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Overview
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Active Learning Projects - Obesity Project - Team 3    
 
Obesity
Team 1   Team 2   Team 3   Team 4   Team 5   Instructions du Projet
 
1. Regulation of food intake and obesity
2. Messengers involved in the homeostatic regulation of food intake
3. Messengers involved in the hedonic regulation of food intake
4. Signalling mechanisms in the arcuate nucleus and the regulation of food intake
5. Treatment of obesity
Instructions du Projet

active learning, any time, any place and anywhere

Homer-donut

3. Mediators of hedonic regulation of food intake

Summary:
Introduction
Reward systems that reinforce (desirable) behaviour
The importance of reward in the regulation of food intake
Intense sweetness surpasses cocaine reward
Neural basis of reward; the dopamine reward circuit
The dopamine reward circuit and feeding behaviour
Focus on the nigrostriatal and mesolimbic system
The dopamine D2 receptor may relay the reward signal
A brief description of the four major brain (reward) circuits that use dopamine
Neurotransmitters connected with the dopamine reward circuit
Anatomy of the dopamine reward circuit
Anorexia and bulimia nervosa
Neurological suspects in anorexia and bulimia nervosa

Auteurs:
Elodie Blanchard, Lucie Blaszczyk, Tifany Deprez, Nathalie Franzl, Audrey Dupuy.

Introduction

reddot We eat in order to provide ourselves with the necessary elements (carbohydrates, amino acids, nucleotides, vitamins, mineral salts and others) that allow our body to function. In this context, appetite, or lack of it, is determined by the lack or abundance of these elements. This we have referred to as homeostatic regulation of food intake (team 1). But this is only half the story. In order to engage and maintain feeding (“ingestive behaviour”) we have to feel good about it. Engaging beneficial behaviours (those that make us survive) are normally linked to a reward system; such behaviours generate “feel good” or “pleasure” sensations. Feeding provides us with these sensations and food can therefore be considered a source of pleasure or, in other words, food has “hedonic valence”. The regulation of food intake by a reward pathway is referred to as hedonic regulation. Both obesity (excess of food intake) and anorexia (lack of food intake) can be considered conditions that are the consequence of inappropriate reward pathways.

Hedonism
Hedonism comes from the Greek hedone ηδονη, meaning pleasure or delight. The basic idea behind hedonistic thought is that humans seek to maximize pleasure. Hedonistic theories have a long history with Aristippus from Cyrene, a pupil of Socrates (circa 400 BCE), being one of the instigators.
For more information; http://en.wikipedia.org/wiki/Hedonism.

Although we all understand the notion of pleasure, what exactly constitutes the pleasure signal(s) remains an important subject of study. Is pleasure put into place in order to facilitate homeostasis, i.e. what is needed for the correct functioning of the organism (physiology) naturally provokes a sense of pleasure as stated by Claude Bernard in his introduction to experimental medicine in 1865: vital mechanisms, however variable, have one main goal, re-establishing the constancy of the conditions of life in the internal environment (» Tous les mécanismes vitaux, quelques variés qu’ils soient n’ont qu’un but, maintenir l’unité des conditions de vie dans le milieu intérieur «)? Or can pleasure be uncoupled from physiological needs; pleasure for the sake of pleasure? (Michel Cabanac, Université Laval, Canada). Recent studies reveal that hedonic regulation of food intake may indeed dominate (or override) homeostatic control (and contribute to pathological behaviour). The franco-italian film La grande bouffe (Marco Ferreri, 1973) provided an early (and much disliked) mirror of a society where the hedonic control of food intake reigns. Matt Groening and his team, provide a more benign image of the food-loving Homo sapiens “Homer Simpson”.
Reward systems that reinforce (desirable) behaviour

reddot Imagine, you have not eaten for a while and you walk along a bakery. The sight and, possibly, smell (visual and olfactory senses) of the products on display will be captured by the brain. These incoming signals will communicate with another part of the brain which stores the memory that when you eat you will no longer be hungry and, instead, you will feel good. As a consequence your brain will instruct your body to purchase a sandwich. After having balanced many other signals (such as graphic memories of your silhouette in front of a mirror, images of the weight indicator of your balance, the time indicated by your watch or knowing whether or not you have sufficient money in your pocket etc etc), you decide to stop, enter the shop and buy a sandwich. Once purchased, and having left the shop, a whole set of further motor instructions will follow: unwrapping the sandwich, bringing it to the mouth, opening the mouth and start chewing. Once your taste buds detect the food, the esophagus passes it on to the stomach and the stomach dilates while receiving it, new signals enter the brain that cause the release of neurotransmitters that, together, provide you a jolt of pleasure (reward). Dopamine is thought to play an important role in all this. In rats, dopamine certainly acts at the level of motivation (cutting-off other input and focusing actions towards the purchase of a sandwich (also referred to as “wanting”) and probably acts at the level of the generation of the pleasant sensation that follows (also referred to as “liking”) (see also below “The dopamine reward circuit and feeding behaviour”). For the latter, endogenous opioids seem also essential. The pleasant sensation is your reward for purchasing and eating the sandwich! At the same time, in order to increase the likelihood that you will repeat the action in due time, the reward pathway also reinforces the memory of what you just did and what pleasure it provoked. This aspect of reward is also referred to as “operant conditioning” (see reference of Skinner below). Finally, the reward pathway strengthens the motor-wiring that coordinates your food seeking and eating behaviour.


We recognize pleasure as the first good innate in us, and from pleasure we begin every act of choice and avoidance, and to pleasure we return again, using the feeling as the standard by which we judge every good (Epicurus)

From: Letter to Menoeceus (p64), in: The Essential Epicurus, Prometheus Books, Amherst, USA

Information sources:

  1. http://learn.genetics.utah.edu/content/addiction/reward/
  2. http://en.wikipedia.org/wiki/Epicurus.
  3. Original article: Skinner BF. The behaviour of organisms: an experimental analysis. Appelton-Century, New York, 1938.
The importance of reward in the regulation of food intake

reddot The importance of hedonic regulation of food intake is perhaps best illustrated in experiments where rats had electrodes implanted in their brain, at different anatomical locations, and could self-administer electrical stimulation by pressing a lever. In the experimental environment, food supply was kept at a distant from the lever that provided electrical stimulation (you either eat or you stimulate electrically). This experimental setup is referred to as brain-stimulation-reward (BSR) and one of its distinguished pioneers is James Olds (see references below). Repeated self-stimulation was observed with electrodes that reached the medial forebrain bundle, the midbrain extension of the MFB, the orbitofrontal cortex, nucleus accumbens (NAc), lateral hypothalamus (or lateral hypothalamic area, LHA), ventral tegmental area (VTA) and brainstem structures (collectively referred to as the “brain pleasure areas”. For anatomical location see figure 2a and 2b). Brain-stimulated-reward experiments provided first evidence that reward circuitry is subdivided along functional and anatomical lines.

reddot Importantly, self-stimulation of the lateral hypothalamus was shown to generate a powerful grip on feeding behaviour as 16 out of 19 rats preferred to go without food or drink, even after days, in order to maintain contact with the manipulator. Rats stimulated in other brain areas were more reasonable and although initially intrigued by the electrical stimulus, 15 out of 19 chose for food after one day testing (G Spies, 1965). From these and other brain-stimulation-reward experiments emerged the idea that the electrical stimulation tapped into the neural circuitry sub serving natural rewards, such as food and water. In other words, food procures a certain pleasure but this sensation can be replaced by electrical stimulation of appropriate areas of the brain.

Definition of Reward
As used here rewards (1) are objects or actions that prioritize behaviour and promote the continuation of ongoing actions, (2) increase the behaviours that lead to the procurement and/or consumption of the reward (positive reinforcement), and (3) direct future behavioural actions.

Figure 1 Rats prefer auto-administration of electrical stimuli, which affect the dopamine reward circuit, over eating of a (normally) appetizing piece of cheese (drawing by Romain Giraud, student of SVI632 in 2010, University of Bordeaux).

reddot The hedonic properties of food are commonly assessed by determining the affective evaluations that are generated in response to direct encounters with food or food-related stimuli. In the case of human participants, the respondent provides a subjective evaluation of a sensory property of food (taste, texture or others) which is reflected by a rating of pleasantness or liking. Similar studies have been performed with mice and rats were taste reactivity is measured by facial reaction patterns to tastants. A commonly used measure of the reward efficacy of food is an operant procedure known as the progressive ratio (PR). The animal is required to perform an increasing number of operant responses for each successive reward. Initially you have to press once to get a sweet pellet, then twice, then three times etc. At some stage the animals give up (break point). The extent to which animals are willing to work for their reward is a measure of the reward magnitude of food.

reddot Animals work harder for caloric food, they work harder when they have been deprived of food or when they have lost weight, and they work harder for food with a sweet taste. Food restriction and weight loss increase sucrose motivation as a function of the concentration of sucrose. All this is not surprising from a physiological (homeostatic) point of view. However, when performing similar tests with obese Zucker “fatty” rats, with obesity prone rats or with overweight children, a similar increase in the break-point was observed. Here there is no obvious physiological need, yet these subjects are willing to work harder (compared to lean counterparts) for food-provided rewards. This can be taken to mean that, in these subjects and under these test conditions, hedonic regulation dominates over homeostatic regulation.

Zucker “fatty” rats have a missense mutation in the leptin receptor and get really fat, like the “obese” mice, which have a mutation in the leptin gene (team 2). They are named after Lois and Theodore Zucker, pioneer researchers in the study of the genetics of obesity.

Information sources:

  1. Zucker LM and Zucker TF. Fatty, a new mutation in the rat. J Hered. 1961;52:275-278.
Intense sweetness surpasses cocaine reward

reddot That we should not underestimate the power of hedonic regulation is perhaps best illustrated by a recent study from a group in our University (led by Serge Ahmed), in which they showed how strong the reward magnitude of sweet taste can be. When rats were allowed to choose mutually-exclusively between water sweetened with saccharin (an intense calorie-free sweetener) and intravenous cocaine (a highly addictive psychoactive substance), 94% of the animals preferred the sweet taste of saccharin. The same preference was also observed with sucrose, a natural sugar. The preference for saccharin was eventually abolished by increasing doses of cocaine. In fact, the preference was even observed in animals that showed signs of cocaine intoxication, sensitization or intake escalation, the latter being a hallmark of drug addiction. These findings clearly demonstrate that intense sweetness can surpass cocaine reward. In relation to food addiction, the supranormal stimulation of sweet-taste receptors by sugar-rich diets, such as those now widely available, could generate a supranormal reward signal, with the potential to override self-control mechanisms and thus to lead to (food) addiction.

Information sources:

  1. Lenoir, M, Serre F, Cantin L, Ahmed SH. Intense sweetness surpasses cocaine reward. PloS ONE 2007;2(8):e698.
Neural basis of reward; the dopamine reward circuit

reddot Manipulation of dopamine-containing neurons modulates the outcome of the above described brain-stimulation-reward experiments, providing first evidence for a role of dopamine in reward-relevant processes. Experiments using either dopamine receptor antagonists or neurotoxins that target dopamine neurons (6-hydroxydopamine) lead to a reduction of brain-stimulation-reward activity. On the contrary, drugs that increase the dopamine tone, such as amphetamine, cocaine, morphine or nicotine, enhance the rewarding effects of electrical stimulation of areas such as the ventral tegmental area (VTA), hypothalamus, nucleus accumbens (NAc) or hippocampus (for anatomical location see figure 2a and 2b). Collectively these areas constitute the “dopamine reward circuit” (see figure 3).

reddot NB: It remains to be elucidated whether or not these electrical stimuli directly activates neurons that release dopamine. It is possible that, instead, the electrically activated nerve fibers make synapses with dopamine-containing neurons and thus indirectly promote its release.

Information sources:

  1. Anatomical location of brain areas was obtained using http://lifesciencedb.jp/?lng=en

Figure 2a lateral view of brain areas that are involved in reward processes

Figure 2b rostral view of brain areas involved in reward processes

reddot Further evidence for a major role of dopamine in reward-relevant processes came from the findings that rats failed to self-administer amphetamine (injected into the nucleus accumbens (NAc), after selective lesion of dopamine neurons terminating in this nucleus. Furthermore, it was shown that normally dopamine neurons fire in a slow irregular fashion, resulting in a tonic release of dopamine, but in response to salient environmental stimuli they fire in bursts, leading to phasic increases of dopamine release. The transient increases in dopamine enhance salient environmental signals while suppressing irrelevant signals and thus drive an animal to focus and respond appropriately to important environmental cues. Consequently, in the absence of dopamine, most environmental cues go unnoticed; animals are hypoactive and appear apathetic.

The dopamine hypothesis
The hypothesis posits that dopamine, released in the above described reward circuit, promotes reward-related activities. In the terminology of Berridge, dopamine promotes “wanting” rewards; hence animals will work harder to obtain food rewards when dopamine signalling increases (bursts of release of the neurotransmitter). Dopamine is also postulated to promote learning associations between food rewards and the environments where they are found.

A corollary of this hypothesis is that animals like the effect of dopamine signalling and hence they will engage in activities that maintain high levels of dopamine, including self administration of drugs that maintain elevated levels of dopamine (cocaine, amphetamine and opiates) or electrical self stimulation of brain regions that activate dopamine neurons. An extension of this idea is that animals will also engage in natural activities such as eating and sex that are known to release dopamine. Low brain dopamine levels may thus promote behaviour directed towards restoration of dopamine. Information sources; Palmitter RD, TiN 2007;30 p377.

Information sources:

  1. Palmitter RD, TiN 2007;30 p377
  2. Berridge KC. The debate over dopamine’s role in reward: the case for incentive salience. Psyochparmacology (Berl.) 2006;191:391-431)

Click on image to learn more about dopamine reward circuits and street drugs (animation by the Genetics Science Learning Center of the University of Utah)

The dopamine reward circuit and feeding behaviour

reddot With respect to feeding behaviour, rodents lacking dopamine in their nerve fibers (through a genetic approach which selective eliminates tyrosine hydroxylase, an enzyme needed for dopamine synthesis) die of starvation or dehydration (as a consequence of “aphagia” and “adipsia”). In light of the dopamine hypothesis, this could be explained by a lack of “motivation” to respond to the presence of food and water; the animal no longer shows goal-directed behaviour because it does not anticipate a reward. In a similar fashion, bilateral ablation of dopamine neurons (using 6-hydroxydopamine), in particular those emanating from the substantia nigra (SN) and projecting to the caudate nucleus and the putamen (components of the “nigrostriatal system”, see figure 3), also resulted in starvation. But these are just a few examples of a long list of studies in which the role of dopamine has been studied (reviewed by Fulton S and by Palmiter RD). The literature is difficult to summarize because each study focuses on a different brain area, using a different tool and observing different effects on behaviour ranging from “taste reactivity”, “free-feeding intake”, “goal-directed behaviour”, “assessing environmental cues” or “learning of taste aversion”. However, there seems to be general agreement that dopamine is important to acquire information about rewards (which cues, which stimuli & storing information) and the behavioral responses to obtain them (goal-directed behaviour, dopamine strengthens action-outcome associations). It seems not to be involved in the events related to the consummatory phase of feeding.

Figure 3 major brain (reward) circuits that use dopamine

reddot A brief description of the four major brain (reward) circuits that use dopamine

  1. Mesolimbic circuit: dopamine-containing neurons that originate in the ventral tegmental area (VTA in midbrain) and innervate the nucleus accumbens (NAc) (ventral striatum), amygdale, hippocampus and the prefrontal cortex. This circuit is known for its role in memory and for motivation. An excess of activity may lead to schizophrenia and hallucinations.
  2. Mesocortical circuit: also originates in the ventral tegmental area (TVA) but innervate only the prefrontal and orbitofrontal cortex. This circuit is also involved in schizophrenia and hallucinations.
  3. Nigrostriatal circuit; here dopamine-containing neurons originate from the substantia nigra (SN) (located just ventrolateral of the ventral tegmental area) and innervate the caudate nucleus and the putamen (which together form the “dorsal striatum”). They have a motor control function, leading to the right movements for the acquisition and uptake of food. This circuit is affected in Parkinson's disease. Dopamine-containing nerve cells in the substantia nigra develop α-synuclein pathology and consequently degenerate, resulting in many of the motor abnormalities that characterize the disease. However, degeneration of nerve cells and α-synuclein pathology are not limited to the substantia nigra, they are also present in several other regions of the central and peripheral nervous systems.
  4. Tuberoinfundibular circuit: this circuit originates in the hypothalamus and innervates the pituitary. It is known for its control of secretion into the blood of, amongst others, prolactin and ACTH (corticotrophin). Both play a role in determining our behaviour: seeking pleasure and/or avoiding pain (fight or flight).
Limbic system
Many parts of the brain described here, and involved in the dopamine reward circuit, are also part of the “limbic system” or the “paleomammalian complex” (including corpus callosum, olfactory tract, mammillary bodies, fornix, anterior part of thalamus, amygdale, hippocampus, cingulated gyrus, hypothalamus). Limbic originates from limbus, meaning belt or border, as it forms the inner border of the brain cortex. Although considered the seat of emotions, areas that cover the limbic system harbour many functions such as long term memory and olfaction.

Corticolimbic circuitry
The corticolimbic circuitry refers to a nerve fiber circuit, incoming and outgoing fibers, between the cortex and the limbic system. It is another name for the above described dopamine-containing reward circuits.

Basal ganglia
The striatum (caudate nucleus, putamen and nucleus accumbens), pallidum, substantia nigra, ventral tegmental area as well as the subthalamic nucleus are brain areas (or nuclei) that are also referred to as the basal ganglia (or basal nuclei). They are part of the reward circuit. They have been studied in the light of motor control and seem to play a role in “executive” functions; they channel motivation into behaviour action (goal-directed behaviour). Their role in motor control is emphasized by neurological disorders caused by loss of basal ganglia. For instance degeneration of the substantia nigra leads to Parkinson’s disease, whereas damage of the striatum leads to Huntington’s disease, a progressive neurodegenerative genetic disorder, which affects muscle coordination (and leads to cognitive decline and dementia).

The triune brain model
The limbic system takes an important place in the “triune brain” model (three-in-one) in which the evolution of the vertebrate forebrain, and concomitantly the evolution of animal behaviour, is described as a sequential addition of brain complexes. According to this model the brain develops in three stages going from 1 to 3):
  1. the reptilian complex (primitive),
  2. the paleomammalian complex (intermediate)
  3. the neomammalian complex (advanced).
With respect to human (mis)behaviour, as reason is harboured by the neomammalian complex (advanced), it was generally considered that aggressive, emotional and unreasonable behaviour occurred through a poor control over the paleomammalian (limbic) and reptilian complex. The American physician and neuroscientist Paul D. MacLean is at the origin of this developmental scheme. It should be stressed that this three-in-one model is not supported by recent advances in the understanding of human brain development.
Focus on the nigrostriatal and mesolimbic system

reddot Of these four circuits described above, the nigrostriatal and mesolimbic system play a role in the hedonic regulation of food intake. The striatum receives dopamine containing neurons from the substantia nigra (SN) and the ventral tegmental area (VTA). There they interact with medium spiny neurons (medium size but with lots of dendrites, a special type of inhibitory cell that controls movement) that either contain the neurotransmitters enkaphilin & GABA or dynorphin & GABA (figure 4a). In the nucleus accumbens-area of the striatum, these neurons send their axons back to the midbrain area (a feedback or feedforward loop). In the case of the striato-nigral pathway, this connection is direct, whereas the neurons returning to the ventral tegmental area (VTA), first connect with the globus pallidum (GP) and the subthalamic nucleus (STN). This connection is therefore referred to as the striato-pallidal pathway). The midbrain area, in turn, is coupled to sensory input and motor output nerves (regulating food seeking behaviour).

Figure 4a Model of the organization of the mesolimbic and nigrostriatal reward circuits. Midbrain dopamine-containing neurons target two medium spiny neuron-populations in the nucleus accumbens (ventral part of striatum). These in turn feed back to the midbrain, either directly, striato-nigral pathway (which employs dynorphin (endogenous opioid) and GABA neurotransmitters) or indirectly, via the globus pallidum and subthalamic nucleus, striatopallidal pathway (which employs enkaphalin (endogenous opioid) and GABA neurotransmitters).
Figure 4b) The medium spiny neurons of the nucleus accumbens carry receptors for dopamine (D1 and D2) but also for other messengers such as endocannabinoïds (CB1), for acetylcholine (muscarinic M1/M4) or for endorphins (mu opioid receptor, MOR). These render them sensitive to other inputs than dopamine.

At the very bottom of this page you will find a more detailed description of the brain areas involved in dopamine-mediated reward signalling.
The dopamine D2 receptor may relay the reward signal

reddot If dopamine is an important mediator of feeding behaviour, the questions follows which of its many receptors relay the signal; D1, D2, D3, D4 or D5? Knock-out mice have been developed in an approach to answer this question but the results of these studies have not been conclusive. Mice lacking D2, D3, D4 or D5 have no real change of body weight compared to the control group. In one study, both D1- and D2-receptors were eliminated but here mice die around birth, before dopamine is thought to be important for feeding.

reddot More information has come from long term treatment of mice (weeks) with antagonists of D2 receptors (olanzapine and quetiapine). This treatment is associated with significantly increased food intake. It was also found that morbidity obese humans have less D2 receptor availability. These results suggest that dopamine signalling through D2 receptors normally suppresses feeding over the long term. As shown in figure 4b, D2 receptors are expressed on neurons of the striatopallidal pathway (involving the globus pallidus and subthalamic nucleus).

Neurotransmitters connected with the dopamine reward circuit

reddot As mentioned previously, opioids also play a role in reward, and indeed, rats will also work (press the lever) for discrete doses of morphine when injected into the ventral tegmental area (VTA) or in the nucleus accumbens (NAc). Direct administration of opioid agonists into both brain regions stimulates food intake. Rats and humans produce endogeneous opioids (see figure 5), which bind the same receptors as morphine and activate similar signalling pathways. Administration of a non-selective opioid receptor-blocker (naloxone) leads to a decrease of food intake in rats, especially when they are offered highly preferred foods such as sucrose or saccharin. This is also true for humans, where opioid receptor antagonists suppress preference for sucrose and decrease pleasantness ratings for the smell and taste of food.

reddot The endocannabinoid receptors (see figure 5) have also received much recent attention for their role in regulating food intake and palatability as the active ingredient in cannabis, delta-9 tetrahydrocannabinol (THC), has long been known to increase food intake, particularly for sucrose. Humans produce endogenous cannabinoids (see figure 6) which bind two types of cannabis receptors (CB1 and CB2). Of these, the type-1 cannabis receptor (CB1) is implicated in ingestive behaviour as it was shown that CB1-antagonists decrease motivation for food uptake.

reddot It is worth noting that the medium spiny neurons in the nucleus accumbens (NAc) carry receptors for a both endogenous opioids and endocannabinoïdes. These receptors are the mu-type morphine receptor (MOR) or the cannabis type-1 receptor (CB1). This provides just one explanation of how these mediators (and their related recreational drugs) regulate reward pathways (see figure 4b).

reddot Another neurotransmitter, serotonin (or 5-HT) has gained much attention because it may act at quite a different phase of ingestive behaviour. Much like CCK (click here for more information) it suppresses feeding by inducing a process of satiation. In rats, this process is manifested by a behavioural sequence (of satiety) which starts with grooming and exploration and ends with resting. Elevated levels of synaptic serotonin inhibit food intake by accelerating the onset of the behavioural sequence of satiety (BSS). Agonists of type 5-HT1B and 5-HT2C receptors have similar effects. It is not clear to us where and how serotonin interferes with brain areas involved in the regulation of ingestive behaviour. One of the subtypes of the serotonin receptor, 5-HT4, is detected in the nucleus accumbens (NAc).

Figure 5 mediators involved in the hedonic regulation of food intake.
(P01210, P01213, P01189) are protein accession numbers for the UniProt database (http://www.uniprot.org)

Recreational drugs
Drugs (both therapeutic and recreational) work because they bind to cellular components, receptive substances or receptors, and through this binding they exert an effect on cell metabolism. In the case of the brain this may lead to an altered production, enhanced release or reduced uptake of neurotransmitters or it may change membrane potential (and thus the firing of the neurons). The receptor theory was first put forward by Ehrlich, in order to explain the therapeutic action of his chemical compounds, and was later elaborated by Langley, in order to explain the action of minute amounts of hormones and their counteracting substances on the beating rate of isolated frog hearts (read article by Maehle et al.).

Two common recreational drugs, morphine and cannabis, are products of the secondary metabolism of plants. They have profound psychotrophic effects because they bind specific receptors in the central nervous system (the brain). Humans carry these receptors not for the sake of drug use but because our bodies also produce messengers (endocannabinoïdes and endogenous opioids) that bind these receptors. Endogenous (produced by our own body) and exogeneous (drugs) products not necessarily have the same effect; meaning that the action of endogenous opioids is not fully explained by the effects of morphine. First of all, endogenous products generally act locally, depending on the desired action; secondly, endogenous products are often released in short bursts and do not float at high concentrations in our body for ours; thirdly, the massive and long term presence of drugs may lead to receptor removal or to receptor desensitization (it no longer signals) and this may have consequences for the neuronal responses (and may lead to the need of higher doses to obtain the same effect (habituation).

Whereas morphine/heroin and cannabis act on specific cell surface receptors that signal into the cell and affect release of neurotransmitters, cocaine acts by blocking the dopaminergic re-uptake transporter (DAT) and therefore transiently increases the amount of dopamine in the synapse. Amphetamines, including amphetamine and ecstasy, seem to employ at least three mechanisms: they increase neurotransmitter production, they prevent their storage in secretory vesicles and they reverse the action of re-uptake transporter (via a phosphorylation mechanism). These mechanisms have been described for dopamine, serotonin and noradrenalin. As a consequence of the three, the aforementioned neurotransmitters accumulate in the cytoplasm of the neuron and subsequently leak into the synapse through their reversed transporters. It is postulated that the anorexigenic action of ecstasy may in part be the consequence of an increased serotonin level, which leads to a more rapid onset of satiation. Due to a high focus on body image, the use of MDMA is encouraged because of both its anorexigenic qualities and its locomotor stimulant effects (you eat less and you move more (in the disco)).

Information sources:

  1. http://en.wikipedia.org/wiki/Dopamine_transporter
  2. Jean A, Conductier G, Manrique C, Bouras C, Berta P, Hen R, Charnay Y, Bockaert J, Compan V. anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increased CART in the nucleus accumbens. PNAS 2007;104:16335-16340.
Morphine, heroin and opium; three of a kind
Opium is the name of the latex that is exuded from the fruit bodies when damaged by a knife cut (poppy tears, lachryma papaveris). Opium contains different substances (so called plant alkaloids) of which morphine, codeine, thebaine and papaverine are the most abundant.

Heroin is chemically modified morphine, an acetyl group has been added which makes the drug more lipid soluble. In the body heroin is converted to morphine and acts as morphine. However, there is a difference between the two compounds. When injected into the blood it reaches the brain more easily because it lipid-soluble characteristics facilitates the passage across the blood-brain-barrier. Once in the brain it is converted into morphine. This advantage is abolished when taken orally because most of the heroin is rapidly converted into morphine during the passage through the liver.

Information sources:

  1. http://en.wikipedia.org/wiki/Opium
Addiction and obsessive-compulsive disorders
The innervations of the caudate nucleus and putamen (dorsal striatum) from the substantia nigra (SN) are implicated in reward-relevant learning and habit formation. It is interesting to consider how these connections may participate in the motivation and craving for tasty and calory-rich foods (and render you fat). Although lacking firm evidence, it is speculated that addiction or obsessive-compulsive disorders are a consequence of a gradual shift in goal directed behaviour from flexible (TVA nucleus accumbens pathway) to persistant control (substantia nigra (SN) dorsal striatum pathway (caudate nucleus, putamen)). Several lines of evidence suggest that reinforcing actions of drugs (addiction) are due, at least in part, to the modulation of dopamine signalling in the nucleus accumbens (NAc). It is thus also possible that bad reward circuitry makes people compulsive eaters.
Food intake behaviour without connections to the forebrain
An anatomical cut that separates forebrain from brainstem (mid- and hindbrain) has been used to evaluate the role of the latter in the regulation of food intake in rats. If regulation occurs at all, it is independent of hypothalamic, cortex and striatum influences. Animals thus treated are paralyzed but can be maintained by placing food in their mouth which they can either reject or swallow. What was learned from these experiments that the rats still are able to terminate their meal, meaning that they respond to satiety signals emanation from the gastro-intestinal tract. These signals reach the brainstem either by the bloodstream (fatty acids, glucose, CCK) or by modulating the activity of the afferent (gut-to-brain) vagal branches. This “reflex arch” is thought to play a role in terminating food uptake upon extensive distention of the stomach wall (mechanoreceptors are gradually made more sensitive through the local release of CCK. At a certain point this leads to gastric stasis (motor component of the vagus nerve).

However, these animals are unable to increase nutrient uptake after a 24 hour food deprivation, they consume exactly the same quantity as in the case of constant supply. Apparently they lost the capacity to compensate for the loss of body weight and they fail to anticipate future shortage.

In conclusion, although we treat the brainstem as just an anatomical structure that relays signal from the brain to motor centers and from peripheral organs to the brain, it apparently is capable of a certain degree of (autonomous) decision taking.
Where hedonic meets homeostatic regulation

reddot Recent results reveal that mediators implicated in controlling the homeostatic regulation also impinge directly on dopamine neurons. For example, leptin and insulin, both satiety messengers, directly inhibit dopamine neurons, whereas ghrelin, an empty stomach messenger, activates them (and leads you to search for food). In rats, insulin and leptin act centrally to decrease food intake.

reddot It has been shown that systemic leptin administration decreases feeding-evoked bursts of dopamine release in the nucleus accumbens (NAc). Infusion of leptin in the ventral tegmental area (VTA) activates expression of the transcription factor STAT3 in dopamine-containing neurons and is also linked to decreased food intake. Conversely, conditional leptin receptor knock-down in the same brain area increases food intake and locomotor activity. Human functional magnetic resonance imaging (fMRI) studies draw special attention to the nucleus accumbens (NAc) as a site that mediates the impact of leptin on food reward. In two subjects with a rare condition of congenital leptin deficiency, the effect of treatment with recombinant human leptin was studied at the level of food intake and of brain activity (fMRI). It was shown that leptin affects the activity of nerves of the mesolimbic reward circuit concomitant with a reduced perception of food reward while enhancing the response to satiety signals generated during food consumption. Collectively, rodent and human studies demonstrate that leptin; (1) modulates feeding behaviour via direct action in the ventral tegmental area (VTA), (2) modulates affective responses for food that coincide with neural activity in the nucleus accumbens (NAc) and (3) regulates dopamine signalling in the pathway linking the ventral tegmental area (VTA) with the nucleus accumbens (NAc). With respect to insulin, it was shown to suppress dopamine tone by increasing expression of the dopaminergic transporter DAT (which rapidly removes dopamine from the synaptic cleft). Levels of mRNA for DAT increase with hypoinsulinemia and decrease when the ventral tegmental area (VTA) is perfused with insulin. Finally, several neuropeptides involved in homeostatic control of appetite, including Npy, AgRP and orexin, also modulate goal-directed behaviour (searching for food): central administration of Npy and AgRP stimulates free-feeding intake, Npy increases the breakpoint for sucrose whereas AgRP increases the reward efficacy of high-fat food.

reddot In line with the above findings, brain areas that are part of the dopamine reward circuits, in particular the mesolimbic and the nigrostriatal pathway, express receptors for mediators involved in homeostatic control. This provides further evidence for their possible role in the regulation of reward circuits. Thus, type-3 and -4 receptors (MC3R/MC4R) of α-MSH (anorexigenic messenger) and type-2 receptors (Y2R) of peptide Y (orexigenic messenger) are also expressed in the prefrontal cortex, amygdale, hippocampus, caudate nucleus, putamen, substantia nigra and ventral tegmental area. The receptor (ObRb) for leptin (anorexigenic messenger) is found in the hippocampus, amygdale, substantia nigra and the ventral tegmental area. The receptor (GHSR) for ghrelin (orexigenic messenger) is found in the hippocampus, substantia nigra and ventral tegmental area. Finally, the receptor (InsR) for insulin (anorexigenic messenger) has been detected in the substantia nigra and the ventral tegmental area (see figure 6).

reddot As discussed by team 2, homeostatic control is focused in hypothalamic brain areas such as the arculate nucleus (Arc), the paraventricular nucleus (PVN), the lateral hypothalamic area (LHA) and the perifornical area (PVN). The nucleus accumbens (NAc) is innervated by these areas as well as by neurons originating at the nucleus of solitary tract (NTS) (see figure 1 and 9 of team 2). Of these areas, the LHA deserves extra attention. It contains neurons that produce orexigenic peptides; orexin and melanin-concentrating hormone (MCH). These neurons not only innervate the nucleus accumbens (NAc) they also reach the ventral tegmental area (VTA) as well as the nucleus of the solitary tract (NTS). In other words, the LHA neurons are likely to influence the tone of dopamine (as they interfere with the mesolimbic and nigrostriatal reward system). Bilateral electrolytic lesions of the LHA result in a profound decrease in feeding, drinking and body weight (back in 1996, LHA was named “the feeding centre”). Electrical stimulation of the LHA elicits a feeding response. It is speculated that orexin-containing neurons in the LHA are part of a circuit that controls intake of fatty foods.

reddot In conclusion, homeostatic and hedonic control mechanisms of ingestive behaviour are intimately linked. The picture that emerges is that numerous signals, emanating from the eyes, the nose, the stomach, adipose tissue, the blood, as well as the brain itself, meet in various brain regions where they are scrutinized for importance and then conducted to motor control areas that ultimately determine whether or not we are going to search for food, engage in the process of eating or not. As a consequence of all this, some remain slim and others gain weight.

Figure 6 receptors of mediators involved in homeostatic regulation are also detected in brain areas known to be involved in hedonic regulation (dopamine reward circuits).

Information sources:

  1. S. Fulton. (review) Appetite and reward, Frontiers in Neuroendocrinology 2010, 31;85-103.
  2. Palmitter RD. (review) Is dopamine a physiological relevant mediator of feeding behaviour? Trends in Neurosc. 2007;30:375-381.
  3. Rodgers RJ, Holch P, Tallett AJ. Behavioural satiety sequence (BSS): separating wheat from chaff in behavioural pharmacology of appetite. Pharm Bioch Beh 2010, in press
  4. Brain stimulation reward
  5. VTA
  6. Everything about the brain at three levels of complexity
  7. Substance use disorders in general

Original articles

  1. Olds, J., and P. Milner. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 1954 ;47:419-27.
  2. Olds, J. "Reward" from brain stimulation in the rat. Science 1955;122:878.
  3. G. Spies. Food versus intracranial self-stimulation reinforcement in food-deprived rats. J. Comperative and Physiological Psychology 1964;60:153.
  4. Berridge, KC. The debate over dopamine’s role in reward: the case for incentive salience. Psyochparmacology (Berl.) 2006;191:391-431.
  5. Ungerstedt U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol Scan 1971;367(Suppl):95-122.
  6. Farooqi SI, Bullmore E, Keogh J, Gillard J, O’Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behaviour. Science 2007;317:1355.
Anorexia and bulimia nervosa

reddot Quite opposite to obesity, anorexia and bulimia nervosa are two eating disorders that result in morbid weight loss. Anorexia nervosa is a disorder of unknown etiology most commonly diagnosed in women during adolescence. The term is of Greek origin: a (prefix of negation), n (link between two vowels) and orexis (appetite), thus meaning a lack of desire to eat. The term nervosa has been added in order to make the distinction between other forms of anorexia for instance anorexia-cachexia induced by inflammation (as a consequence of an infection or as occurring in advanced stages of cancer).

reddot The diagnostic & statistical manuel (DSM) for mental and behavioral disorders describes the following criteria:

  1. Refusal to maintain body weight at or above a minimally normal weight for age and height
  2. Intense fear of gaining weight or becoming fat, even though underweight
  3. Disturbance in the way in which one’s body weight or shape is experienced (see figure 7),
  4. In postmenarcheal females, amenorrhea (i.e. the absence of at least three consecutive menstrual cycles

reddot Specific type:

  1. restricting (eating less and selectively)
  2. binge eating/purging type (regular engagement in binge-eating or purging behaviour (self-induced vomiting, misuse of laxatives, diuretics or enemas)

reddot Bulimia nervosa is a related disorder. The term bulimia derives from the Latin, which originally comes from the Greek βολιμια, a compound word of bous, ox and limos, hunger (hunger like an ox). The following criteria apply:

  1. Recurrent episodes of binge eating, either consuming an excess in a short period of time or eating over a long period of time (can’t stop)
  2. Recurrent inappropriate compensatory behaviour in order to prevent weight gain, such as self-induced vomiting, misuse of laxatives, diuretics, fasting or excessive exercise
  3. The cycle of excesses occur, on average, at least twice a week for three months
  4. Self-evaluation is unduly influenced by body shape and weight
  5. The disturbance does not occur exclusively during episodes of anorexia nervosa

reddot Anorexia and bulimia nervosa affect a small percentage of females (a maximum of 0,7% and 2,5% respectively), it occurred centuries ago, it has substantial heritability and a developmentally specific age-of-onset distribution. These finding underscore the possibility that changes in body composition during puberty (hormonal and otherwise) contribute to vulnerability for these disorders. Contrary to popular believes, it is unlikely a consequence of the current cultural pressure for thinness.

reddot The pathogenesis of the disturbed eating behaviour is poorly understood. Individuals with anorexia nervosa rarely have complete suppression of appetite, but rather exhibit an “ego-syntonic” (driven by the needs of the ego) resistance to feeding, while simultaneously being pre-occupied with food and eating rituals to the point of obsession. By it auto-destructive nature it seems as if the adolescent want to show that, despite the profound changes that occur during puberty, she (he) can nevertheless control her (his) body. Bulimia nervosa is not associated with a pathological increase in appetite; it is not preceded by a phase of overweight. Like for anorexia nervosa, those who have the disorder manifest an extreme fear of weight gain accompanied by a distorted view of their actual body shape. People with these disorders have elevated rates of lifetime diagnosis of anxiety and depressive disorders as well as obsessive-compulsive disorder. Anxiety disorder often begins in childhood, before the onset of an eating disorder. It is possible that malnutrition, as a consequence of anorexia, amplifies the above described behavioural traits.

Figure 7 One of the diagnostic criteria for anorexia and bulimia nervosa is the distorted view of body shape (dysmorphobia).

Neurological suspects in anorexia and bulimia nervosa

reddot Although neurobiological vulnerabilities are likely to make a substantial contribution to the anorexia and bulimia nervosa, there nevertheless is little understanding of what brain systems are primarily involved and how these neurobiological vulnerabilities disturb them. Do we deal primarily with anomalies in homeostatic control, hedonic control, body proprioreception, mood or impulse control (bulimia), or a combination of all this? It may not come to a surprise that the above described reward mechanisms play a role but the exact implication of dopamine, endogeneous opoids or serotonin remains to be discovered. Until today, most theories are hypothetical. Genetic analysis has shown that anorexia associates with polymorphisms of agouti-related peptide (AgRP), brain-derived neurotrophic factor (BNF), opioid delta-1 receptors (DOR-1), catechol-0-methyltransferase (enzyme that degrades catecholamines such as dopamine, adrenaline and noradrenaline) and a Ca2+-activated K+-channel (KCa2.3 of SK3).

Information sources:

  1. http://en.wikipedia.org/wiki/Anorexia_nervosa
  2. http://en.wikipedia.org/wiki/Bulimia_nervosa
  3. http://en.wikipedia.org/wiki/Diagnostic_and_Statistical_Manual_of_Mental_Disorders

review article

  1. Kay W. Neurobiology of anorexia and bulimia nervosa. Physiol Beh 2008;94:121-135.
  2. Wagner A, Aizenstein H, Venkatraman VK, Fudge J, May JC, Mazurkewicz L, Frank GK, Bailer UF, Fischer L, Nguyen V, Carter C, Putnam K, Kaye WH. Altered reward processing in women recovered from anorexia nervosa. Am J Psychiatry. 2007 Dec;164(12):1842-9.

 

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Last Updated March 9, 2014 9:02 PM | admin news