The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives

Alterations in emotion regulation processes may form the basis of psychopathologies. The endocannabinoid (eCB) system, composed of endogenous ligands, the enzymatic machinery in charge of their metabolism and the specific metabotropic receptors, has emerged as a major neuromodulatory system critically involved in the control of emotional homeostasis and stress responsiveness. Data from animal models indicate that the eCB system plays a key role in brain development, and is probably involved in the control of emotional states from early developmental stages. The present review summarizes the latest information on the role of the eCB system in emotionality and anxiety-related disorders throughout the lifespan. Putative therapeutic strategies based on the pharmacological modulation of this system will be discussed. Given the fact that the pharmacological modulation of the eCB system has recently arisen as a promising strategy in the management of anxiety and mood disorders, the potential efficacy of this pharmacological approach (i.e. blockers of the catabolic pathway) will be discussed, as well as pharmacological alternatives such as modulators of cannabinoid receptors other than the classical CB1 receptor, or administration of other plant-derived compounds (e.g. cannabidiol).     

Modulation of the serotonin system by endocannabinoid signaling

The cannabinoid CB₁ receptors and their endogenous agonists, endocannabinoids (eCBs), are ubiquitously distributed throughout the central nervous system (CNS), where they play a key role in the regulation of neuronal excitability. As such, CB signaling has been implicated in the regulation of a myriad of physiological functions ranging from feeding homoeostasis to emotional and motivational processes. Ample evidence from behavioral studies also suggests that eCBs are important regulators of stress responses and a deficit in eCB signaling contributes to stress-related disorders such as anxiety and depression. The eCB-induced modulation of stress-related behaviors appears to be mediated, at least in part, through the regulation of the serotoninergic system. In this article, we review the role of eCB signaling in the regulation of the serotoninergic system with special emphasis on the cellular mechanisms by which cannabinoid CB₁ receptors modulate the excitability of dorsal raphe serotonin neurons.     

Role of ghrelin in the pathophysiology of eating disorders: implications for pharmacotherapy

Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gut-brain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs.     

Anorexia nervosa and bulimia nervosa: An appraisal

Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by an aberrant pattern of eating behavior, relentless pursuit of thinness, an intense fear about weight gain and an altered perception of body shape. The pathobiology of eating disorders is complex. Several social, psychological and developmental phenomena are proposed to contribute to the etiology of eating disorders. The role of neuropeptide Y, corticotropin releasing hormone and leptin has also been investigated to understand the pathogenesis of eating disorders. However, most of the neuropeptide alterations noted in eating disorders are secondary to starvation. Several nonpharmacological approaches such as cognitive and behavior-based therapy and interpersonal therapy have been developed to assist weight gain and to modify the behavioral impairment associated with eating disorders. Pharmacotherapy serves as an adjunct in AN, whereas it plays a more significant role in the management of BN. Antidepressants are effective in a limited number of AN patients with comorbid depression. On the other hand, the efficacy of fluoxetine in BN patients in reducing the frequency of binge eating and in the severity of behavioral abnormalities is quite impressive. Several adjunct therapies such as prokinetics and anxiolytics have also been used in AN and BN to assist eating behavior. An insight into genetic and neurochemical abnormalities occurring in eating disorders will help to find better therapeutic agents for these disorders. (c) 2001 Prous Science. All rights reserved.     

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

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

The role of melanocortin peptides and receptors in regulation of energy balance

Energy balance is a highly regulated, complex process which is modulated by central and peripheral systems. Dysregulation of energy homeostasis can result in metabolic disorders, such as obesity and type II diabetes. Obesity and type II diabetes are two of the most prevalent and challenging clinical conditions in society today. A growing body of evidence has implicated the melanocortin system as an important component in the maintenance of energy balance. alpha-MSH, a 13 amino acid peptide secreted as a product of the pro-opiomelanocortin (POMC) gene in the pituitary is a potent agonist of 4 of the 5 cloned melanocortin receptors (MCR). MC receptors are members of a G-protein-coupled receptor (GPCR) family, which signal through cAMP. Agouti and agouti-related protein (AGRP) are natural antagonists of melanocortin receptors and participate in regulation of skin/fur pigmentation, body weight, and adiposity. Stimulation of MC receptors has pleiotropic effects, which impact the nervous system as well as endocrine and immune functions. One of the most prominent effects of MC receptor stimulation is a dramatic suppression of food intake and body weight, which has led to the hypothesis that the MC receptor system plays a primary role in the maintenance of energy balance. This idea is supported by a large body of pharmacological, molecular and human genetic evidence. The following review summarizes the role of melanocortin receptors in the regulation of food intake and energy homeostasis and highlights the opportunities for MC receptors as drug development targets in treating eating disorders and diabetes.     

Endocannabinoids and traumatic brain injury

Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI.     

Orphan G-protein-coupled receptors : strategies for identifying ligands and potential for use in eating disorders

G-protein-coupled receptors (GPCRs) are key regulators of intercellular interactions, participating in almost every physiological response. They exert their effects by being activated by a variety of endogenous ligands. Traditionally, these ligands were identified first, providing tools to characterise the receptors. However, since the late 1980s, homology screening approaches have allowed the GPCRs to be found first, and in turn used as orphan targets to identify their ligands. Over the last decade this method has led to the identification of 12 novel neuropeptide families. Interestingly, four of these deorphanised GPCR systems, melanin-concentrating hormone, ghrelin, orexin and neuropeptide B/neuropeptide W, have been found to play a role in the control of energy balance. This article reviews the role of these GPCR systems in the control of food intake and energy expenditure, and discusses their potential use in therapies directed at eating disorders. As obesity has reached epidemic proportions across the developed world, pharmacotherapy has focused on this condition. However, difficulties in weight control also characterise disorders of binge eating such as bulimia and binge-eating disorder. Consequently, hypophagic treatments may be of potential benefit in normal, overweight or obese individuals displaying aberrant (out of control) eating behaviour.     

Hypothalamic control of energy balance

Over the last decade, understanding of the circuits and molecules involved in the regulation of energy balance has expanded dramatically. A complex system has evolved which allows the brain to read, interpret and integrate a wide range of signals and to elicit appropriate changes in food intake and energy expenditure as a result of the information. A series of short-term signals derived from the gastrointestinal tract, such as cholecystokinin, govern meal size. Other hormones e.g. insulin and leptin, and circulating nutrients offer long-term regulation. These signals act at a variety of central nervous system sites, but the majority of pathways converge on the hypothalamus, which itself contains numerous peptides and neurotransmitters that influence feeding and energy expenditure. Mutations in key components of these circuits underlie some of the syndromes of genetic obesity in rodents, but are responsible for only a small percentage of human obesity--which is largely attributed to an adverse lifestyle. However, various abnormalities have been identified in dietary-obese rodents, which is the closest model to 'common' human obesity. The relevance of these to energy homeostasis in humans remains uncertain, but some are likely to emerge as therapeutic targets for the treatment of both obesity and eating disorders.     

Neurobiological Interactions Between Stress and the Endocannabinoid System

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.     

Approaches to anorexia in rodents: focus on the anx/anx mouse

Eating disorders constitute major medical health problems in the western world. Even though little is known about the mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. We have identified a mutation in anx/anx mice that is likely to cause the anorectic phenotype. Using RNA profiling, we have found 29 genes with differential expression in the anx/anx mouse brain. The anx gene, its protein product or molecules in the anx pathway may thus be interesting targets for development of new pharmaceuticals for the treatment of eating disorders. Based on the histochemical alterations found in the anx/anx mouse, we hypothesised and showed that many sera from anorectic/bulimic patients contain antibodies that bind specifically to the hypothalamic food intake regulatory system in rat. This finding represents a novel research avenue that may lead to a better understanding of eating disorders. It also suggests that targeted immunological approaches may be used in therapy.     

Monoacylglycerol lipase – a target for drug development?

The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. 'Drugable' selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents.     

Inflammation in rosacea and acne: Implications for patient care

Rosacea and acne are chronic inflammatory skin conditions that share an inflammatory pathogenesis, but clinically remain quite distinct. Although many have long assumed that these conditions are primarily infectious, emerging evidence suggests that inflammation plays a critical role in the pathogenesis of these disorders. Part of the innate immune system, the antimicrobial and proinflammatory cathelicidins, may be downregulated by both azelaic acid and sub antimicrobial doxycycline. In acne, the creation of papules, pustules and nodules is clearly mediated through immune mechanisms, and the antiinflammatory effects of retinoids play a key role in management. Recent observations help us understand in greater detail the role that inflammation plays in these two diseases, and the mechanisms by which commonly used medications exert their effect by modulating inflammatory processes. This review will present and synthesize recently acquired information as it relates to inflammatory acne and rosacea pathogenesis and clinical management.     

Endocannabinoids in the regulation of appetite and body weight

The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as delta9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.     

Chemical-induced autoimmune reactions and Spanish toxic oil syndrome. Focus on hydantoins and related compounds

Autoimmune diseases comprise a wide spectrum of overlapping, systemic and organ-specific disorders. Although, etiology and pathogenesis of such disorders are largely unknown, endogenous host factors and exogenous agents, such as viruses, bacteria, and small molecular weight chemicals, drugs and food components, are believed to be involved. The toxicological significance of low molecular weight compounds on induction of autoimmune disorders is illustrated by the toxic oil syndrome (TOS), a chemically induced epidemic, observed in Spain since 1981. The causative chemical(s) of TOS is still elusive, but an association between ingestion of refined aniline-adulterated rapeseed oil and the syndrome is well-documented. Epidemiological, clinical and immunopathological symptoms of TOS are briefly reviewed. The striking resemblance with immunological disorders, observed in man upon medication with hydantoins and related compounds, is demonstrated. The likeliness of formation of a hydantoin-related compound in the aniline-adulterated oil is evidenced and its role as possible toxic agent in TOS is proposed. Further, the presence of hydantoins and related compounds in food is briefly reviewed and it is suggested that these chemicals may account for a portion of idiopathic autoimmune diseases observed in man. The need for development of animal models to assess this kind of immunotoxicological effects is stressed.     

Role of central melanocortin signaling in eating disorders

Melanocortins are derived from posttranslational processing of the precursor protein pro-opiomelanocortin (POMC). The central melanocortinergic system consists of endogenous agonist alpha-melanocyte-stimulating hormone, the naturally occurring antagonist Agouti-related protein (AGRP), and two melanocortin receptors (MC3R, MC4R). Activation of central melanocortin receptors inhibits feeding and leads to weight loss, whereas blockade of the central melanocortin signaling pathway increases food consumption and promotes weight gain. This review will focus on the role of central melanocortin signaling in eating behavior and will evaluate studies of the neural pathways of POMC and AGRP systems, the effects of the central melanocortinergic system on food intake and body weight, and the regulation of hypothalamic POMC and AGRP neurons in response to altered feeding state and energy balance. In addition, this review will explore what is known about the interplay between the central melanocortinergic system and peripheral signals of energy homeostasis, i.e., leptin and glucocorticoids. Furthermore, evidence will be presented that genetic defects within the melanocortin signaling system are involved in determining susceptibility to obesity and anorexia in humans, and the therapeutic potential of melanocortin agonists and antagonists in the treatment of these disorders will be discussed.     

The role of food addiction in clinical research

Recent research has uncovered neurobiological and behavioral similarities between substance dependence and excess consumption of highly processed foods. These findings have led to the theory that food addiction may play a role in obesity and disordered eating. The inclusion of validated food addiction measures in clinical research, such as the Yale Food Addiction Scale, will add to the understanding of the clinical utility of this concept. Further exploring the food-addiction construct may also lead to a better clinical understanding of obesity and eating disorders and suggest future avenues for more effectively treating these problems.     

Involvement of the endocannabinoid system in reward processing in the human brain

Rationale  

Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear.     

Targeting mitochondrial function to protect against vision loss

Introduction: Mitochondria, essential to multicellular life, convert food into ATP to satisfy cellular energy demands. Since different tissues have different energy requirements, mitochondrial density is high in tissues with high metabolic needs, such as the visual system, which is therefore highly susceptible to limited energy supply as a result of mitochondrial dysfunction.

Areas covered: Vision impairment is a common feature of most mitochondrial diseases. At the same time, there is mounting evidence that mitochondrial impairment contributes to the pathogenesis of major eye diseases such as glaucoma and might also be involved in the reported vision impairment in neurodegenerative disorders such as Alzheimer’s disease.

Expert opinion: Rather than relying on symptomatic treatment, acknowledging the mitochondrial origin of visual disorders in mitochondrial, neurodegenerative and ocular diseases could lead to novel therapeutics that aim to modulate mitochondrial function in order to protect against vision loss. This approach has already shown some promising clinical results in inherited retinal disorders, which supports the idea that targeting mitochondria could also be a treatment option for other optic neuropathies.