Under- to Over-eating

How Do Serotonin Receptors Contribute?

Valérie Compan

Disclosures

Future Neurology. 2013;8(6):701-714. 

In This Article

Abstract and Introduction

Abstract

In numerous pathological states, the brain can restrict food intake to a lethal level despite mounting requirements for energy as seen in adolescents with anorexia nervosa. How the brain reduces food intake to the point of death while eating is a cornerstone of survival that remains just as 'cryptic' as the association between anorexia and overeating. This review provides a recent snapshot of the neural underpinnings of the rewarding effects of anorexia that may compete with the adaptive decision-making process to eat, and with survival instinct. Among a plethora of factors, impaired activity of the serotonin receptors in the reward system underlies the ability of animals to self-impose food restriction, and the transition from under- to over-eating. However, the triumvirate association between serotonin, overeating and addiction appears unlikely. Considering the implication of the serotonin receptors in the hypothalamus, anorexia and bulimia nervosa could result from an impairment of a 'synchronic activity' between the autonomic and voluntary nervous systems.

Introduction

The brain may self-impose food restriction to a lethal level, as seen in stressed adolescents with anorexia nervosa without any possibilities for neuroplasticity to prevent it. Whether overeating exists to compensate undereating is unclear, it is also unknown why neuroplasticity would trigger one disease to overcome another. To address these questions, first, a crucial point would be to show how the brain reduces eating until death while eating is a cornerstone of survival mechanisms. The second would be to understand the transition from under- to over-eating. In addition to therapeutic relevance, these questions refer to the attempts to discover the neural substrates of the survival instinct (obviously related to 'species preservation'), which are related to those of decision-making to eat or not, independently of requirements for energy.

In this context, and among a cumulative plethora of neural factors and hormones related to feeding behaviors, serotoninergic systems remain central since their damage impairs survival instinct (depression), adjoined to motivation (addiction) and feeding behaviors (anorexia and bulimia). New recent findings regarding the serotonin (5-hydroxytryptamine [5-HT]) receptors may provide further insights to treat anorexia and bulimia nervosa, two incurable life-threatening pathologies. Individuals suffering from anorexia nervosa usually die following a chronic self-imposed restriction of food (restrictive-type anorexia nervosa), while of all cases, 80% also struggle with bulimia; in other words, overeating with purging, which therefore differs from food binging,[1] as recently defined.[2] Anorexia nervosa includes other symptoms such as emaciation, amenorrhea and overexercise. Anorexia nervosa is the first natural cause of death of adolescents in Europe, and carries the highest mortality rate among mental diseases.[3–5] In addition, the hospitalization cost of anorexia nervosa is, however, a poor demonstration of the inefficacy of treatments. This cost amounts to €195 million.[6] The annual cost per patient is €5300 with hospitalization costs of €12,800, while the average cost of hospitalization is €3600.[6]

Anorexia and bulimia nervosa remain, in part, incurable, probably because the exact causes of these diseases have not been determined.

This review could contribute to a better understanding of the neural substrates of eating disorders, taking into account a possible dual action of the serotoninergic systems; in baseline conditions, 5-HT receptors (5-HTRs) distributed in an autonomic executive system (the hypothalamus) may contribute to stabilize the usual amount of consumed food, whereas following environmental changes (i.e., stress[7]), 5-HTRs located in a more adaptive–decisive system (voluntary nervous system), including the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc), may become involved in adaptive feeding responses to stress.[8] Such an 'organization' could favor decisional processing but reduce autonomic input by synchronizing the mPFC and NAc, and desynchronizing the NAc and hypothalamus, resulting in dysfunctional feeding irrespective to requirements for energy. When feeding responses (increases or decreases in food intake) to stress are transient, survival is not compromised and this behavior may well be adaptive, but when these feeding responses to stress persist, survival is compromised. This review includes some new explanations about how the brain prevents the transition from a transient reduction in food intake (hypophagia) to anorexia.[8]

At a molecular level, new findings further demonstrate not only decreases, but also increases, or an absence of changes in food intake following stimulation of 5-HTRs in different brain structures. A new point of understanding at the molecular level has also been recently found in taking into account peculiar properties of G-protein coupled receptors (GPCRs). Few GPCRs display a constitutive activity, in other words, in the absence of their endogenous ligand (in this case, in the absence of 5-HT), GPCRs can activate their signaling pathways. This property was discovered in vitro, with rare demonstration of related physiological consequences, with the exception of the MCR4; inhibiting the constitutive activity of MCR4 increased food intake.[9] As an additional example, anorexia may result from an excessive constitutive activity of the 5-HTR4 in the NAc, while its inhibition provokes overeating,[101] consistently with previous studies,[10,11] and providing a potential substrate of undereating–overeating alternation.

In consequence, these studies introduced that the neural causative factors of anorexia can be located in the reward system since these neural substrates of anorexia appear to counteract those of survival. Since only the attractiveness of a positive reward can induce risky and, potentially, lethal behavior, limiting food intake to a lethal point may have a rewarding effect, mimicking addiction by leading to 'spiral' restrictions.[10,11] Accordingly, anorexia may have a molecular addictive facet,[10,11] consistent with anorexia dependence of patients with anorexia nervosa, described to be 'hooked on the self-starvation'.[12] Consistently, animal models persist to self-restrict their intake of food without being forced following an upstream period of food restriction, suggesting their preference for diet.[11] In addition, these animal models have been described to consume more cocaine than wild-type (WT) animals. Not only humans, therefore, but also animals can self-impose food restriction following a period of food deprivation.[11] Considering that these behaviors were observed in mice, these studies suggest a reduced importance of the socioeconomic impact on the emergence of anorexia. These animal models display deficits in 5-HT volume transmission in a part of the reward system, the NAc, in agreement with relations between persistent refusal to eat, and motivational deficits (as observed in depression), maladaptive decision-making and/or perception of rewarding effects of food.[13] Taking into account that decision-making results from the comparison between positive and negative values of rewards, deciphering the neural substrates of the rewarding effect of anorexia may favor a better understanding of the neural underpinnings of deciding whether or not to eat. However, the neural underpinnings of decision-making to eat are unknown.

Finally, numerous studies favor the assumption that there is a dual control of food intake by the autonomic and voluntary nervous systems. Hunger, in other words the physiological need for food, may trigger food intake; one may then decide or not decide to eat, but to feel hungry is apparently out of decisional control (voluntary nervous system). Hunger appears to depend on the activity of the autonomic nervous system as no one apparently decides to feel hungry. Hunger, and then part of consuming food, appears to be autonomously controlled, but consuming food does not appear only as an 'unconscious automatism'. Consuming food can be voluntarily controlled despite hunger, physiological needs and even appetite (pleasure to eat and/or to eat specific categories of macronutrients).

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