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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

The brain serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the neurobiological control of feeding and appears to be dysfunctional in patients suffering from feeding disorders, such as anorexia, bulimia, and obesity. Thanks to the identification and cloning of 5-HT receptors, the production of agonist and antagonist compounds, and the generation of 5-HT receptor knock-out mice, our knowledge on the implication of different 5-HT receptor subtypes in feeding behavior has greatly increased. A number of studies have demonstrated an involvement of the hypothalamic 5-HT1B and 5-HT2C receptors in food intake and body weight control, but the downstream events induced by such signaling remain to be explored. Moreover, little is known about the influence of 5-HT on the rewarding value of eating. Such value may not necessarily be linked to food consumption, but rather to voluntary reduction of food intake, as recently demonstrated upon activation of the 5-HT4 receptors in the nucleus accumbens. Thus, abnormalities in the reward system in addition to those in the central control of the autonomic nervous system might contribute to the anorexic behavior. Recent studies have also reported an involvement of the 5-HT6 and 5-HT7 receptors in feeding behavior. Potential 5-HT receptor agonists/antagonists could then be developed and used in association with psychological treatment to better cope with the stressors that trigger anorexia and drug dependence. WIREs Membr Transp Signal 2012, 1:715–729. doi: 10.1002/wmts.45

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INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

The description of some characteristics of eating disorders related to insufficient or excessive food consumption, including complex devastating mental diseases such as anorexia (anorexia nervosa) and bulimia (bulimia nervosa), can be found in a myriad of texts from the past six centuries. To the best of our knowledge, the most illustrious example is that of Catherine de Sienne (1347–1380). However, only in the seventeenth century anorexia became the subject of a clinical description (Thomas Morton, 1689), and the first scientific accounts by Charles Lasègue in France and William Gull in England date from the beginning of the nineteenth century.

Eating disorders are now classified as mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR, APA, 2003). To simplify, bulimia is characterized by impulsive and repeated phases of high food intake, whereas the main characteristic of anorexia is a self-imposed food restriction despite the energy requirements. The patients, usually women, may suffer from either anorexia or bulimia (DSM IV-TR diagnostic codes 307.1 and 307.51, respectively), or from both disorders simultaneously. These disorders are obviously complex dysfunctions of the central nervous system, as they often coexist with other mental diseases, such as pathological anxiety1 and depression.2 Furthermore, a recent study has strengthened the notion that anorexia-like behavior includes an addictive component.3

In industrialized countries, patients suffering from anorexia nervosa have the highest mortality rate among people with mental diseases (4.5–5.9%; 0.56% per year).4,5 At least 36% die within 20 years from diagnosis (i.e., between 30 and 35 years of age as the disease usually begins during adolescence). Associated symptoms include emaciation, amenorrhea, and, less known although quite frequent, over-exercise and hyperactivity (DSM IV-TR, APA, 2003). Understanding such a complex disease obviously requires deciphering the associations between non-voluntary and voluntary brain controls, biological and environmental factors, genetic and epigenetic influences, and thus the collaborative effort of psychologists, psychiatrists, and neurobiologists.

The central nervous system controls the organism energy balance by regulating food intake and energy expenditure. The neurobiological abnormalities related to anorexia nervosa are poorly understood. However, as in most eating disorders, altered 5-hydroxytryptamine (5-HT) transmission is at the forefront of the investigations. It is generally admitted that increased activity of 5-HT neurons and higher 5-HT expression in brain trigger the reduction in food intake and body weight loss. Indeed, anorexia-like behavior (self-imposed food deprivation despite the energy requirement) can be induced by treatments that increase 5-HT release in brain.6 For instance, fenfluramine, which increases the extracellular 5-HT levels, lowers the consumption of food in humans and rodents.7,8 Similarly, amphetamine and 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) diminish food consumption in rats9 and humans10 and reduce deprivation-induced eating in mice.11

The 5-HT neurons and receptors (5-HTR) are distributed throughout the brain, including all anatomical regions classically involved in feeding behavior (Figure 1, Table 1 and Figure 3). Over the past three decades, seven families of 5-HTR have been identified with 18 5-HTR subtypes, without including mRNA editing and splice variant isoforms (Table 1, Figure 3). The implication of these receptors in behavior has been widely described in studies using mice in which the genes encoding the subtypes 5-HT1A,12 5-HT1B,13 5-HT2A,14 5-HT2B,15 5-HT2C,16 5-HT3,17 5-HT4,18 5-HT5A,12 5-HT6,13 or 5-HT714 had been genetically invalidated (Table 2). Hypothalamus plays a central role in the regulation of feeding behaviors, but motivation disorders in which patients self-impose food restriction despite the energy demand (anorexia) may also involve prominent disturbances in the nucleus accumbens (NAc), a key brain reward structure.3,19 Both hypothalamic and NAc neurons express 5-HTR, particularly 5-HTR1B, 5-HTR2C, and 5-HTR4 that have been shown to influence food intake (Figure 1, Table 1 and Figure 3). Therefore, in this brief article, we focus mostly on genetic and pharmacological studies concerning these three 5-HTRs as they could become targets for the pharmacological treatment of feeding disorders.

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Figure 1. Schematic representation of (a) brain regions involved in feeding behavior and their innervation by 5-HT neurons, (b) 5-HT receptor subtypes present in these brain regions (see also Table 3), and (c) changes in food intake and body weight observed in the different 5-HTR KO mice (see also Table 2).

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Figure 2. Adaptive changes in 5-HT parameters in 5-HTR KO mice. CX, cortex; GP, globus pallidus; LC, locus coeruleus; OB, olfactory bulb; SN, substantia nigra.

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Figure 3. Schematic representation of the main 5-HTR4 (Gs-dependent or not) signaling pathways that have been identified in neurons (black) or other cell lines (gray) and in vivo in the nucleus accumbens of mice (red). Among these signaling pathways, anorexia-like behavior is associated with activation of the cAMP/PKA cascade.

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Table 1. Metabotropic (5-HTR1, 5-HTR2, 5-HTR4, 5-HTR5, 5-HTR6, and 5-HTR7) and Ionotropic (5-HTR3) 5-HT Receptors (Reprinted with Permission from Refs 6. Copyright 2007 New Frontiers in Neurosciences and 20. Copyright 2006 Cell Tissue Res)Thumbnail image of
Table 2. Effect of Stress on the Eating Behavior of 5-HTR KO Mice
 ActivityBody WeightFood IntakeFood Intake Following Stressors
  • 1

    Compan (unpublished); ?, Unknown.

5-HTR1AUnchanged12,21Increased22,23?Latency to eat in the open-field: increased24
5-HTR1BUnchanged25Increased/no change7,23,26–29Unchanged7,11Fenfluramine-induced anorexia: suppressed7
    MDMA-induced anorexia: maintained11
5-HTR2AUnchanged14Unchanged14?Latency to eat in the open-field: decreased14
5-HTR2B15????
    Enhanced response to repeated stress (in old mice)30
5-HTR2CIncreased16Increased31Increased31Fenfluramine-induced anorexia: reduced8
    MDMA-induced anorexia: decreased post-RS10222111
5-HTR3?Unchanged32Unchanged32?
    Attenuated response to stress-induced anorexia18
5-HTR4Unchanged18Unchanged18Unchanged18MDMA-induced anorexia: reduced3
    Cocaine-induced anorexia: reduced1
5-HTR5AUnchanged33Unchanged33??
5-HTR6Unchanged34Unchanged34Unchanged34 
5-HTR735????

POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

During the last decade, many studies on eating disorders have focused on HTR2A, the gene that encodes human 5-HTR2A. Both association and lack of association between HTR2A gene polymorphisms and eating disorders have been described.72–78 A polymorphism (1438A/G) in the promoter region of HTR2A was also reported to be associated (but also not) with anorexia and bulimia nervosa.73–79 Conversely, this polymorphism (1438A/G) was not linked with binge eating, whereas a positive association with obesity was found.80 Likewise, allelic variations in the HTR2C gene encoding 5-HTR2C have often been associated with obesity, but not systematically.81–88 Indeed, the HTR2C polymorphism at codon 23 (cys23ser) was not found in bulimia nervosa, binge eating, or obesity,81,83 and its association with both weight loss and gain is unclear.74,83,89 The association between the -759C/T polymorphism of HTR2C and weight gain (obesity and body weight gain induced by anti-psychotic drugs) appears to be more consistent as a positive link has been reported in at least four studies.85,87,88,90 In summary, positive or negative associations between polymorphisms in the HTR2A/2C genes and eating disorders appear to depend mainly on the studied polymorphism (for review see Ref 91), and may also reflect the complexity of the psychiatric diagnoses. It has also been reported that defects in 5-HTR2C pre-mRNA processing, controlled by small nuclear RNA, may contribute to the Prader–Willi syndrome, which includes hyperphagia and obesity among its symptoms.82

Fewer studies have examined the association between polymorphisms in other human 5-HTR genes and feeding disorders. Hinney et al. (1999)92 have concluded that polymorphisms in the HTR1Dß (phe124cys: T371G) and HTR7 (pro279leu) genes, which encode 5-HTR1Dß (the human homologue of rodent 5-HTR1B) and 5-HTR7, respectively, are probably not related to the regulation of body weight or anorexia nervosa. In contrast, the G861C polymorphism in HTR1Dß has been associated with the minimum and maximum lifetime body mass indices in women suffering from bulimia,93 and could be related to a predisposition to obsessive-compulsive disorders.94 A recent study reported that the C(-1019)G polymorphism in the HTR1A gene is associated with eating disorders (bulimia) in Korean female adolescents.95

SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

The obesity and over-eating behavior observed in 5-HTR2C knock-out (KO) mice suggests that 5-HTR2C contributes to regulate feeding behavior.16 5-HTR1A and 5-HTR1B KO mice generated by mating homozygous pairs are heavier at birth,11,22,23,26,27 while loss of 5-HTR2A, 5-HTR3A, 5-HTR4, 5-HTR5A, 5-HTR6, or 5-HTR7 function does not induce any change in body weight in basal conditions14,18,32–34 (Figure 1, Table 2). Overweight has been reported in male,22 but not in female 5-HTR1A KO mice.23 To our knowledge, information is still lacking about the amount of food consumed over time in basal conditions by mice in which the mHtr1A gene had been ablated.

Three studies have reported that male 5-HTR1B KO mice are overweight and consume a higher amount of food than wild-type mice.22,26,27 Female 5-HTR1B KO mice are also overweight.22 These results have raised an interesting debate because such animals were the offspring of homozygous mating, suggesting a possible influence of parental care.26 However, also when the homozygous offspring of heterozygous breeding pairs were used, no differences in either baseline food intake or body weight were detected between wild-type and 5-HTR1B KO mice,7 even after a 24-h period of food deprivation11; see also Refs 29 and 96. Housing animals with identical genotype together or not may also be a pertinent issue (I. Seif, personal observation), including also for the assessment of the feeding behavior, as mutant mice may show increased aggressiveness (5-HTR1B KO mice13), hyper-anxious-like state (5-HTR1A KO animals12,21), and maladaptive feeding responses to stress (5-HTR2C KO30 and 5-HTR4 KO mice18).

Indeed, 5-HTR2C KO mice display opposite feeding responses to mild stress depending on their age.30 Specifically, in response to daily cage changes, young (12 weeks old) 5-HTR2C KO mice exhibited hyperphagia, while old (32–34 weeks old) KO animals displayed hypophagia.30 Accordingly and in agreement with a previous pharmacological study suggesting that 5-HTR2A/2C are implicated in feeding responses following stress,97 body weight loss that was associated with increased blood levels of stress hormones was observed only in old mutant mice compared to wild-type animals following repeated restraint stress.30 The 5-HTR4 KO mouse is, so far, the only known animal model displaying a paradoxical attenuation of stress-induced hypophagia.18,98 This maladaptive feeding response to restraint stress is observed in males and might be due to a specific decrease in the firing activity of midbrain 5-HT neurons in the absence of 5-HTR428 (Figure 2), rather than a direct consequence of the hyperactivity of the hypothalamo-pituitary axis.18

Only few results concerning food intake have been reported for other 5-HTR KO models in response to stressful conditions, such as the brightly lit open-field test. In the novelty suppressed feeding paradigm, starved mice face a dual conflict between safety and the physiological drive to explore a novel environment for getting food14,24 (Table 2). When possible biases in locomotor and exploratory activity can be controlled, the latency to eat in this test is interpreted as an index of anxious-like state. Under these conditions, the latency to eat was increased in starved 5-HTR1A KO mice24and reduced in 5-HTR2A KO mice,14 a result which may reflect their hyper- and hypo-anxious-like status, respectively (for review see Ref 6). Accordingly, feeding disorders in 5-HTR4 KO mice may indeed be related to their higher level of anxious-like behavior following stress.18

Altogether, but for the case of 5-HTR2C KO mice, these findings suggest that, in animal models, feeding disorders associated with a genetic deficit might be best revealed in a stressful context or following a pharmacological challenge.

SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

Activation of 5-HTR (5-HTR1B, 5-HTR2C, 5-HTR4) commonly causes hypophagia, as summarized in Table 3.3,117–119 In contrast, activation of 5-HTR1A and 5-HTR2B in the arcuate nucleus of hypothalamus increases food intake.120 Similarly, systemic administration of 8-OH-DPAT, a 5-HTR1A agonist, increases food intake121,122 and 5-HTR1A agonist-induced hyperphagia appears to be associated with the negative feed-back of such activated receptors on the firing activity of 5-HT neurons.39,99,101,123–127

Table 3. Food Consumption and 5-HT ReceptorsThumbnail image of

In the last five years, a number of studies have examined the involvement of hypothalamic 5-HTR2C in feeding behavior. In brief,153 in the arcuate nucleus, two chemically defined neuronal populations that contain neuropeptide Y/agouti-related peptide (NPY/AgRP) or cocaine- and amphetamine-regulated transcript/pro-opiomelanocortin (CART/POMC) appear to be controlled by several messengers (leptin, ghrelin, orexin, etc.), including 5-HT. Their regulation might be mediated by 5-HTR2C, which is expressed in CART/POMC neurons, via increased release of α-melanocyte-stimulating hormone (α-MSH) and consequent decrease in food intake.117

The hypothalamus appears to be a pivotal interface between brain and periphery, regulating the energy balance and accordingly the feeding behavior through the brain 5-HT system.154 Feeding disorders with a strong motivational component seem closely related to disturbances in the brain reward system that includes the NAc.3 Three studies support this view. It has been reported that injection of agonists of 5-HTR1/7 (5-CT), 5-HTR6 (EMD 386088) and 5-HTR2C (RO 60-0175) into the NAc, respectively, decreases, increases, or does not modify food intake.155 This suggests that complex interactions between different signal transduction pathways activated by different 5-HTR may be involved. Moreover, 5-HT injection into the NAc reduces the hyperphagia associated with hypoactivity of the medial raphe nucleus.156 Finally, we demonstrated that activation of 5-HTR4 in the NAc inhibits the physiological drive to eat through the cAMP/PKA/CART cascade. This signaling cascade contributed also to the reduction of the physiological feeding behavior induced by the psychogenic compound of ecstasy (MDMA).3 We concluded from these observations that the neuronal network underlying addiction may include the neuronal pathways involved in anorexia.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES

Using a multidisciplinary approach, from genetics to molecular biology and from cellular interactions to neurophysiology, many studies have reported that among the molecules involved in feeding behavior regulation (GABA, glutamate, leptine, orexin, hypocretin, CART, NPY, POMC, CRH, TRH) the brain 5-HT system is central in the control of food intake and particularly in eating disorders. The 5-HT system may further activate addiction-related components to reduce feeding despite the need of energy, suggesting that a rewarding effect may interfere with the homeostasis rules and trigger eating disorders. Several findings favor the hypothesis that the neuronal network underlying feeding behavior is part of a larger network implicating reward and decision-making systems that are obviously interacting with the environment. Accordingly, environmental changes (stress) could alter the adaptive decision-making concerning feeding. If the adaptive response to stress depends on the 5-HT system, eating disorders could thus emerge when 5-HT neurons reach the limit of their adaptive capacities.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. POLYMORPHISM IN HUMAN 5-HT RECEPTOR GENES AND EATING DISORDERS
  5. SEROTONIN RECEPTOR KNOCK-OUT MICE AND EATING DISORDERS
  6. SEROTONIN RECEPTOR ANTAGONISTS/AGONISTS AND EATING DISORDERS
  7. CONCLUSION
  8. Acknowledgements
  9. REFERENCES
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