Information Systems Curriculum

    Science.gov (United States)

    Brooks, Nita G.; Greer, Timothy H.; Morris, Steven A.

    2018-01-01

    The authors' focus was the assessment of skill requirements for information systems security positions to understand expectations for security jobs and to highlight issues relevant to curriculum management. The analysis of 798 job advertisements involved the exploration of domain-related and soft skills as well as degree and certification…

  9. Aircraft Alerting Systems Standardization Study. Phase IV. Accident Implications on Systems Design.

    Science.gov (United States)

    1982-06-01

    computing and processing to assimilate and process status informa- 5 tion using...provided with capabilities in computing and processing , sensing, interfacing, and controlling and displaying. 17 o Computing and Processing - Algorithms...alerting system to perform a flight status monitor function would require additional sensinq, computing and processing , interfacing, and controlling

  10. Policy implications of considering pre-commitments in U.S. aggregate energy demand system

    International Nuclear Information System (INIS)

    Rowland, Christopher S.; Mjelde, James W.; Dharmasena, Senarath

    2017-01-01

    Linear approximations of the Generalized Almost Ideal Demand System and Almost Ideal Demand System for U.S. energy are compared to contrast the explicit inclusion and exclusion of pre-committed consumption levels. Results indicate that pre-commitment levels, the quantity of a good that is consumed in the short run with little regard for price, helps to better explain energy demand in the U.S. compared to the system that does not explicitly consider pre-commitments. Policy implications are if pre-commitments are a legitimate assumption, larger price changes are necessary to achieve a given policy objective than if there are no pre-commitments. - Highlights: • Pre-commitments are the quantity that is consumed with little regard for price. • Demand systems with pre-commitment levels better explain energy demand. • Elasticities from assuming pre-commitments are more elastic. • Estimated elasticities apply to discretionary and not pre-commitment consumption. • Pre-commitments require larger price changes to achieve a given policy objective.

  11. Coping with human errors through system design: Implications for ecological interface design

    DEFF Research Database (Denmark)

    Rasmussen, Jens; Vicente, Kim J.

    1989-01-01

    Research during recent years has revealed that human errors are not stochastic events which can be removed through improved training programs or optimal interface design. Rather, errors tend to reflect either systematic interference between various models, rules, and schemata, or the effects...... of the adaptive mechanisms involved in learning. In terms of design implications, these findings suggest that reliable human-system interaction will be achieved by designing interfaces which tend to minimize the potential for control interference and support recovery from errors. In other words, the focus should...... be on control of the effects of errors rather than on the elimination of errors per se. In this paper, we propose a theoretical framework for interface design that attempts to satisfy these objectives. The goal of our framework, called ecological interface design, is to develop a meaningful representation...

  12. Implications of Upwells as Hydrodynamic Jets in a Pulse Jet Mixed System

    Energy Technology Data Exchange (ETDEWEB)

    Pease, Leonard F. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bamberger, Judith A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Minette, Michael J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2017-02-28

    This report evaluates the physics of the upwell flow in pulse jet mixed systems in the Hanford Tank Waste Treatment and Immobilization Plant (WTP). Although the initial downward flow and radial flow from jets characteristic of pulse jet mixers (PJMs) has been analyzed, the upwells have received considerably less attention despite having significant implications for vessel mixing. Do the upwells behave like jets? How do the upwells scale? When will the central upwell break through? What proportion of the vessel is blended by the upwells themselves? Indeed, how the physics of the central upwell is affected by multiple PJMs (e.g., six in the proposed mixing vessels), non-Newtonian rheology, and significant multicomponent solids loadings remain unexplored.

  13. Development and validation of a quantitative method for the determination of 12 endocannabinoids and related compounds in human plasma using liquid chromatography-tandem mass spectrometry

    NARCIS (Netherlands)

    Balvers, M.G.J.; Verhoeckx, K.C.M.; Witkamp, R.F.

    2009-01-01

    A sensitive and specific LC¿MS/MS method for the quantification of the endocannabinoids and related structures anandamide, 2-arachidonoyl glycerol, 2-arachidonyl glycerol ether, O-arachidonoyl ethanolamide, dihomo-¿-linolenoyl ethanolamide, docosatetraenoyl ethanolamide, N-arachidonoyl dopamine,

  14. Implications of access hole size on tank waste retrieval system design and cost

    International Nuclear Information System (INIS)

    Babcock, S.M.; Kwon, D.S.; Burks, B.L.; Stoughton, R.S.; Evans, M.S.

    1994-05-01

    The DOE Environmental Restoration and Waste Management Robotics Technology Development Program has been investigating the application of robotics technology to the retrieval of waste from single-shell storage tanks for several years. The use of a large, ''long-reach'' manipulator to position and orient a variety of tools and other equipment has been recommended. The objective of this study is to determine the appropriate access hole size for the tank waste retrieval system installation. Previous reports on the impact of access hole size on manipulator performance are summarized. In addition, the practical limitation for access hole size based on structural limitations of the waste storage tanks, the state-of-the-art size limitations for the installation of new risers, the radiation safety implications of various access hole sizes, and overall system cost implications are considered. Basic conclusions include: (1) overall cost of remediation will; be dominated by the costs of the balance of plant and time required to perform the task rather than the cost of manipulator hardware or the cost of installing a riser, (2) the most desirable solution from a manipulator controls point of view is to make the manipulator as stiff as possible and have as high as possible a natural frequency, which implies a large access hole diameter, (3) beyond some diameter; simple, uniform cross-section elements become less advantageous from a weight standpoint and alternative structures should be considered, and (4) additional shielding and contamination control measures would be required for larger holes. Parametric studies summarized in this report considered 3,790,000 1 (1,000,000 gal) tanks, while initial applications are likely to be for 2,840,000 1 (750,000 gal) tanks. Therefore, the calculations should be somewhat conservative, recognizing the limitations of the specific conditions considered

  15. Individual differences and vulnerability to drug addiction: a focus on the endocannabinoid system.

    Science.gov (United States)

    Sagheddu, Claudia; Melis, Miriam

    2015-01-01

    Vulnerability to drug addiction depends upon the interactions between the biological makeup of the individual, the environment, and age. These interactions are complex and difficult to tease apart. Since dopamine is involved in the rewarding effects of drugs of abuse, it is postulated that innate differences in mesocorticolimbic pathway can influence the response to drug exposure. In particular, higher and lower expression of dopamine D2 receptors in the ventral striatum (i.e. a marker of dopamine function) has been considered a putative protective and a risk factor, respectively, that can influence one's susceptibility to continued drug abuse as well as the transition to addiction. This phenomenon, which is phylogenetically preserved, appears to be a compensatory change to increased impulse activity of midbrain dopamine neurons. Hence, dopamine neuronal excitability plays a fundamental role in the diverse stages of the drug addiction cycle. In this review, a framework for the evidence that modulation of dopamine neuronal activity plays in the context of vulnerability to drug addiction will be presented. Furthermore, since endogenous cannabinoids serve as retrograde messengers to shape afferent neuronal activity in a short- and long-lasting fashion, their role in individual differences and vulnerability to drug addiction will be discussed.

  16. Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

    Science.gov (United States)

    Bedse, Gaurav; Hartley, Nolan D; Neale, Emily; Gaulden, Andrew D; Patrick, Toni A; Kingsley, Philip J; Uddin, Md Jashim; Plath, Niels; Marnett, Lawrence J; Patel, Sachin

    2017-10-01

    Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ 9 -tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  17. The Endocannabinoid System as a Target for Treatment of Breast Cancer

    Science.gov (United States)

    2011-08-01

    cannabinoids with radiation in MCF-7, MDA-MB-231, and 4T1 breast tumor cell lines. Interestingly, the high efficacy synthetic cannabinoid agonist...tumorgenesis in FAAH (-/-) mice vs. wild type mice; and 2) the synthetic cannabinoid receptor agonist WIN55,212-2 in combination with radiation or adriamycin...THC (the primary active psychoactive constituent present in marijuana ), cannabidiol (CBD: a marijuana -derived cannabinoid that lacks psychomimetic

  18. Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

    Science.gov (United States)

    2014-04-01

    chloroquine (CQ) at 5 µM in combination with the WIN2/IR combination before quantification of cell viability using trypan blue exclusion. At 96 h, CQ had no...viability was quantified using trypan blue exclusion in MCF-7 cells treated as in (A) with a co-treatment of either vehicle or 5 µM chloroquine (B...Acridine orange staining was used to image autophagic vesicles in MCF-7 cells treated with vehicle, 1 µM ADR or ADR + 5 µM chloroquine (C). In (B

  19. The role of cannabinoids and endocannabinoid system in the treatment of epilepsy

    Directory of Open Access Journals (Sweden)

    Pędracka Monika

    2015-12-01

    Full Text Available Introduction. The treatment of epilepsy is still a major challenge. Despite the introduction of many new antiepileptic drugs, approximately 30% of patients still remain drug resistant. In the absence of a satisfactory therapy outcome, which is sometimes associated with numerous side effects, there is a need for new and effective drugs with low toxicity. Cannabinoids have been shown in preliminary animal model studies and in studies of patients with epilepsy to have antiepileptic activity.

  20. Involvement of the Endocannabinoid System in the Development and Treatment of Breast Cancer

    Science.gov (United States)

    2013-02-01

    possesses antinociceptive actions in preclinical models of cancer pain (Guerrero et al. 2008) and can suppress radiation induced- emesis in the least...as, chemotherapy and radiation associated emesis in preclinical models. This could offer a third facet to WIN55,212-2’s mechanism of action, which... emesis in the least shrew. Eur J Pharmacol 563(1-3):187- 96. Guerrero AV, Quang P, Dekker N, Jordan RC, Schmidt BL. 2008. Peripheral cannabinoids

  1. Assessment of economic factors affecting the satellite power system. Volume 2: The systems implications of rectenna siting issues

    Science.gov (United States)

    Chapman, P. K.; Bugos, B. J.; Csigi, K. I.; Glaser, P. E.; Schimke, G. R.; Thomas, R. G.

    1979-01-01

    The feasibility was evaluated of finding potential sites for Solar Power Satellite (SPS) receiving antennas (rectennas) in the continental United States, in sufficient numbers to permit the SPS to make a major contribution to U.S. generating facilities, and to give statistical validity to an assessment of the characteristics of such sites and their implications for the design of the SPS system. It is found that the cost-optimum power output of the SPS does not depend on the particular value assigned to the cost per unit area of a rectenna and its site, as long as it is independent of rectenna area. Many characteristics of the sites chosen affect the optimum design of the rectenna itself.

  2. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    Science.gov (United States)

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

  3. The Ovine Cerebral Venous System: Comparative Anatomy, Visualization, and Implications for Translational Research

    Science.gov (United States)

    Nitzsche, Björn; Lobsien, Donald; Seeger, Johannes; Schneider, Holm; Boltze, Johannes

    2014-01-01

    Cerebrovascular diseases are significant causes of death and disability in humans. Improvements in diagnostic and therapeutic approaches strongly rely on adequate gyrencephalic, large animal models being demanded for translational research. Ovine stroke models may represent a promising approach but are currently limited by insufficient knowledge regarding the venous system of the cerebral angioarchitecture. The present study was intended to provide a comprehensive anatomical analysis of the intracranial venous system in sheep as a reliable basis for the interpretation of experimental results in such ovine models. We used corrosion casts as well as contrast-enhanced magnetic resonance venography to scrutinize blood drainage from the brain. This combined approach yielded detailed and, to some extent, novel findings. In particular, we provide evidence for chordae Willisii and lateral venous lacunae, and report on connections between the dorsal and ventral sinuses in this species. For the first time, we also describe venous confluences in the deep cerebral venous system and an ‘anterior condylar confluent’ as seen in humans. This report provides a detailed reference for the interpretation of venous diagnostic imaging findings in sheep, including an assessment of structure detectability by in vivo (imaging) versus ex vivo (corrosion cast) visualization methods. Moreover, it features a comprehensive interspecies-comparison of the venous cerebral angioarchitecture in man, rodents, canines and sheep as a relevant large animal model species, and describes possible implications for translational cerebrovascular research. PMID:24736654

  4. Supporting cognition in systems biology analysis: findings on users' processes and design implications.

    Science.gov (United States)

    Mirel, Barbara

    2009-02-13

    Current usability studies of bioinformatics tools suggest that tools for exploratory analysis support some tasks related to finding relationships of interest but not the deep causal insights necessary for formulating plausible and credible hypotheses. To better understand design requirements for gaining these causal insights in systems biology analyses a longitudinal field study of 15 biomedical researchers was conducted. Researchers interacted with the same protein-protein interaction tools to discover possible disease mechanisms for further experimentation. Findings reveal patterns in scientists' exploratory and explanatory analysis and reveal that tools positively supported a number of well-structured query and analysis tasks. But for several of scientists' more complex, higher order ways of knowing and reasoning the tools did not offer adequate support. Results show that for a better fit with scientists' cognition for exploratory analysis systems biology tools need to better match scientists' processes for validating, for making a transition from classification to model-based reasoning, and for engaging in causal mental modelling. As the next great frontier in bioinformatics usability, tool designs for exploratory systems biology analysis need to move beyond the successes already achieved in supporting formulaic query and analysis tasks and now reduce current mismatches with several of scientists' higher order analytical practices. The implications of results for tool designs are discussed.

  5. Implications of sustainability assessment for electricity system design: The case of the Ontario Power Authority's integrated power system plan

    International Nuclear Information System (INIS)

    Winfield, Mark; Gibson, Robert B.; Markvart, Tanya; Gaudreau, Kyrke; Taylor, Jennifer

    2010-01-01

    This paper explores the results and implications of an illustrative application of a sustainability assessment framework in the design and evaluation of a major integrated power system plan. The paper examines the integrated power system plan developed by the Ontario Power Authority in 2007. The basic framework rests on a generic set of evaluation criteria reflecting basic requirements for progress towards sustainability that was adopted, reinterpreted and applied by the Authority in support of its proposed plan. In response to evident deficiencies in the Authority's work, the authors and colleagues undertook a re-examination using a more fully elaborated sustainability assessment framework, specified for application to power system planning. The results point to a plan and plan components substantially different from those proposed by the Authority. More generally, the results highlight three advantages of applying such a sustainability assessment framework: comprehensive coverage of key requirements for progress towards sustainability while ensuring careful attention to the context and concerns of the sector; emphasis on identifying plan options that avoid major trade-offs among the sustainability criteria and recognition of interactions among the social, ecological, economic and technological realms favouring options that offer multiple, mutually reinforcing and lasting benefits.

  6. Implications of Schwann Cells Biomechanics and Mechanosensitivity for Peripheral Nervous System Physiology and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Gonzalo Rosso

    2017-10-01

    Full Text Available The presence of bones around the central nervous system (CNS provides it with highly effective physiologically crucial mechanical protection. The peripheral nervous system (PNS, in contrast, lacks this barrier. Consequently, the long held belief is that the PNS is mechanically vulnerable. On the other hand, the PNS is exposed to a variety of physiological mechanical stresses during regular daily activities. This fact prompts us to question the dogma of PNS mechanical vulnerability. As a matter of fact, impaired mechanics of PNS nerves is associated with neuropathies with the liability to mechanical stresses paralleled by significant impairment of PNS physiological functions. Our recent biomechanical integrity investigations on nerve fibers from wild-type and neuropathic mice lend strong support in favor of natural mechanical protection of the PNS and demonstrate a key role of Schwann cells (SCs therein. Moreover, recent works point out that SCs can sense mechanical properties of their microenvironment and the evidence is growing that SCs mechanosensitivity is important for PNS development and myelination. Hence, SCs exhibit mechanical strength necessary for PNS mechanoprotection as well as mechanosensitivity necessary for PNS development and myelination. This mini review reflects on the intriguing dual ability of SCs and implications for PNS physiology and pathophysiology.

  7. System dynamics model of taxi management in metropolises: Economic and environmental implications for Beijing.

    Science.gov (United States)

    Wang, Hao; Zhang, Kai; Chen, Junhua; Wang, Zhifeng; Li, Guijun; Yang, Yuqi

    2018-05-01

    Taxis are an important component of urban passenger transport. Research on the daily dispatching of taxis and the utility of governmental management is important for the improvement of passenger travel, taxi driver income and environmental impacts. However, urban taxi management is a complex and dynamic system that is affected by many factors, and positive/negative feedback relationships and nonlinear interactions exist between each subsystem and variable. Therefore, conventional research methods can hardly depict its characteristics comprehensively. To bridge this gap, this paper develops a system dynamics model of urban taxi management, in which the empty-loaded rate and total demand are selected as key factors affecting taxi dispatching, and the impacts of taxi fares on driver income and travel demand are taken into account. After the validation of the model, taxi operations data derived from a prior analysis of origin-destination data of Beijing taxis are used as input for the model to simulate the taxi market in Beijing. Finally, economic and environmental implications are provided for the government to optimise policies on taxi management. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Genomic sequencing: assessing the health care system, policy, and big-data implications.

    Science.gov (United States)

    Phillips, Kathryn A; Trosman, Julia R; Kelley, Robin K; Pletcher, Mark J; Douglas, Michael P; Weldon, Christine B

    2014-07-01

    New genomic sequencing technologies enable the high-speed analysis of multiple genes simultaneously, including all of those in a person's genome. Sequencing is a prominent example of a "big data" technology because of the massive amount of information it produces and its complexity, diversity, and timeliness. Our objective in this article is to provide a policy primer on sequencing and illustrate how it can affect health care system and policy issues. Toward this end, we developed an easily applied classification of sequencing based on inputs, methods, and outputs. We used it to examine the implications of sequencing for three health care system and policy issues: making care more patient-centered, developing coverage and reimbursement policies, and assessing economic value. We conclude that sequencing has great promise but that policy challenges include how to optimize patient engagement as well as privacy, develop coverage policies that distinguish research from clinical uses and account for bioinformatics costs, and determine the economic value of sequencing through complex economic models that take into account multiple findings and downstream costs. Project HOPE—The People-to-People Health Foundation, Inc.

  9. Endocrine disrupting compounds in drinking water supply system and human health risk implication.

    Science.gov (United States)

    Wee, Sze Yee; Aris, Ahmad Zaharin

    2017-09-01

    To date, experimental and epidemiological evidence of endocrine disrupting compounds (EDCs) adversely affecting human and animal populations has been widely debated. Notably, human health risk assessment is required for risk mitigation. The lack of human health risk assessment and management may thus unreliably regulate the quality of water resources and efficiency of treatment processes. Therefore, drinking water supply systems (DWSSs) may be still unwarranted in assuring safe access to potable drinking water. Drinking water supply, such as tap water, is an additional and crucial route of human exposure to the health risks associated with EDCs. A holistic system, incorporating continuous research in DWSS monitoring and management using multi-barrier approach, is proposed as a preventive measure to reduce human exposure to the risks associated with EDCs through drinking water consumption. The occurrence of EDCs in DWSSs and corresponding human health risk implications are analyzed using the Needs, Approaches, Benefits, and Challenges (NABC) method. Therefore, this review may act as a supportive tool in protecting human health and environmental quality from EDCs, which is essential for decision-making regarding environmental monitoring and management purposes. Subsequently, the public could have sustainable access to safer and more reliable drinking water. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Implications of the New Regional Trade Agreements for the World Trading System

    Directory of Open Access Journals (Sweden)

    Agnes Ghibuțiu

    2017-04-01

    Full Text Available The year 2013 witnessed an outstanding rise in the pace and scale of negotiations on regional trade agreements (RTAs. While RTAs are not a new phenomenon, current negotiations involve multiple parties and/or major trading countries that have a significant combined economic weight, i.e. mega-RTAs. This paper looks at the recent surge in trade regionalism and addresses some of the key issues related to the potential impact of mega-RTAs upon the world trading system and global trade patterns. It examines the peculiarities of the new mega-RTAs and the factors underlying their proliferation, and discusses the main concerns raised by their foreseeable impact on excluded countries and the wider trading system. The paper finds that, if successfully concluded, mega-RTAs are likely to have far-reaching implications for the world trading regime, affecting its transparency and coherence. Nevertheless, the adverse effects could be cushioned through a revival of trading nations’ interest in the multilateral Doha Round talks.

  11. Oil-in-water lipid emulsions: implications for parenteral and ocular delivering systems.

    Science.gov (United States)

    Tamilvanan, S

    2004-11-01

    Lipid emulsions (LEs) are heterogenous dispersions of two immiscible liquids (oil-in-water or water-in-oil) and they are subjected to various instability processes like aggregation, flocculation, coalescence and hence eventual phase separation according to the second law of thermodynamics. However, the physical stability of the LE can substantially be improved with help of suitable emulsifiers that are capable of forming a mono- or multi-layer coating film around the dispersed liquid droplets in such a way to reduce interfacial tension or to increase droplet-droplet repulsion. Depending on the concentrations of these three components (oil-water-emulsifier) and the efficiency of the emulsification equipments used to reduce droplet size, the final LE may be in the form of oil-in-water (o/w), water-in-oil (w/o), micron, submicron and double or multiple emulsions (o/w/o and w/o/w). The o/w type LEs (LE) are colloidal drug carriers, which have various therapeutic applications. As an intravenous delivery system it incorporates lipophilic water non-soluble drugs, stabilize drugs that tend to undergo hydrolysis and reduce side effects of various potent drugs. When the LE is used as an ocular delivery systems they increase local bioavailability, sustain the pharmacological effect of drugs and decrease systemic side effects of the drugs. Thus, the rationale of using LE as an integral part of effective treatment is clear. Following administration of LE through these routes, the biofate of LE associated bioactive molecules are somehow related to the vehicles disposition kinetics inside blood or eyeball. However, the LE is not devoid from undergoing various bio-process while exerting their efficacious actions. The purpose of this review is therefore to give an implication of LE for parenteral and ocular delivering systems.

  12. Electric vehicle charging in China's power system : Energy, economic and environmental trade-offs and policy implications

    NARCIS (Netherlands)

    Li, Ying; Davis, Chris; Lukszo, Zofia; Weijnen, Margot

    2016-01-01

    This work investigates different scenarios for electric vehicle (EV) deployment in China and explores the implications thereof with regard to energy portfolio, economics and the environment. Specifically, we investigate how to better deliver the value of EVs by improving designs in the power system

  13. Modulation of limbic noradrenergic circuits by cannabinoids

    OpenAIRE

    Carvalho, Ana Raquel Franky Gomes

    2010-01-01

    Tese de doutoramento Medicina The endocannabinoid system has been implicated in the regulation of several physiological functions. The widespread distribution of the endocannabinoid system in the central nervous system (CNS) accounts for many effects attributed to cannabinoids. Importantly, cannabinoids have been shown to modulate mood, cognition and memory. There is growing evidence suggesting that cannabinoids can interact with the noradrenergic system. Noradrenergic trans...

  14. Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation.

    Science.gov (United States)

    Köse, Sevil; Aerts-Kaya, Fatima; Köprü, Çağla Zübeyde; Nemutlu, Emirhan; Kuşkonmaz, Barış; Karaosmanoğlu, Beren; Taşkıran, Ekim Zihni; Altun, Belgin; Uçkan Çetinkaya, Duygu; Korkusuz, Petek

    2018-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrβ). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34 + HSCs express CB1, CB2, and Adrβ subtypes. CD34 + HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  15. Milkfish (Chanos chanos Fry Concession System in Bolinao, Pangasinan: Implications to Coastal Resources Management

    Directory of Open Access Journals (Sweden)

    Severino Salmo III

    2000-12-01

    Full Text Available The ecological and socioeconomic implications of the concession system on milkfish (Chanos chanos Forssk. fry in Bolinao, Pangasinan were evaluated from 1996 to 1999. Monitoring of landed catch from 1996 to 1998 showed that the seasonal trend and annual volume of catch varied widely during the three-year period. The fry season in 1996 and 1997 lasted seven months, starting from the second week of April to the second week of October. However, during the 1998 season, fry were available for eight months starting in the second week of March and ending in November. The peak period also varied considerably during the three-year period. In 1996, peak abundance of fry was observed in the last week of July while in 1997 and 1998, the peak was during the second week of May. The volume of total catch for the entire season also varied widely, from as low as ~400,000 fry (1997 to as high as 2,400,000 fry (1996. The concessionaire “postor” has the sole right to buy all fry caught within the municipal waters. Thus, s/he dictates the buying price. Moreover, the existing concession system has no mechanism to regulate harvest of milkfish fry gathering. This arrangement allows the concessionaire to enjoy huge economic benefits while the fry gatherers only get a minimal share in the income. To promote sustainable and equitable harvest of milkfish fry, a new access arrangement through a permit system was proposed by the fry gatherers. The proposed permit system will promote a sustainable harvest of milkfish fry through the implementation of a closed period during the fry season. Compared to the present concession system, the permit system is believed to be more equitable because of the abolition of the 1/3 cut levied by the concessionaire on the landed catch. The permit system also facilitates a mechanism that provides for transparency on the selling/buying price. More importantly, fry gatherers will have the opportunity to sell to buyers offering a relatively

  16. Vehicle emission implications of drivers' smart advisory system for traffic operations in work zones.

    Science.gov (United States)

    Li, Qing; Qiao, Fengxiang; Yu, Lei

    2016-05-01

    Wireless communication systems have been broadly applied in various complicated traffic operations to improve mobility and safety on roads, which may raise a concern about the implication of the new technology on vehicle emissions. This paper explores how the wireless communication systems improve drivers' driving behaviors and its contributions to the emission reduction, in terms of Operating Mode (OpMode) IDs distribution used in emission estimation. A simulated work zone with completed traffic operation was selected as a test bed. Sixty subjects were recruited for the tests, whose demographic distribution was based on the Census data in Houston, Texas. A scene of a pedestrian's crossing in the work zone was designed for the driving test. Meanwhile, a wireless communication system called Drivers Smart Advisory System (DSAS) was proposed and introduced in the driving simulation, which provided drivers with warning messages in the work zone. Two scenarios were designed for a leading vehicle as well as for a following vehicle driving through the work zone, which included a base test without any wireless communication systems, and a driving test with the trigger of the DSAS. Subjects' driving behaviors in the simulation were recorded to evaluate safety and estimate the vehicle emission using the Environmental Protection Agency (EPA) released emission model MOVES. The correlation between drivers' driving behavior and the distribution of the OpMode ID during each scenario was investigated. Results show that the DSAS was able to induce drivers to accelerate smoothly, keep longer headway distance and stop earlier for a hazardous situation in the work zone, which driving behaviors result in statistically significant reduction in vehicle emissions for almost all studied air pollutants (p-values range from 4.10E-51 to 2.18E-03). The emission reduction was achieved by the switching the distribution of the OpMode IDs from higher emission zones to lower emission zones

  17. Threshold behaviour in hydrological systems as (human geo-ecosystems: manifestations, controls, implications

    Directory of Open Access Journals (Sweden)

    M. Sivapalan

    2009-07-01

    Full Text Available In this paper we review threshold behaviour in environmental systems, which are often associated with the onset of floods, contamination and erosion events, and other degenerative processes. Key objectives of this review are to a suggest indicators for detecting threshold behavior, b discuss their implications for predictability, c distinguish different forms of threshold behavior and their underlying controls, and d hypothesise on possible reasons for why threshold behaviour might occur. Threshold behaviour involves a fast qualitative change of either a single process or the response of a system. For elementary phenomena this switch occurs when boundary conditions (e.g., energy inputs or system states as expressed by dimensionless quantities (e.g. the Reynolds number exceed threshold values. Mixing, water movement or depletion of thermodynamic gradients becomes much more efficient as a result. Intermittency is a very good indicator for detecting event scale threshold behavior in hydrological systems. Predictability of intermittent processes/system responses is inherently low for combinations of systems states and/or boundary conditions that push the system close to a threshold. Post hoc identification of "cause-effect relations" to explain when the system became critical is inherently difficult because of our limited ability to perform observations under controlled identical experimental conditions. In this review, we distinguish three forms of threshold behavior. The first one is threshold behavior at the process level that is controlled by the interplay of local soil characteristics and states, vegetation and the rainfall forcing. Overland flow formation, particle detachment and preferential flow are examples of this. The second form of threshold behaviour is the response of systems of intermediate complexity – e.g., catchment runoff response and sediment yield – governed by the redistribution of water and sediments in space and time

  18. Medical tourism and policy implications for health systems: a conceptual framework from a comparative study of Thailand, Singapore and Malaysia

    Science.gov (United States)

    2011-01-01

    Medical tourism is a growing phenomenon with policy implications for health systems, particularly of destination countries. Private actors and governments in Southeast Asia are promoting the medical tourist industry, but the potential impact on health systems, particularly in terms of equity in access and availability for local consumers, is unclear. This article presents a conceptual framework that outlines the policy implications of medical tourism's growth for health systems, drawing on the cases of Thailand, Singapore and Malaysia, three regional hubs for medical tourism, via an extensive review of academic and grey literature. Variables for further analysis of the potential impact of medical tourism on health systems are also identified. The framework can provide a basis for empirical, in country studies weighing the benefits and disadvantages of medical tourism for health systems. The policy implications described are of particular relevance for policymakers and industry practitioners in other Southeast Asian countries with similar health systems where governments have expressed interest in facilitating the growth of the medical tourist industry. This article calls for a universal definition of medical tourism and medical tourists to be enunciated, as well as concerted data collection efforts, to be undertaken prior to any meaningful empirical analysis of medical tourism's impact on health systems. PMID:21539751

  19. Medical tourism and policy implications for health systems: a conceptual framework from a comparative study of Thailand, Singapore and Malaysia

    Directory of Open Access Journals (Sweden)

    Phua Kai Hong

    2011-05-01

    Full Text Available Abstract Medical tourism is a growing phenomenon with policy implications for health systems, particularly of destination countries. Private actors and governments in Southeast Asia are promoting the medical tourist industry, but the potential impact on health systems, particularly in terms of equity in access and availability for local consumers, is unclear. This article presents a conceptual framework that outlines the policy implications of medical tourism's growth for health systems, drawing on the cases of Thailand, Singapore and Malaysia, three regional hubs for medical tourism, via an extensive review of academic and grey literature. Variables for further analysis of the potential impact of medical tourism on health systems are also identified. The framework can provide a basis for empirical, in country studies weighing the benefits and disadvantages of medical tourism for health systems. The policy implications described are of particular relevance for policymakers and industry practitioners in other Southeast Asian countries with similar health systems where governments have expressed interest in facilitating the growth of the medical tourist industry. This article calls for a universal definition of medical tourism and medical tourists to be enunciated, as well as concerted data collection efforts, to be undertaken prior to any meaningful empirical analysis of medical tourism's impact on health systems.

  20. Medical tourism and policy implications for health systems: a conceptual framework from a comparative study of Thailand, Singapore and Malaysia.

    Science.gov (United States)

    Pocock, Nicola S; Phua, Kai Hong

    2011-05-04

    Medical tourism is a growing phenomenon with policy implications for health systems, particularly of destination countries. Private actors and governments in Southeast Asia are promoting the medical tourist industry, but the potential impact on health systems, particularly in terms of equity in access and availability for local consumers, is unclear. This article presents a conceptual framework that outlines the policy implications of medical tourism's growth for health systems, drawing on the cases of Thailand, Singapore and Malaysia, three regional hubs for medical tourism, via an extensive review of academic and grey literature. Variables for further analysis of the potential impact of medical tourism on health systems are also identified. The framework can provide a basis for empirical, in country studies weighing the benefits and disadvantages of medical tourism for health systems. The policy implications described are of particular relevance for policymakers and industry practitioners in other Southeast Asian countries with similar health systems where governments have expressed interest in facilitating the growth of the medical tourist industry. This article calls for a universal definition of medical tourism and medical tourists to be enunciated, as well as concerted data collection efforts, to be undertaken prior to any meaningful empirical analysis of medical tourism's impact on health systems.

  1. How countries link REDD+ interventions to drivers in their readiness plans: implications for monitoring systems

    International Nuclear Information System (INIS)

    Salvini, G; Herold, M; De Sy, V; Kissinger, G; Brockhaus, M; Skutsch, M

    2014-01-01

    Countries participating in the REDD+ scheme are in the readiness phase, designing policy interventions to address drivers of deforestation and forest degradation (DD). In order for REDD+ interventions to be effective, it is essential that they take into account the specific drivers that they aim to address. Moreover it is crucial to design systems that monitor the effectiveness of the planned interventions. In this article we provide a comprehensive and comparative assessment of interventions proposed by 43 REDD+ countries in 98 readiness documents. We summarize the types of interventions and assess if they are formulated referring to the drivers of DD that they are aiming to address. Based on this assessment we consider the implications for systems for monitoring effectiveness of proposed interventions. Most countries reviewed link proposed interventions to specific drivers of DD. The majority of the countries making this link have better driver data quality, in particularly those that present their data in ratio or ordinal terms. Proposed interventions focus not only on activities to reduce deforestation, but also on other forest related REDD+ activities such as sustainable forest management, which reduce forest degradation and enhance forest stocks. Moreover, driver-specific interventions often relate to drivers not only inside but also outside the forest sector. Hence we suggest that monitoring systems need to assess not only deforestation rates through remote sensing, but also degradation and other carbon stock changes within the forest, using more detailed ground level surveys and measurements. In addition, the performance of interventions outside the forest need to be monitored, even if the impacts of these cannot be linked to specific changes in forest carbon stock in specific locations. (paper)

  2. Prevention of Congenital Transmission of Malaria in Sub-Saharan African Countries: Challenges and Implications for Health System Strengthening

    OpenAIRE

    Osungbade, Kayode O.; Oladunjoye, Olubunmi O.

    2012-01-01

    Objectives. Review of burden of congenital transmission of malaria, challenges of preventive measures, and implications for health system strengthening in sub-Saharan Africa. Methods. Literature from Pubmed (MEDLINE), Biomed central, Google Scholar, and Cochrane Database were reviewed. Results. The prevalence of congenital malaria in sub-Saharan Africa ranges from 0 to 23%. Diagnosis and existing preventive measures are constantly hindered by weak health systems and sociocultural issues. WHO ...

  3. Would Virchow be a systems biologist? A discourse on the philosophy of science with implications for pathological research.

    Science.gov (United States)

    Stenzinger, Albrecht; Klauschen, Frederick; Wittschieber, Daniel; Weichert, Wilko; Denkert, Carsten; Dietel, Manfred; Roller, Claudio

    2010-06-01

    Research in pathology spans from merely descriptive work to functional studies, "-omics" approaches and, more recently, systems biology. The work presented here aims at placing pathological research into an epistemological context. Aided by Rudolf Virchow, we give an overview on the philosophy of science including the Wiener Kreis, Popper, Kuhn, Fleck and Rheinberger and demonstrate their implications for routine diagnostics and science in pathology. A focus is on the fields of "-omics" and systems pathology.

  4. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine

    DEFF Research Database (Denmark)

    Artmann, Andreas; Petersen, Gitte; Hellgren, Lars

    2008-01-01

    and docosahexaenoylethanolamide) with similar changes in precursor lipids. The AA-diet and FO-diet had no effect on N-acylethanolamines, endocannabinoids or precursor lipids in brain. All N-acylethanolamines activated PPAR-alpha. In conclusion, short-term feeding of diets resembling human diets (Mediterranean diet high...... (AA)) on tissue levels of 2-arachidonoylglycerol, anandamide, oleoylethanolamide, palmitoylethanolamide, stearoylethanolamide, linoleoylethanolamide, eicosapentaenoylethanolamide, docosahexaenoylethanolamide and tissue fatty acid composition. The LA-diet increased linoleoylethanolamide and linoleic...... acid in brain, jejunum and liver. The OA-diet increased brain levels of anandamide and oleoylethanolamide (not 2-arachidonoylglycerol) without changing tissue fatty acid composition. The same diet increased oleoylethanolamide in liver. All five dietary fats decreased oleoylethanolamide in jejunum...

  5. Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders.

    Science.gov (United States)

    Borrow, Amanda P; Cameron, Nicole M

    2014-10-03

    Clinical research has demonstrated a significant sex difference in the occurrence of depressive disorders. Beginning at pubertal onset, women report a higher incidence of depression than men. Women are also vulnerable to the development of depressive disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. These disorders are associated with reproductive stages involving changes in gonadal hormone levels. Specifically, female depression and female affective behaviors are influenced by estradiol levels. This review argues two major mechanisms by which estrogens influence depression and depressive-like behavior: through interactions with neurotrophic factors and through an influence on the serotonergic system. In particular, estradiol increases brain derived neurotrophic factor (BDNF) levels within the brain, and alters serotonergic expression in a receptor subtype-specific manner. We will take a regional approach, examining these effects of estrogens in the major brain areas implicated in depression. Finally, we will discuss the gaps in our current knowledge of the effects of estrogens on female depression, and the potential utility for estrogen receptor modulators in treatment for this disorder. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. MicroRNAs: Key Regulators in the Central Nervous System and Their Implication in Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Dan-Dan Cao

    2016-05-01

    Full Text Available MicroRNAs (miRNAs are a class of small, well-conserved noncoding RNAs that regulate gene expression post-transcriptionally. They have been demonstrated to regulate a lot of biological pathways and cellular functions. Many miRNAs are dynamically regulated during central nervous system (CNS development and are spatially expressed in adult brain indicating their essential roles in neural development and function. In addition, accumulating evidence strongly suggests that dysfunction of miRNAs contributes to neurological diseases. These observations, together with their gene regulation property, implicated miRNAs to be the key regulators in the complex genetic network of the CNS. In this review, we first focus on the ways through which miRNAs exert the regulatory function and how miRNAs are regulated in the CNS. We then summarize recent findings that highlight the versatile roles of miRNAs in normal CNS physiology and their association with several types of neurological diseases. Subsequently we discuss the limitations of miRNAs research based on current studies as well as the potential therapeutic applications and challenges of miRNAs in neurological disorders. We endeavor to provide an updated description of the regulatory roles of miRNAs in normal CNS functions and pathogenesis of neurological diseases.

  7. The Malaysian Intermodal Terminal System: The Implication on the Malaysian Maritime Cluster

    Directory of Open Access Journals (Sweden)

    Mohamad Rosni Othman

    2016-06-01

    Full Text Available The maritime sector in Malaysia is best known globally due to the Straits of Malacca and being a nation surrounded by sea. Malaysia also has a substantial maritime industry consisting of numerous shipyards, ports and terminal faculties, ship services and a plethora of other companies and institutions with maritime oriented activities and become essential components of the Malaysia's maritime clusters. Issues such as underutilised intermodal terminals, uneven proportions in the freight transport infrastructure and road and seaport congestions prevent Malaysian seaports from achieving their full potential in serving their respective hinterlands. The key factors to improve Malaysian dry port or intermodal terminals are transport network; container planning; competition; location and, externalities. The paper does not only present the critical challenges faced by Malaysian intermodal terminals especially dry ports and the implications for seaport competency but it also provides strategies to utilise the Malaysian freight multimodal system to amplify seaports
tm performance in serving their hinterlands. As such, this may warrant policy makers to devise a comprehensive national master plan for the maritime sector in order for Malaysia to further develop her maritime industry and economies.

  8. New Implications for the Melanocortin System in Alcohol Drinking Behavior in Adolescents: The Glial Dysfunction Hypothesis

    Science.gov (United States)

    Orellana, Juan A.; Cerpa, Waldo; Carvajal, Maria F.; Lerma-Cabrera, José M.; Karahanian, Eduardo; Osorio-Fuentealba, Cesar; Quintanilla, Rodrigo A.

    2017-01-01

    Alcohol dependence causes physical, social, and moral harms and currently represents an important public health concern. According to the World Health Organization (WHO), alcoholism is the third leading cause of death worldwide, after tobacco consumption and hypertension. Recent epidemiologic studies have shown a growing trend in alcohol abuse among adolescents, characterized by the consumption of large doses of alcohol over a short time period. Since brain development is an ongoing process during adolescence, short- and long-term brain damage associated with drinking behavior could lead to serious consequences for health and wellbeing. Accumulating evidence indicates that alcohol impairs the function of different components of the melanocortin system, a major player involved in the consolidation of addictive behaviors during adolescence and adulthood. Here, we hypothesize the possible implications of melanocortins and glial cells in the onset and progression of alcohol addiction. In particular, we propose that alcohol-induced decrease in α-MSH levels may trigger a cascade of glial inflammatory pathways that culminate in altered gliotransmission in the ventral tegmental area and nucleus accumbens (NAc). The latter might potentiate dopaminergic drive in the NAc, contributing to increase the vulnerability to alcohol dependence and addiction in the adolescence and adulthood. PMID:28424592

  9. A systems approach identifies networks and genes linking sleep and stress: implications for neuropsychiatric disorders.

    Science.gov (United States)

    Jiang, Peng; Scarpa, Joseph R; Fitzpatrick, Karrie; Losic, Bojan; Gao, Vance D; Hao, Ke; Summa, Keith C; Yang, He S; Zhang, Bin; Allada, Ravi; Vitaterna, Martha H; Turek, Fred W; Kasarskis, Andrew

    2015-05-05

    Sleep dysfunction and stress susceptibility are comorbid complex traits that often precede and predispose patients to a variety of neuropsychiatric diseases. Here, we demonstrate multilevel organizations of genetic landscape, candidate genes, and molecular networks associated with 328 stress and sleep traits in a chronically stressed population of 338 (C57BL/6J × A/J) F2 mice. We constructed striatal gene co-expression networks, revealing functionally and cell-type-specific gene co-regulations important for stress and sleep. Using a composite ranking system, we identified network modules most relevant for 15 independent phenotypic categories, highlighting a mitochondria/synaptic module that links sleep and stress. The key network regulators of this module are overrepresented with genes implicated in neuropsychiatric diseases. Our work suggests that the interplay among sleep, stress, and neuropathology emerges from genetic influences on gene expression and their collective organization through complex molecular networks, providing a framework for interrogating the mechanisms underlying sleep, stress susceptibility, and related neuropsychiatric disorders. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  10. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica.

    Directory of Open Access Journals (Sweden)

    Hannah L Pellkofer

    Full Text Available Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO. While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST following the protocol of the German Research Network on Neuropathic Pain (DFNS. Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11 suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG. These data emphasize the high prevalence of neuropathic pain and hyperalgesia

  11. Cannabinoids: Medical implications.

    Science.gov (United States)

    Schrot, Richard J; Hubbard, John R

    2016-01-01

    Herbal cannabis has been used for thousands of years for medical purposes. With elucidation of the chemical structures of tetrahydrocannabinol (THC) and cannabidiol (CBD) and with discovery of the human endocannabinoid system, the medical usefulness of cannabinoids has been more intensively explored. While more randomized clinical trials are needed for some medical conditions, other medical disorders, like chronic cancer and neuropathic pain and certain symptoms of multiple sclerosis, have substantial evidence supporting cannabinoid efficacy. While herbal cannabis has not met rigorous FDA standards for medical approval, specific well-characterized cannabinoids have met those standards. Where medical cannabis is legal, patients typically see a physician who "certifies" that a benefit may result. Physicians must consider important patient selection criteria such as failure of standard medical treatment for a debilitating medical disorder. Medical cannabis patients must be informed about potential adverse effects, such as acute impairment of memory, coordination and judgment, and possible chronic effects, such as cannabis use disorder, cognitive impairment, and chronic bronchitis. In addition, social dysfunction may result at work/school, and there is increased possibility of motor vehicle accidents. Novel ways to manipulate the endocannbinoid system are being explored to maximize benefits of cannabinoid therapy and lessen possible harmful effects.

  12. Life-cycle cost implications of a system using bare SNF transfer

    International Nuclear Information System (INIS)

    Rose, M.

    1995-01-01

    The U.S. Department of Energy (DOE) is planning the use of the Multi-Purpose Canister (MPC) to handle transportation, storage, and disposal of civilian spent nuclear fuel. This canister, which would be loaded and sealed at the utility site, would remain sealed through waste emplacement in a Mined Geologic Disposal System (MGDS). Two sizes of MPCs are now being considered: large and small rail. The large rail canister has design requirements to be compatible with a 125 ton hook weight crane when fully loaded in the pool with fuel assemblies, water, transportation overpack, and the lifting yoke. The small rail canister under the same conditions weighs less than 75 tons. At present, it is estimated that between four and seventeen reactors will not be able to accommodate either canister. One method of accommodating MPCs at all reactors is the use of Bare Spent nuclear fuel Transfer (BST). In this concept, a small transfer cask is used to move small numbers of assemblies from the spent fuel pool to an external transfer station where a large MPC is loaded. After several of these transfers, the MPC is sealed and either stored on-site, transported to a central storage site, or transported to the MGDS. This paper addresses the total system cost implications of use of BST at 20 sites (31 reactors) which are currently projected to be unable to use the large rail MPC. Results are presented parametrically as a function of the BST capital cost and the time required to load a MPC. This analysis indicates use of BST may be economically favorable if the combination of MPC load times and capital expenditures can be kept to a reasonable level

  13. The effects of chromium(VI) on the thioredoxin system: Implications for redox regulation

    Science.gov (United States)

    Myers, Charles R.

    2014-01-01

    Hexavalent chromium [Cr(VI)] compounds are highly redox active and have long been recognized as potent cytotoxins and carcinogens. The intracellular reduction of Cr(VI) generates reactive Cr intermediates, which are themselves strong oxidants, as well as superoxide, hydrogen peroxide, and hydroxyl radical. These probably contribute to the oxidative damage and effects on redox-sensitive transcription factors that have been reported. However, the identification of events that initiate these signaling changes has been elusive. More recent studies show that Cr(VI) causes irreversible inhibition of thioredoxin reductase (TrxR) and oxidation of thioredoxin (Trx) and peroxiredoxin (Prx). Mitochondrial Trx2/Prx3 are more sensitive to Cr(VI) treatment than cytosolic Trx1/Prx1, although both compartments show thiol oxidation with higher doses or longer treatments. Thiol redox proteomics demonstrate that Trx2, Prx3, and Trx1 are among the most sensitive proteins in cells to Cr(VI) treatment. Their oxidation could therefore represent initiating events that have widespread implications for protein thiol redox control and for multiple aspects of redox signaling. This review summarizes the effects of Cr(VI) on the TrxR/Trx system and how these events could influence a number of downstream redox signaling systems that are influenced by Cr(VI) exposure. Some of the signaling events discussed include the activation of apoptosis signal regulating kinase and MAP kinases (p38 and JNK) and the modulation of a number of redox-sensitive transcription factors including AP-1, NF-κB, p53, and Nrf2. PMID:22542445

  14. Competency Evaluations in the Next Accreditation System: Contributing to Guidelines and Implications.

    Science.gov (United States)

    Park, Yoon Soo; Zar, Fred A; Norcini, John J; Tekian, Ara

    2016-01-01

    CONSTRUCT: This study examines validity evidence of end-of-rotation evaluation scores used to measure competencies and milestones as part of the Next Accreditation System (NAS) of the Accreditation Council for Graduate Medical Education (ACGME). Since the implementation of the milestones, end-of-rotation evaluations have surfaced as a potentially useful assessment method. However, validity evidence on the use of rotation evaluation scores as part of the NAS has not been studied. This article examines validity evidence for end-of-rotation evaluations that can contribute to developing guidelines that support the NAS. Data from 2,701 end-of-rotation evaluations measuring 21 out of 22 Internal Medicine milestones for 142 residents were analyzed (July 2013-June 2014). Descriptive statistics were used to measure the distribution of ratings by evaluators (faculty, n = 116; fellows, n = 59; peer-residents, n = 131), by postgraduate years. Generalizability analysis and higher order confirmatory factor analysis were used to examine the internal structure of ratings. Psychometric implications for combining evaluation scores using composite score reliability were examined. Milestone ratings were significantly higher for each subsequent year of training (15/21 milestones). Faculty evaluators had greater variability in ratings across milestones, compared to fellows and residents; faculty ratings were generally correlated with milestone ratings from fellows (r = .45) and residents (r = .25), but lower correlations were found for Professionalism and Interpersonal and Communication Skills. The Φ-coefficient was .71, indicating good reliability. Internal structure supported a 6-factor solution, corresponding to the hierarchical relationship between the milestones and the 6 core competencies. Evaluation scores corresponding to Patient Care, Medical Knowledge, and Practice-Based Learning and Improvement had higher correlations to milestones reported to the ACGME. Mean evaluation

  15. Bioenergy costs and potentials with special attention to implications for the land system

    Science.gov (United States)

    Popp, A.; Lotze-Campen, H.; Dietrich, J.; Klein, D.; Bauer, N.; Krause, M.; Beringer, T.; Gerten, D.

    2011-12-01

    In the coming decades, an increasing competition for global land and water resources can be expected, due to rising demand for agricultural products, goals of nature conservation, and changing production conditions due to climate change. Especially biomass from cellulosic bioenergy crops, such as Miscanthus or poplar, is being proposed to play a substantial role in future energy systems if climate policy aims at stabilizing greenhouse gas (GHG) concentration at low levels. However, the potential of bioenergy for climate change mitigation remains unclear due to large uncertainties about future agricultural yield improvements, land availability for biomass plantations, and implications for the land system. In order to explore the cost-effective contribution of bioenergy to a low carbon transition with special attention to implications for the land system, we present a modeling framework with detailed biophysical and economic representation of the land and energy sector: We have linked the global dynamic vegetation and water balance model LPJmL (Bondeau et al. 2007, Rost et al. 2008), the global land and water use model MAgPIE (Lotze-Campen et al. 2008, Popp et al. 2010), and the global energy-economy-climate model ReMIND (Leimbach et al. 2009). In this modeling framework LPJmL supplies spatially explicit (0.5° resolution) agricultural yields as well as carbon and water stocks and fluxes. Based on this biophysical input MAgPIE delivers cost-optimized land use patterns (0.5° resolution), associated GHG emissions and rates of future yield increases in agricultural production. Moreover, shadow prices are calculated for irrigation water (as an indicator for water scarcity), food commodities, and bioenergy (as an indicator for changes in production costs) under different land use constraints such as forest conservation for climate change mitigation and as a contribution to biodiversity conservation. The energy-economy-climate model ReMIND generates the demand for

  16. Functional programming of the autonomic nervous system by early life immune exposure: implications for anxiety.

    Directory of Open Access Journals (Sweden)

    Luba Sominsky

    Full Text Available Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p. exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA axis functioning. Altered autonomic nervous system (ANS activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH in the adrenal glands on postnatal days (PNDs 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli. Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of

  17. Alpharma Beef Cattle Nutrition Symposium: implications of nutritional management for beef cow-calf systems.

    Science.gov (United States)

    Funston, R N; Summers, A F; Roberts, A J

    2012-07-01

    The beef cattle industry relies on the use of high-forage diets to develop replacement females, maintain the cow herd, and sustain stocker operations Forage quantity and quality fluctuate with season and environmental conditions Depending on class and physiological state of the animal, a forage diet may not always meet nutritional requirements, resulting in reduced ADG or BW loss if supplemental nutrients are not provided It is important to understand the consequences of such BW loss and the economics of providing supplementation to the beef production system Periods of limited or insufficient nutrient availability can be followed by periods of compensatory BW gain once dietary conditions improve This may have less impact on breeding animals, provided reproductive efficiency is not compromised, where actual BW is not as important as it is in animals destined for the feedlot A rapidly evolving body of literature is also demonstrating that nutritional status of cows during pregnancy can affect subsequent offspring development and production characteristics later in life The concept of fetal programming is that maternal stimuli during critical periods of fetal development have long-term implications for offspring Depending on timing, magnitude, and duration of nutrient limitation or supplementation, it is possible that early measures in life, such as calf birth BW, may be unaffected, whereas measures later in life, such as weaning BW, carcass characteristics, and reproductive traits, may be influenced This body of research provides compelling evidence of a fetal programming response to maternal nutrition in beef cattle Future competitiveness of the US beef industry will continue to be dependent on the use of high-forage diets to meet the majority of nutrient requirements Consequences of nutrient restriction or supplementation must be considered not only on individual animal performance but also the developing fetus and its subsequent performance throughout life.

  18. The melatonergic system: effects on sleep and implications for the treatment of psychiatric disorders

    Directory of Open Access Journals (Sweden)

    De Berardis D

    2011-12-01

    Full Text Available Domenico De Berardis1,2, Tiziano Acciavatti1, Giuseppe Di Iorio1, Mariangela Corbo1, Nicola Serroni2, Daniela Campanella2, Fabiola Di Emidio2, Monica Piersanti3, Marilde Cavuto4, Giovanni Martinotti5, Francesco Saverio Moschetta2, Massimo Di Giannantonio11Department of Neurosciences and Imaging, Chair of Psychiatry, University “G. D'Annunzio”, Chieti; 2NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”; 3NHS, Pharmaceutical Service, Hospital “G. Mazzini”, Teramo; 4IASM, L'Aquila; 5Institute of Psychiatry, Catholic University Medical School, Rome, ItalyAbstract: The circadian pacemaker or biological clock, located in the hypothalamic suprachiasmatic nucleus, is the generation site of circadian rhythms. The light/dark cycle is the circadian pacemaker's dominant synchronizing agent, though it is also influenced by neurotransmitters and the phase-shifting effects of various chemical and pharmacological components, of which melatonin (N-acetyl-5-methoxytryptamine is the most well established. In recent years, melatonin and melatonin analogs have been commercialized in many countries, mainly with hypnotic purposes. A new compound, agomelatine, has been recently synthesized and studied. Among melatonin analogs, this drug possesses unique pharmacological and clinical features; it is an antagonist at 5-HT2B and 5-HT2C receptors and has well established antidepressant and anxiolytic properties. Agomelatine opens new perspectives in the chronobiotic treatment of depression. The purpose of the present review was to elucidate the effects of the melatonergic system on sleep and the implications for the treatment of psychiatric disorders.Keywords: melatonin, agomelatine, circadian rhythms, depression

  19. UV-associated decline in systemic folate: implications for human nutrigenetics, health, and evolutionary processes.

    Science.gov (United States)

    Lucock, Mark; Beckett, Emma; Martin, Charlotte; Jones, Patrice; Furst, John; Yates, Zoe; Jablonski, Nina G; Chaplin, George; Veysey, Martin

    2017-03-01

    The purpose of this study was to examine whether UV exposure alters folate status according to C677T-MTHFR genotype, and to consider the relevance of this to human health and the evolutionary model of skin pigmentation. Total Ozone Mapping Spectrometer (TOMS) satellite data were used to examine surface UV-irradiance, as a marker of UV exposure, in a large (n = 649) Australian cross-sectional study population. PCR/RFLP analysis was used to genotype C677T-MTHFR. Overall, cumulative UV-irradiance (42 and 120 days pre-clinic) was significantly negatively related to red cell folate (RCF) levels. When the cohort was stratified by MTHFR-C677T genotype, the relationship between UV-irradiance (42 days pre-clinic) and RCF remained significant only in the cohorts containing carriers of the T allele. Statistically significant z-score statistics and interaction terms from genotype and UV-irradiance (p-interaction) demonstrated that genotype did modify the effect of UV-irradiance on RCF, with the largest effect of UV being demonstrated in the 677TT-MTHFR subjects. Data provide strong evidence that surface UV-irradiance reduces long-term systemic folate levels, and that this is influenced by the C677T-MTHFR gene variant. We speculate this effect may be due to 677TT-MTHFR individuals containing more 5,10CH 2 -H 4 PteGlu, and that this folate form may be particularly UV labile. Since UV-irradiance lowers RCF in an MTHFR genotype-specific way, there are likely implications for human health and the evolution of skin pigmentation. © 2016 Wiley Periodicals, Inc.

  20. Functional programming of the autonomic nervous system by early life immune exposure: implications for anxiety.

    Science.gov (United States)

    Sominsky, Luba; Fuller, Erin A; Bondarenko, Evgeny; Ong, Lin Kooi; Averell, Lee; Nalivaiko, Eugene; Dunkley, Peter R; Dickson, Phillip W; Hodgson, Deborah M

    2013-01-01

    Neonatal exposure of rodents to an immune challenge alters a variety of behavioural and physiological parameters in adulthood. In particular, neonatal lipopolysaccharide (LPS; 0.05 mg/kg, i.p.) exposure produces robust increases in anxiety-like behaviour, accompanied by persistent changes in hypothalamic-pituitary-adrenal (HPA) axis functioning. Altered autonomic nervous system (ANS) activity is an important physiological contributor to the generation of anxiety. Here we examined the long term effects of neonatal LPS exposure on ANS function and the associated changes in neuroendocrine and behavioural indices. ANS function in Wistar rats, neonatally treated with LPS, was assessed via analysis of tyrosine hydroxylase (TH) in the adrenal glands on postnatal days (PNDs) 50 and 85, and via plethysmographic assessment of adult respiratory rate in response to mild stress (acoustic and light stimuli). Expression of genes implicated in regulation of autonomic and endocrine activity in the relevant brain areas was also examined. Neonatal LPS exposure produced an increase in TH phosphorylation and activity at both PNDs 50 and 85. In adulthood, LPS-treated rats responded with increased respiratory rates to the lower intensities of stimuli, indicative of increased autonomic arousal. These changes were associated with increases in anxiety-like behaviours and HPA axis activity, alongside altered expression of the GABA-A receptor α2 subunit, CRH receptor type 1, CRH binding protein, and glucocorticoid receptor mRNA levels in the prefrontal cortex, hippocampus and hypothalamus. The current findings suggest that in addition to the commonly reported alterations in HPA axis functioning, neonatal LPS challenge is associated with a persistent change in ANS activity, associated with, and potentially contributing to, the anxiety-like phenotype. The findings of this study reflect the importance of changes in the perinatal microbial environment on the ontogeny of physiological processes.

  1. Implications of Upwells as Hydrodynamic Jets in a Pulse Jet Mixed System

    Energy Technology Data Exchange (ETDEWEB)

    Pease, Leonard F. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bamberger, Judith A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Minette, Michael J. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-08-01

    This report evaluates the physics of the upwell flow in pulse jet mixed systems in the Hanford Tank Waste Treatment and Immobilization Plant (WTP). Although the initial downward flow and radial flow from pulse jet mixers (PJMs) has been analyzed in some detail, the upwells have received considerably less attention despite having significant implications for vessel mixing. Do the upwells behave like jets? How do the upwells scale? When will the central upwell breakthrough? What proportion of the vessel is blended by the upwells themselves? Indeed, how the physics of the central upwell is affected by multiple PJMs (e.g., six in the proposed mixing vessels), non-Newtonian rheology, and significant multicomponent solids loadings remain unexplored. The central upwell must satisfy several criteria to be considered a free jet. First, it must travel for several diameters in a nearly constant direction. Second, its velocity must decay with the inverse of elevation. Third, it should have an approximately Gaussian profile. Fourth, the influence of surface or body forces must be negligible. A combination of historical data in a 12.75 ft test vessel, newly analyzed data from the 8 ft test vessel, and conservation of momentum arguments derived specifically for PJM operating conditions demonstrate that the central upwell satisfies these criteria where vigorous breakthrough is achieved. An essential feature of scaling from one vessel to the next is the requirement that the underlying physics does not change adversely. One may have confidence in scaling if (1) correlations and formulas capture the relevant physics; (2) the underlying physics does not change from the conditions under which it was developed to the conditions of interest; (3) all factors relevant to scaling have been incorporated, including flow, material, and geometric considerations; and (4) the uncertainty in the relationships is sufficiently narrow to meet required specifications. Although the central upwell

  2. The Cannabinoid System and Pain

    Science.gov (United States)

    Woodhams, Stephen G.; Chapman, Victoria; Finn, David P.; Hohmann, Andrea G.; Neugebauer, Volker

    2018-01-01

    Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. PMID:28625720

  3. ENDOCANNABINOID 2-ARACHIDONOYLGLYCEROL SELF-ADMINISTRATION BY SPRAGUE-DAWLEY RATS AND STIMULATION OF IN VIVO DOPAMINE TRANSMISSION IN THE NUCLEUS ACCUMBENS SHELL

    Directory of Open Access Journals (Sweden)

    Maria Antonietta eDe Luca

    2014-10-01

    Full Text Available 2-Arachidonoylglycerol (2-AG is the most potent endogenous ligand of brain cannabinoid CB1 receptors and is synthesized on demand from 2-arachidonate-containing phosphoinositides by the action of diacyglycerol lipase in response to increased intracellular calcium. Several studies indicate that the endocannabinoid (eCB system is involved in the mechanism of reward and that diverse drugs of abuse increase brain eCB levels. In addition, eCB are self-administered (SA by squirrel monkeys, and anandamide increases nucleus accumbens (NAc shell dopamine (DA in rats. To date, there is no evidence on the reinforcing effects of 2-AG and its effects on DA transmission in rodents. In order to fill this gap, we studied intravenous 2-AG SA and monitored the effect of 2-AG on extracellular DA in the NAc shell and core via microdialysis in male Sprague-Dawley rats. Rats were implanted with jugular catheters and trained to self-administer 2-AG (25g/kg/inf iv in single daily 1h sessions for 5 weeks under initial Fixed Ratio (FR 1 schedule. The ratio was subsequently increased to FR2. Active nose-poking increased from the 6th SA session (acquisition phase but no significant increase of nose-pokes was observed after FR2. When 2-AG was substituted for vehicle (25th SA session, extinction phase, rate responding, as well as number of injections, slowly decreased. When vehicle was replaced with 2-AG, SA behavior immediately recovered (reacquisition phase. The reinforcing effects of 2-AG in SA behavior were fully blocked by the CB1 receptor inverse agonist/antagonist rimonabant (1 mg/kg ip, 30 min before SA session. In the microdialysis studies, we observed that 2-AG (0.1-1.0 mg/kg iv preferentially stimulates NAc shell as compared to the NAc core. NAc shell DA increased by about 25% over basal value at the highest doses tested (0.5 and 1.0 mg/kg iv. The results obtained suggest that the eCB system, via 2-AG, plays an important role in reward.

  4. 75 FR 13329 - Implications of Financial Accounting System (FAS) 166 on SBA Guaranteed Loan Programs

    Science.gov (United States)

    2010-03-19

    ... SMALL BUSINESS ADMINISTRATION [Docket No. SBA-2010-0005] Implications of Financial Accounting... from the public on: (1) The effect that the accounting changes mandated by the Financial Accounting Standards Board (FASB) in Financial Accounting Standard (FAS) 166 have on SBA Lender and investor...

  5. A closed-loop forward osmosis-nanofiltration hybrid system: Understanding process implications through full-scale simulation

    KAUST Repository

    Phuntsho, Sherub

    2016-12-30

    This study presents simulation of a closed-loop forward osmosis (FO)-nanofiltration (NF) hybrid system using fertiliser draw solution (DS) based on thermodynamic mass balance in a full-scale system neglecting the non-idealities such as finite membrane area that may exist in a real process. The simulation shows that the DS input parameters such as initial concentrations and its flow rates cannot be arbitrarily selected for a plant with defined volume output. For a fixed FO-NF plant capacity and feed concentration, the required initial DS flow rate varies inversely with the initial DS concentration or vice-versa. The net DS mass flow rate, a parameter constant for a fixed plant capacity but that increases linearly with the plant capacity and feed concentration, is the most important operational parameter of a closed-loop system. Increasing either of them or both increases the mass flow rate to the system directly affecting the final concentration of the diluted DS with direct energy implications to the NF process. Besides, the initial DS concentration and flow rates are also limited by the optimum recovery rates at which NF process can be operated which otherwise also have direct implications to the NF energy. This simulation also presents quantitative analysis of the reverse diffusion of fertiliser nutrients towards feed brine and the gradual accumulation of feed solutes within the closed system.

  6. Private investment in hospitals: a comparison of three healthcare systems and possible implications for real estate strategies.

    Science.gov (United States)

    van der Zwart, Johan; van der Voordt, Theo; Jonge, Hans de

    2010-01-01

    This article explores lessons to be learned from three different healthcare systems and the possible implications for the management of healthcare real estate, in particular in connection to the Dutch system. It discusses similarities and differences among the different systems, in search of possible consequences on cost, financing, and design innovation. To keep healthcare affordable in the future, the Dutch government is currently in the process of changing legislation to move from a centrally directed system to a so-called regulated market system. The deregulation of real estate investment that accompanies the new healthcare delivery system offers healthcare organizations new opportunities, but also more responsibility and greater risk in return on investment. Consequently, healthcare organizations must find new methods of financing. Private investment is one of the options. Three healthcare systems were analyzed on the basis of a literature review and document analysis, then schematized to show similarities and dissimilarities with regard to private investment in hospitals. Observations are based on a selection of recently published articles on private-sector financing and its implications for healthcare real estate decision making in the Netherlands, the United Kingdom, and Germany. The strengths and weaknesses of three healthcare systems with differing proportions of private and public investment in hospitals were explored. Research revealed a gap between intended effects and actual effects with regard to quality and cost. Costly private finance does not necessarily lead to "value for money." Transferring real estate decisions to private investors decreases the influence of the healthcare organization on future costs and quality. The three healthcare systems show substantial differences between public and private responsibilities. Less governmental involvement affords both opportunities and risks for hospitals. Private investment may lead to innovation

  7. Usability evaluation of an experimental text summarization system and three search engines: implications for the reengineering of health care interfaces.

    Science.gov (United States)

    Kushniruk, Andre W; Kan, Min-Yem; McKeown, Kathleen; Klavans, Judith; Jordan, Desmond; LaFlamme, Mark; Patel, Vimia L

    2002-01-01

    This paper describes the comparative evaluation of an experimental automated text summarization system, Centrifuser and three conventional search engines - Google, Yahoo and About.com. Centrifuser provides information to patients and families relevant to their questions about specific health conditions. It then produces a multidocument summary of articles retrieved by a standard search engine, tailored to the user's question. Subjects, consisting of friends or family of hospitalized patients, were asked to "think aloud" as they interacted with the four systems. The evaluation involved audio- and video recording of subject interactions with the interfaces in situ at a hospital. Results of the evaluation show that subjects found Centrifuser's summarization capability useful and easy to understand. In comparing Centrifuser to the three search engines, subjects' ratings varied; however, specific interface features were deemed useful across interfaces. We conclude with a discussion of the implications for engineering Web-based retrieval systems.

  8. Exchange credit risk: Measurement and implications on the stability of partially dollarized financial systems

    Directory of Open Access Journals (Sweden)

    Ernesto Mordecki

    2013-06-01

    Full Text Available Some emergent economies present a high financial dollarization in loans and deposits, generating a specific risk in the banking activity. We quantify this exchange credit risk as the price of an option equivalent to this loan, and discuss the financial stability implications due to the (implicit issuance of these options. The exchange rate is modeled through a Levy process. The depth of the market depends on the type of the currencies involved. Whenever possible, we depart from option prices to calibrate a model, like in the EUR/USD market. But if the market is not liquid, as the USD/UYU market, we provide alternative pricing methodologies.

  9. Aviation System Safety and Pilot Risk Perception: Implications for Enhancing Decision-Making Skills

    Science.gov (United States)

    Green, Mavis F.

    2001-01-01

    This research explores risk perception in a defined population of flight instructors and the implications of these views for flight training. Flight instructors and students engaged in collegiate aviation flight training were interviewed for this qualitative study. Thirty-three percent of the instructors interviewed reported that flying is not a risky activity. This is important because research identifies risk perception as one factor influencing instructional choices. These choices can then impact the subsequent decision-making processes of flight students. Facilitating pilot decision-making through the use of an appropriate type of learning that incorporates the modeling of consensually validated cognitive procedures and risk management processes is discussed.

  10. An Innovation Systems Assessment of the Australian Biofuel Industry. Policy and Private Sector Implications

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, Jason D.

    2006-07-15

    A strong biofuel industry in Australia has the potential to provide numerous benefits to the nation and its peoples. The benefits include; reduced emissions of greenhouse gases and harmful particulate matter, a boost to rural development goals, enhanced fuel security and a lower balance of payments. For biofuels to be seriously considered as alternatives to traditional petroleum based automotive fuels they must be economically viable. The findings from a series of Australian Bureau of Agricultural and Resource Economics (ABARE) investigations suggest that ethanol and biodiesel production would be economically viable, in the Australian context, with oil prices in the range of 30-40 USD a barrel. Despite the price of oil being in or above this range for over two years a strong home grown biofuel industry has failed to develop in Australia. The purpose of this master's thesis therefore is to identify the critical issues facing biofuel industry development in Australian and to propose possible policy and private sector strategies for dealing with them. The analysis was done in the following three steps; the first was to map the development of the ethanol and biodiesel industries, the second was to analyse the performance of the industries overtime and the third was to identify the mechanisms which have either induced or blocked their growth. The strategies proposed by this thesis were derived from analysing the inducing and blocking mechanisms and the related issues. The innovation systems approach was chosen because of its ability to provide insights into key industry players, their network interactions and the institutional setup within which they work together to develop, diffuse and use their products. The data needed for the analysis stated above included information related to the development, diffusion and use of ethanol and biodiesel; that is, details about the industry actors and their activities, industry networks, product standards, excise arrangements

  11. An Innovation Systems Assessment of the Australian Biofuel Industry. Policy and Private Sector Implications

    Energy Technology Data Exchange (ETDEWEB)

    Nielsen, Jason D

    2006-07-15

    A strong biofuel industry in Australia has the potential to provide numerous benefits to the nation and its peoples. The benefits include; reduced emissions of greenhouse gases and harmful particulate matter, a boost to rural development goals, enhanced fuel security and a lower balance of payments. For biofuels to be seriously considered as alternatives to traditional petroleum based automotive fuels they must be economically viable. The findings from a series of Australian Bureau of Agricultural and Resource Economics (ABARE) investigations suggest that ethanol and biodiesel production would be economically viable, in the Australian context, with oil prices in the range of 30-40 USD a barrel. Despite the price of oil being in or above this range for over two years a strong home grown biofuel industry has failed to develop in Australia. The purpose of this master's thesis therefore is to identify the critical issues facing biofuel industry development in Australian and to propose possible policy and private sector strategies for dealing with them. The analysis was done in the following three steps; the first was to map the development of the ethanol and biodiesel industries, the second was to analyse the performance of the industries overtime and the third was to identify the mechanisms which have either induced or blocked their growth. The strategies proposed by this thesis were derived from analysing the inducing and blocking mechanisms and the related issues. The innovation systems approach was chosen because of its ability to provide insights into key industry players, their network interactions and the institutional setup within which they work together to develop, diffuse and use their products. The data needed for the analysis stated above included information related to the development, diffusion and use of ethanol and biodiesel; that is, details about the industry actors and their activities, industry networks, product standards, excise arrangements

  12. An Innovation Systems Assessment of the Australian Biofuel Industry. Policy and Private Sector Implications

    International Nuclear Information System (INIS)

    Nielsen, Jason D.

    2006-07-01

    A strong biofuel industry in Australia has the potential to provide numerous benefits to the nation and its peoples. The benefits include; reduced emissions of greenhouse gases and harmful particulate matter, a boost to rural development goals, enhanced fuel security and a lower balance of payments. For biofuels to be seriously considered as alternatives to traditional petroleum based automotive fuels they must be economically viable. The findings from a series of Australian Bureau of Agricultural and Resource Economics (ABARE) investigations suggest that ethanol and biodiesel production would be economically viable, in the Australian context, with oil prices in the range of 30-40 USD a barrel. Despite the price of oil being in or above this range for over two years a strong home grown biofuel industry has failed to develop in Australia. The purpose of this master's thesis therefore is to identify the critical issues facing biofuel industry development in Australian and to propose possible policy and private sector strategies for dealing with them. The analysis was done in the following three steps; the first was to map the development of the ethanol and biodiesel industries, the second was to analyse the performance of the industries overtime and the third was to identify the mechanisms which have either induced or blocked their growth. The strategies proposed by this thesis were derived from analysing the inducing and blocking mechanisms and the related issues. The innovation systems approach was chosen because of its ability to provide insights into key industry players, their network interactions and the institutional setup within which they work together to develop, diffuse and use their products. The data needed for the analysis stated above included information related to the development, diffusion and use of ethanol and biodiesel; that is, details about the industry actors and their activities, industry networks, product standards, excise arrangements

  13. Macroeconomic policy interaction: State dependency and implications for financial stability in UK: A systemic review

    Directory of Open Access Journals (Sweden)

    Muhammad Ali Nasir

    2016-12-01

    Full Text Available The association between economic and financial stabilities and influence of macroeconomic policies on the financial sector creates scope of active policy role in financial stability. As a contribution to the existing body of knowledge, this study has analysed the implications of macroeconomic policy interaction/coordination for financial stability, proxied by financial assets, i.e. equity and bonds price oscillation. The critical review and analysis of the existing literature on the subject suggests that there is also ample evidence of interdependence between monetary and fiscal policies and this interrelation necessitates coordination between them for the sake of financial stability. There is also a case for analysing the symmetry of financial markets responses to macroeconomic policy interaction. On methodological and empirical grounds, it is vital to test the robustness of policy recommendations to overcome the limitation of a single empirical approach (Jeffrey–Lindley’s paradox. Hence, the Frequentist and Bayesian approaches should be used in commentary manner. The policy interaction and optimal policy combination should also be analysed in the context of institutional design and major financial events to gain insight into the implications of policy interaction in the periods of stable economic and financial environments as well as period of financial and economic distress.

  14. Principles of General Systems Theory: Some Implications for Higher Education Administration

    Science.gov (United States)

    Gilliland, Martha W.; Gilliland, J. Richard

    1978-01-01

    Three principles of general systems theory are presented and systems theory is distinguished from systems analysis. The principles state that all systems tend to become more disorderly, that they must be diverse in order to be stable, and that only those maximizing their resource utilization for doing useful work will survive. (Author/LBH)

  15. Neural systems supporting cognitive-affective interactions in adolescence: The role of puberty and implications for affective disorders

    Directory of Open Access Journals (Sweden)

    Cecile D. Ladouceur

    2012-08-01

    Full Text Available Evidence from longitudinal studies suggests that adolescence may represent a period of vulnerability that, in the context of adverse events, could contribute to developmental trajectories toward behavioral and emotional health problems, including affective disorders. Adolescence is also a sensitive period for the development of neural systems supporting cognitive-affective processes, which have been implicated in the pathophysiology of affective disorders such as anxiety and mood disorders. In particular, the onset of puberty brings about a cascade of physical, hormonal, psychological, and social changes that contribute in complex ways to the development of these systems. This article provides a brief overview of neuroimaging research pertaining to the development of cognitive-affective processes in adolescence. It also includes a brief review of evidence from animal and human neuroimaging studies suggesting that sex steroids influence the connectivity between prefrontal cortical and subcortical limbic regions in ways that contribute to increased reactivity to emotionally salient stimuli. We integrate these findings in the context of a developmental affective neuroscience framework suggesting that the impact of rising levels of sex steroids during puberty on fronto-limbic connectivity may be even greater in the context of protracted development of prefrontal cortical regions in adolescence. We conclude by discussing the implications of these findings for future research aimed at identifying neurodevelopmental markers of risk for future onset of affective disorders.

  16. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Science.gov (United States)

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

  17. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults.

    Science.gov (United States)

    Rigamonti, Antonello E; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  18. Anticipatory and consummatory effects of (hedonic chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    Directory of Open Access Journals (Sweden)

    Antonello E. Rigamonti

    2015-11-01

    Full Text Available Background: Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods: To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1, peptide YY (PYY, anandamide (AEA, 2-AG, palmitoylethanolamide (PEA, and oleoylethanolamide (OEA in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results: The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions: When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity.

  19. Permeation of hydrogen at low pressures through stainless steel and implications for tritium control in fusion reactor systems

    International Nuclear Information System (INIS)

    Axtmann, R.C.; Johnson, E.F.; Kuehler, C.W.

    1976-01-01

    New experimental data on the permeation of hydrogen through stainless steel indicate that at driving pressures below 10 -2 torr, the permeation rate is linearly dependent on the driving pressure. A possible consequence is that the permeation rates of hydrogenic species in fusion reactor systems might be much lower than those reported in contemporary conceptual design studies which assume that the rates are dependent on the square root of the driving pressure. The important implications of these low permeation rates are: (1) tritium losses to the environment may be more dependent on ordinary leaks from equipment than on permeation to the steam cycle; (2) recovery of tritium from breeding blankets via permeation windows may be impracticable; and (3) recovery of tritium from breeding blankets not dependent on permeation windows may be simplified by the possibility of operating at much higher average tritium concentrations in the blanket and cooling systems

  20. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

    Directory of Open Access Journals (Sweden)

    Marina Rubio

    Full Text Available Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716 during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

  1. Implication of the dominant design in electronic initiation systems in the South African mining industry

    CSIR Research Space (South Africa)

    Smit, FC

    1998-11-01

    Full Text Available This article analyzes an emerging technological innovation, namely, electronic initiation systems for mining explosives in South Africa. The concept of electronic initiation is presenting itself as a challenge to traditional initiation systems...

  2. Air Education and Training Command Cost and Capacity System: Implications for Organizational and Data Flow Changes

    National Research Council Canada - National Science Library

    Manacapilli, Thomas

    2004-01-01

    .... It briefly reviews training management systems and associated organizational arrangements in the other services and the private sector to draw insights for a model management system for the Air Force...

  3. Responses to Information Systems Graduate Preparation and Job Needs: Implications for Higher Education

    Science.gov (United States)

    Simon, DeShea; Jackson, Kanata

    2015-01-01

    This study examined the perspectives on academic preparation and job skill needs of Information Systems program graduates from an Eastern state in the US. A historical review of the literature surrounding information systems skill requirements was conducted for this study, to provide an understanding of the changes in information systems over the…

  4. Transformations of television systems: Implications for media content, political parties and political attitudes

    NARCIS (Netherlands)

    Arbaoui, B.

    2014-01-01

    This thesis investigates the transformation of West-European television systems since the onset of the liberalisation process through a systematic comparison of 17 television systems between 1980 and 2008. The transformation of West-European television systems is analysed through a dualistic

  5. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.

    Science.gov (United States)

    Patel, Sachin; Kingsley, Philip J; Mackie, Ken; Marnett, Lawrence J; Winder, Danny G

    2009-12-01

    Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.

  6. Electric vehicle charging in China’s power system: Energy, economic and environmental trade-offs and policy implications

    International Nuclear Information System (INIS)

    Li, Ying; Davis, Chris; Lukszo, Zofia; Weijnen, Margot

    2016-01-01

    Highlights: • We investigate the energy, economic and environmental implications of deploying EVs for China’s power system by 2030. • EVs outperform gasoline-powered vehicles in terms of average fueling costs. • Controlled EV charging given the expected 2030 capacity portfolio results in more CO_2 emissions than uncontrolled charging. • Controlled charging has absolute advantages in mitigating the peak load and facilitating RES generation. • Controlled (dis)charging will not reduce CO_2 for China without generation decarbonization and CO_2-influenced dispatch. - Abstract: This work investigates different scenarios for electric vehicle (EV) deployment in China and explores the implications thereof with regard to energy portfolio, economics and the environment. Specifically, we investigate how to better deliver the value of EVs by improving designs in the power system and charging strategies, given expected developments by 2030 in both the power system and EV penetration levels. The impact of EV charging is quantified by applying an integrated transportation-power system model on a set of scenarios which represent uncertainties in charging strategies. We find that deploying EVs essentially shifts the use of gasoline to coal-fired power generation in China, thus leading to more coal consumption and CO_2 emissions of the power system. Economically, EVs outperform gasoline-powered vehicles in terms of average fueling costs. However, the impact of EVs in terms of CO_2 emissions at the national level largely depends on the charging strategy. Specifically, controlled charging results in more CO_2 emissions associated with EVs than uncontrolled charging, as it tends to feed EVs with electricity produced by cheap yet low-efficiency coal power plants located in regions where coal prices are low. Still, compared with uncontrolled charging, controlled charging shows absolute advantages in: (1) mitigating the peak load arising from EV charging; (2) facilitating RES

  7. Toward social system theory: implications for older people with developmental disabilities and service delivery.

    Science.gov (United States)

    Dossa, P A

    1990-01-01

    The literature refers to older people with developmental disabilities as the "new service population." How and why this population emerged as a special category is discussed conceptually with reference to social systems theory. A brief review of social systems theory and some basic systemic tenets are presented. Systemic tenets are employed in examining the historical development of social gerontology and present trends in the service-delivery system. I show that the systemic variable of the economic model of human development has significantly impacted on the making of older people with developmental disabilities a dependent population. In the conclusion the systems perspective is explored in relation to recognizing the liminal, in-between parts between components. It is argued that such a perception minimizes the dichotomy between older people with developmental disabilities and the non-disabled population, paving the way for a genuine encounter.

  8. Sex differences in drug-related stress-system changes: implications for treatment in substance-abusing women.

    Science.gov (United States)

    Fox, Helen C; Sinha, Rajita

    2009-01-01

    Extensive research indicates that chronic substance abuse disrupts stress and reward systems of the brain. Gender variation within these stress-system alterations, including the impact of sex hormones on these changes, may influence sex-specific differences in both the development of, and recovery from, dependency. As such, gender variations in stress-system function may also provide a viable explanation for why women are markedly more vulnerable than men to the negative consequences of drug use. This article therefore initially reviews studies that have examined gender differences in emotional and biophysiological changes to the stress and reward system following the acute administration of drugs, including cocaine, alcohol, and nicotine. The article then reviews studies that have examined gender differences in response to various types of stress in both healthy and drug-abusing populations. Studies examining the impact of sex hormones on these gender-related responses are also reported. The implications of these sex-specific variations in stress and reward system function are discussed in terms of both comorbid psychopathology and treatment outcome.

  9. Assessing the Organizational Social Context (OSC) of child welfare systems: implications for research and practice.

    Science.gov (United States)

    Glisson, Charles; Green, Philip; Williams, Nathaniel J

    2012-09-01

    The study: (1) provides the first assessment of the a priori measurement model and psychometric properties of the Organizational Social Context (OSC) measurement system in a US nationwide probability sample of child welfare systems; (2) illustrates the use of the OSC in constructing norm-based organizational culture and climate profiles for child welfare systems; and (3) estimates the association of child welfare system-level organizational culture and climate profiles with individual caseworker-level job satisfaction and organizational commitment. The study applies confirmatory factor analysis (CFA) and hierarchical linear models (HLM) analysis to a US nationwide sample of 1,740 caseworkers from 81 child welfare systems participating in the second National Survey of Child and Adolescent Wellbeing (NSCAW II). The participating child welfare systems were selected using a national probability procedure reflecting the number of children served by child welfare systems nationwide. The a priori OSC measurement model is confirmed in this nationwide sample of child welfare systems. In addition, caseworker responses to the OSC scales generate acceptable to high scale reliabilities, moderate to high within-system agreement, and significant between-system differences. Caseworkers in the child welfare systems with the best organizational culture and climate profiles report higher levels of job satisfaction and organizational commitment. Organizational climates characterized by high engagement and functionality, and organizational cultures characterized by low rigidity are associated with the most positive work attitudes. The OSC is the first valid and reliable measure of organizational culture and climate with US national norms for