In this article, I will briefly review mechanisms that are discussed in more detail in the addiction section of this website.
The basis of learning and reward in our brain is centered in an area of the brain called the Nucleus Accumbens. When we have a pleasurable experience, such as sex, using drugs,or eating a good meal, there are several physiologic events. Specifically, a neurotransmitter called dopamine is released which is crucial for learning new behaviors. In addition to dopamine, beta endorphin is released which results in our experiencing pleasure and being able to relax. The result is that we will want to repeat the behavior in order to keep experiencing these effects.
When we use drugs, these neurotransmitters are released in amounts much greater and for much longer periods, than is normally accomplished physiologically. After the initial high, our brain adapts to these effects. Changes in the brain develop including a relative absence of dopamine and an insensitivity of the target cells to dopamine and endorphin. These changes cause us to feel depressed, anxious and looking for ways to restore the dopamine and endorphin activity of our brain to normal. We will want to repeat any activity that we have learned will increase these neurotransmitters.
What has become apparent over the last few years is that highly processed carbohydrates and fatty food also cause releases of these transmitters. Certainly, they cause a greater release than naturally occurring food. These foods make us feel happy. We learn to keep eating in order to regain this feeling.
Therefore, there are two ways we may feel hungry. The normal hunger occurs when the hypothalamus, after measuring what is happening in our body, tells us we need to eat by creating the feeling of hunger. The abnormal hunger occurs when we are responding to imbalances in several area of our brain which lead to abnormal signalling of the hypothalamus. And of course, the food we crave for is the highly fatty and/or highly processed carbohydrates, food that we have learned gives us the most pleasure. This kind of eating continues to release high amounts of dopamine and endorphins, which leads to even more unhealthy eating.
When we are stressed and/or depressed, we want to feel better. We know what makes us feel better. When we are bored, our brain wants pleasurable stimulation. Again, we know what will get us this feeling. And when we are exposed to food triggers, like that plate of cookies at work, we are stimulated to want this food. Remember too, some triggers can be quite subtle; we are barely aware of them but they will make us want to eat.
Recently, it was discovered that in many cases of addiction, there is an abnormality in the front of the brain. It consists of overactive opioid receptors. This imbalance leads to increased craving for food and increased impulsiveness. Why and how this imbalance arises is still being researched.
If we can change the way these transmitters behave in our brain, we can change the experience of eating. Medications exist that can moderate the effects of the transmitter release. This, hopefully, will allow us to be more immune to the craving and compulsions of food. We can than begin the process of unlearning our unhealthy eating behaviors.
Unfortunately, intervening directly with dopamine levels, or its' targets, has not really been worthwhile; no good interventions exist. However, we can reduce the effects of endorphin using naltrexone. Additionally, there are indirect ways of affecting dopamine activity. GABA, glutamate, seratonin and anandamide are all transmitters that impact upon dopamine function. (andamide is the natural chemical that is imitated by marijuana). Several medications exist that have an impact on these chemicals and reduce food cravings.
I want to apologize tor the technical details of this article. There is a great deal of ongoing research in this field and our knowledge changes frequently. In this article I will attempt to pull together different aspects of knowledge into one place. Don't feel bad if it is overwhelming, I have to keep reading this stuff over and over to keep it clear in my own mind; even, then, it is difficult to put all the different parts in one coherent model. Yet, these are the mechanisms that increase or decrease appetite. They can be targeted by medication. They are the bases for the medications I use.
The hypothalamus is the area of the brain where appetite is controlled. In order to control appetite, there needs to be a way for this structure to measure the current energy stores as well as the current energy needs. There needs to be a way for it to recognize the long term nutritional status of the body as well. Once it is able to determine these factors, it needs to be able to modulate appetite and metabolism for the good of the person.
In order to increase our appetite, it needs to connect with the motivational parts of the brain such as the Nucleus Accumbens. This is where we will focus on eating and plan how we can obtain food. In addition, it also connects with the posterior striate cortex- this is where the actual hunger feelings emanate from.
One particular area of the hypothalamusthe arcuate nucleus, is in a unique position to both monitor the blood as well as the brain. In this area, two opposing nerve groups are found. Their names are quite the mouthful. The first of these is the Cocaine and Amphetamine-related transcript/proopiomelanocortin (CART) group, which secetes a neurotransmitter called melanocortin as well as endorphin,. The second is the NeuropeptideY/Agouti related protein (NPY) group.
These two tracts interconnect with each other in many ways, trying to inhibit and influence each other. They also go to different areas within the hypothalamus where they have opposing effects on the target areas.
Easily, the more important tract is the CART. Activity of this nerve group suppresses appetite. Whenever these nerves have been inhibited in lab animals, a profound amount of weight is gained. As detailed below, it is also able to increase metabolism. The NPY neurons, on the other hand, increase our appetite and decrease our metabolism. Abnormalities in this group do not result in as big a difference in weight as the CART. Nevertheless, if we want to lose weight, we want the NPY tract to be less active.
The CART neurons are influenced by several important parts of the brain. It is affected by connections originating from the Amygdala and Vagus nerve. The Amygdala modulates fear and stress and lets the hypothalamus know if there is danger. The vagus nerve is able to monitor what the stomach and intestines are doing and sense the presence of food. The vagus nerve can tell the hypothalamus if we have been fed. The mechanics of these connections are still being studied.
The CART neurons than go on to effect multiple areas of the hypothalamus and brain. The destinations include the nucleus accumbens where it works to inhibit appetite. In addition to connecting to the Nucleus Accumbens, there are also connections from there as well, perhaps in some type of feedback loop. This means our appetite can be affected by what is going on in the Nucleus Accumbens. As explained in articles elsewhere in this website, the Nucleus Accumbens is the key target of all addictive substances and is dysfunctional in most diseases of addiction.
It also connects to the area controlling the Vagus nerve and may have an effect on how the intestine handles food. Likely, it slows down activity in the gut. Perhaps this explains why stress may cause some people to have stomach upset.
One easy way to remember all these effects is to realize that if we are in danger and need to react, what is known as the "fight or flight" reaction, increased activity of the CART neurons is crucial. It receives alarm signals from the Amygdala. It then suppresses hunger, turns off the gut and increases metabolic output to optimize the energy reserves for the muscles to act.
In contrast to the CART, NPY neurons increase appetite. Its function seems less potent than the CART since abnormalities in its function have less impact on weight gain or loss. The connections of NPY neurons are more localized than those of the CART. Most remain within different areas of the hypothalamus. These areas are listed below.
In the para ventricular nucleus of the hypothalamus, input from POMC and the NPY are both received. There, the two opposing forces duke it out.. The summation of these opposing forces will affect metabolic rate. One way that metabolic rate is affected is through increasing or decreasing thyroid activity. They also affect the ACTH/cortisol hormone axis.
The NPY neurons also go to the Lateral hypothalamus. There they stimulates neurons that contain orexin, a neurotransmitter that increases appetite. These orexin neurons travel to the Nucleus accumbens and increases hunger. This may be the most important cause of hunger we have.
The lateral hypothalamus also receives input from the prefrontal cortex- the executive area of out brain. In the last few years, we have shown that imbalance here, caused by overly sensitive endorphin receptors, will also lead to over-stimulation of the lateral hypothalamus. This causes abnormal hunger and therefore cravings for drugs and food (leading to drug consumption and binge eating)
The lateral hypothalamus may by the mechanism by which THC (marijuana's active ingredient) causes increased appetite as THC will lead to increase orexin release.
Localized effects within the Arcuate Nucleus
There are many neurological connections within the Arcuate nucleus and because of this, there is a soup of chemicals which are known to be neurotransmitters. It is helpful to consider the effects of these chemicals without trying to attribute them to any individual nerve.
It is well known that serotonin affects appetite. Redux, fenfluramine and Meridia are all well known diet drugs that worked by increasing activity of serotonin. It turns out that one type of seratonin receptor (the 5ht2c) increases activity of the CART. Another receptor, the 5HT1a, reduces activity at the NPY neuron. Much of the current research in anti-obesity treatment is focused on manipulating these receptors.
Other transmitters to consider are the opioids. CART/POMC neurons are actually a major source of these endorphins within the limbic system- supplying them to the nucleus accumbens as well as other areas implicated in drug use. When the CART neurons are more active they make more endorphins. These endorphins feedback on the CART to slow them down. These endorphins also interact with the NPY neurons to facilitate an increase in appetite. Therefore, opiate blockers will serve to reduce appetite by blocking both mechanisms.
Responses to hormones from other parts of the body
Both the POMC and NPY are able to respond to a variety of nutrients and hormones in the blood. Abnormalities of these processes have been implicated in weight control issues.
Leptin was described some time ago. It is made by the fat cells and is proportional to the bodies fat content. Therefore, high Leptin tells the hypothalamus that fat stores are adequate. Leptin directly increases CART activity. Of course, this decreases appetite and increases metabolism. In addition, Leptin reduces orexin activity in the lateral hypothalamus.
The CART also responds to blood sugar and insulin which are increased after eating; so insulin and higher sugars decrease our appetite by stimulating the CART.
Glucagon Like Peptide (GLP) which comes from the gut also stimulates the CART. GLP is increased after eating. GLP is already targeted by a number of medications that are used in treating diabetes. These medications have lead to weight loss.
In addition to GLP, the Pancreas also secretes another hormone called Amylin. This has multiple effects on suger metabolism but has also been demonstrated to decrease appette by stimulating the CART neurons. This is important because a medication that mimics amylin, which was approved to treat diabetes, has been proven in a study to lead to weight loss even in a non-diabetic population.
Does an empty stomach make you hungry? That is because an empty stomach secretes ghrelin which increases activity of NPY neurons. However, after we eat, peptide YY from the gut, and pancreatic polypeptide from the pancreas inhibit the NPY neurons and decreases appetite.
Cholycystokinin and oxyntomodulin from the gut will also reduce hunger after we eat. They effect the Vagus Nerve, which in turn, affects the CART nerves