The disease of addiction has many factors but the most important reason underlying the use of drugs is that they cause us to get high. We are temporarily rewarded for the behavior of using drugs. Not only that, but any one who has ever experienced relapse can tell you that the initial use of a drug or alcohol led to the second use and than the third use and so on and so on. We refer to this property as reinforcement: the rewarding of a behavior causing it to be repeated.
Although the range of addictive substances includes a variety of different chemicals with different biological activities, it seems that reinforcement, leading to continued use, is the result of a common physiology that exists for all drugs of abuse.
To understand how this works, you must know a little of how the brain works. The brain is bunches of individual nerves that communicate with each other and which are arranged into distinct areas to serve specific functions. When one nerve communicates with a second, it releases a chemical called a neurotransmitter into the space between them; this space is called a synapse. The second nerve reacts after its receptor binds to this chemical. Depending on which chemical is released, the activity of the second nerve can either increase or decrease. All drugs act either by affecting how much of a neurotransmitter is in the synapse or interacting directly with a receptor. Whole areas of the brain can be excited or depressed in this fashion.
There is an area of the brain in which increased activity will be perceived as pleasurable. We know that lab animals with electrodes planted in this area of their brains, given small electric shocks, will continue to seek this stimulation. They will ignore all other bodily needs such as eating, drinking and sex. The pleasure they are apparently feeling reinforces whatever behavior is needed to continue the shocks. This area is called the Nucleus Accumbens (NAC)and may be thought of as the pleasure center of the brain.
In this area of the brain live special nerve cells called Medial Spinal Neurons (MSNs). Whenever these cells are stimulated, we feel pleasure. Other nerves, emanating from different brain areas, affect these MSNs. Many of them contain. DOPAMINE . When dopamine is released, the MSNs are stimulated and we feel euphoria. Almost all drugs of abuse have been implicated in increasing dopamine. Cocaine and other stimulants directly increase the amount dopamine in the synapse and quickly increase the activity of this area. Heroin, pills, alcohol and even marijuana have been shown to increase activity as well albeit by more indirect means.
In the lab, one is able to breed mice that do not have dopamine receptors. Nevertheless, these mice also become addicted. Therefore,there must be another mechanism of euphoria.
It turns out that beta endorphin also has a role. B-endorphin is one of our natural feel - good chemicals. Through a mechanism known a gaba disinhibition (see below) , beta endorphin also increases MSN activity This results in a feeling of pleasure that is independent from that caused by dopamine. Opioid, marijuana and alcohol all increase this activity.
Of course, this does not explain the disease of addiction. All persons , both with and without the disease of addiction, will have euphoria when using drugs. Nevertheless, this is a necessary step in understanding why some go on to develop substance abuse disorders.
Research has been done to find out how the various drugs lead to neurotransmitter release. We are trying to develop medications that will interfere in this step and block acquisition of addiction . This has already begun. A drug called naltrexone blocks endorphin. It affects the way heroin, marijuana and alcohol work. It prevents the high from these drugs. When a person takes naltrexone, their drug use goes down.
Dopamine pathways in the brain. Most begin in the brain "switching station" called the VTA
Recent studies have begun to point to reasons that persons with substance abuse disorders might be biologically predisposed to their problems. I do not mean to disregard the psychosocial and spiritual aspects of this disease that I feel are very significant. However, biology does play a major role in the cause of this disease. I apologize in advance for the technical aspects of this article and have simplified (and even over simplified) whenever I could.
In a previous article (Why we use drugs), I outlined which part of our brain was the target of the drugs we abuse. Specifically, there is an area called the Nucleus Accumbens ( N. Accumbens) where stimulation causes a pleasurable sensation. For this reason, this area can be considered the ‘pleasure center’ of the brain. This area is felt to be the main target of all drugs of abuse. Normally much of the stimulation to this area is from a neural tract that begins in a part of the brain call the Ventral Tegmentum (VT) and ends in the N. Accumbens. A neural tract is a great number of nerve cells that run together. The VT simulates this tract that in turn releases dopamine into the N. Accumbens. The dopamine, in turn, stimulates the nerves that begin in this area. This causes pleasure. Almost all drugs of abuse will increase dopamine in the N. Accumbens and cause pleasure. That is why they are abused.
Proper function of this neural tract is necessary in order for the N. Accumbens to function at a normal level of activity. A lack of proper activity in the N. Accumbens has unproven consequences but it seems reasonable that there would be less sensations of pleasure. This could cause chronic depression since experiencing appropriate degrees of pleasure are necessary for emotional health. Also, just as a hungry person is less able to resist food, a person with a chronic low N. Accumbens activity may be less able to resist any activity or drug that increases the sensation of pleasure. They will be hungrier for pleasure compared to persons with normally functioning pleasure centers. This hunger predisposes the person towards use of addictive medication.
At this time, I am aware of no studies that clearly document malfunction of this tract in humans. However, there have been studies in laboratory rats that are very significant. While we are much different than rats in many ways, we are also very similar. The VT and N. Accumbens areas are also found in the rat brain and have similar roles. One advantage of looking at laboratory rats is that they almost identical twins to one another. They are alike in every way except in those specific ways you breed them to be different. Well, some people decided to breed alcoholic rats. This was done by taking the rats in each generation that showed the most liking for alcohol and allowing them to make more rats. This was done for many generations. To contrast with these, abstinent rats were also bred over several generations. They differed in their appetite for alcohol but, otherwise, were identical to the alcoholic rats. It turns out that the rats more likely to abuse alcohol are also more likely to abuse other substances compared to their abstinent cousins. Therefore, scientists were able to breed rats that were predisposed to addiction to all types of substances.
The brains of the alcoholic and abstinent rats were compared before there was any exposure to alcohol (not even uterine exposure prior to birth). There were significant differences. These differences were specifically located in this tract from the VT to the N. Accumbens. It seems that, in the alcoholic rats, the nerve cells were scrawnier. Also, the ability to get the dopamine, needed to stimulate the N. Accumbens, to the right part of the nerve was impaired. It seems reasonable to assume that the abnormalities in these nerve cells result in less dopamine being available in the N. Accumbens and therefore less activity in this area. Therefore, these rats might be born with less pleasure sensation and a greater hunger for pleasure.
Other studies have shown that when you force the normal rats, not predisposed to addiction, to drink (or use other drugs), they acquire similar abnormalities of these same nerve tracts. The nerves appear scrawnier and more disorganized compared to their twins who were not exposed to alcohol. Even one year after the last exposure to alcohol, the nerves were still abnormal. Since rats only live for two years, it is possible that this nerve abnormality is a permanent condition. The conclusion is that alcohol and drug exposure can damage a normal pleasure center. This may lead to a chronic condition where the rat acquires a hunger for pleasure.
Does the same thing happen in humans? There is no way to test this possibility at this time. However, we know that there is a subset of substance abusers that develop their problems very early; this group tends to have a very high prevalence of substance abuse in their family history. It seems reasonable that some sort of genetic predisposition exists. A hereditary abnormality resulting in less N. Accumbens activity and pleasure might be an explanation for this.
Similarly, there are those who do not have an obvious problem early in their lives. However, they develop progressively worse problems as the years and alcohol exposure go on. This pattern does not run in families to the degree that the other pattern does. A process where continued drug exposure leads to a gradual reduction in N. Accumbens activity may explain this pattern of disease.
A purist may argue that we are far from proving that N. Accumbens underactivity contributes to addictive tendencies. And, they would be right. As we learn more, we are finding other biologic abnormalities that predispose toward addiction. Yet, it is an intriguing possibility. Remember, even seizures were once relegated to being psychiatric symptoms or signs of demonic possession. As we learn more about the brain, more and more of psychiatric illness become explainable as biologic abnormalities. Hopefully, as research continues to uncover the biologic abnormalities that lead to addiction, the stigma of addiction, and the inequities that people seeking treatment experience, will begin to disappear.
For those of you who are curious, I will review GABA disinhibition. It is necessary to point out that all neurons, if left to their own devices will discharge repeatedly in a non-controlled way. This will have fatal consequences if severe and lead to seizures and other issues when less severe.
We have evolved a chemical called GABA that acts like a brake; it applies a constant inhibitory effect. A good metaphor is a car that is idling. When you put it into gear, the idling speed will have it go forward unless you put on the brake. If you release the brake, the car will speed up (within limits).
Any drug that reduces GABA will reduce the "braking" effect on the target nerves. They become disinhibited. Endorphin, and all opioid drugs, do this; they will reduce GABA activity and therefore allow the inhibited nerves to speed up. In the case of drug euphoria, the MSNs are the nerves that speed up
One of the most problematic aspects of maintaining recovery is the long-standing cravings to use the medication. Months or years later, people still find themselves thinking about the drug or suddenly wanting the drug for no explicable reason. It seems that the triggers to use are extremely pervasive and difficult to ignore. And what's more, it seems that our desires to use occur without triggers.
To understand this, one must understand learning. If you remember, way back in high school, you learned about classical conditioning. Dr. Pavlov trained his dog to salivate to a bell. By pairing a bell when he gave the dog a steak, the dog learned that the bell meant food. The bell was a "trigger" for the dogs response which was salivating. The learning was rewarded (reinforced) by the meat.
When applied to drug use, a trigger might be a person, place or feeling and the response is the craving for the drug. The drug "high" is the reinforcement for the learning.
Normal learning process relies on internal reward. Dopamine is the chemical that rewards us when we learn. The first time we eat at a good restaurant, or get an unexpected reward such as being paid as a kid for shoveling a driveway, we experience a sense of pleasure from an unanticipated reward. We also learn to repeat the behavior. Dopamine release moderates this response.
There are changes in our biology when this happens. In the synapse, where one nerve communicates with another, certain receptors for a neurotransmitter called glutamate become both more plentiful and more sensitive to subsequent stimulation. The number of synapses also increase. Subsequent signalling will be more pronounced and we become sensitized to triggers. This is called LONG TERM POTENTIATION (LTP)and it is the cellular basis of learning.
When we experience normal rewards, like chocolate or sex, a certain amount of dopamine is released. This leads to changes in the synapse for up to a week. This has normalized by 3 weeks. However, after drug use, the LTP changes are still there 3 weeks and even 3 months later. That is because the dopamine release is so much more- up to 10x what we would expect from non drug stimuli.
Under normal, non drug circumstances, once we are used to the reward, the pleasure and novelty wear off. We loved our first paycheck but get less pleasure from subsequent paychecks since receiving such paychecks are normal and expected. We love our first day in the gym (exercise releases dopamine) but the same workout routine can become a drudgery. The reason this feeling wears off is that dopamine no longer flows with habitual behavior.. Once a behavior is well learned, it is no longer associated with dopamine release.
However, when we use drugs, the dopamine surges are much higher and much more prolonged than what occurs naturally. Also, even after the 500th time using a drug, there is still dopamine release. This means that the stimulation to learn is huge.
Now, if a non-drug stimulus becomes unpleasant, we learn to stop the behavior. We won't go to a restaurant that sells bad food and we won't go to work if we no longer get paid. When our behavior is no longer rewarded, especially if it is punished, we stop it. The behavior is extinguished
However, drug using behavior becomes so well learned we cannot easily unlearn it. Not even after it has destroyed our lives, not even after spending months or years away from the drug. This is pathological learning. It has become mired into the habit or unthinking part of our brain- the POSTERIOR STRIATE CORTEX
Studies have been done that show this part of the brain lights up in addicts when they are exposed to drug triggers-it is the seat of cravings or hunger for the drug
Triggers can be quite subtle. A study was once done on alcoholics. They were given a video to watch with no apparent alcohol references. Than, images were flashed for a fraction of a second in a process consistent with subliminal advertising. The alcoholics could not describe what they saw, and were unaware of the images. Yet, they developed significant alcohol cravings. The pathologic learning process resulted in an excess response to even a minimal trigger.
We don't need to despair, the responses can be unlearned (extinguished). The first time an alcoholic in recovery walks by the bar, he will fight the urge to go in. But the 500th time, the cravings will be less.
Often, one needs to be exposed to the trigger to extinguish the response. Thats why some patients relapse even after they have been away from home for months or years. They never learned to get used to a specific person, or a specific area of the neighborhood. They also need to learn new behaviors and responses to these triggers when they get home. It is doable but is difficult and takes time. Counseling, which helps us anticipate triggers and find alternative behavior helps
AMPA glutamate receptors increase after drug exposure
It is easy to understand that our endorphin biology is abnormal in addiction. Opioids mimic them and interact with opioid receptors, alcohol, marijuana, carbohydrates and others all release them. Imbalances in endorphins and their receptors play a significant role in acute withdrawal. So what happens to them weeks and months after our last use?
We know that during intoxication there is an increases in endorphin activity. The brain responds by reducing the activity and/or numbers to try to reduce the effect of this overstimulation. When the drug is withdrawn, there is acute withdrawal, in part, due to underactivity of these receptors.
Or so I thought.
Its true that underactivity of endorphins or their receptors causes acute opioid withdrawal and probably contributes to withdrawal from other drugs. However, it may be wrong to think that the brain has a consistent response. In fact some areas of the brain are more affected than others and some not at all.
However, scientific findings that have emerged recently, is that there are areas of the brain where the endorphin receptors are hyper sensitive and there will be to much opioid activity at rest and in response to stimuli. This is especially true in areas of the Medial Prefrontal Cortex (mPFC), part of the executive area of the brain.
We have known for years that there was a change in receptor biology in early recovery. In a normal brain, naltrexone has no direct effects on these receptors. However, in early recovery, we see there is a direct effect from naltrexone. It becomes an Inverse Agonist . Receptors that are empty, without a drug of neuro transmitter, still spring to action. This is referred to as baseline activity and it occurs at a certain rate. When the receptors are hyper sensitive, this baseline rate is increased. Naltrexone, reduces this increased from baseline activity.
When opioids are infused only into this part of the brain, addicted rats become more drug seeking and impulsive in general. There is increase in impulse outflow from this area of the brain to the Lateral Hypothalamus , the area of out brain most responsible for increasing our appetite and making us hungry. From there, impulse go to out Ventral tegmentum, our main emotional switching area than into out habit circuitry. It is a reason our habit circuitry dominates our though process and behavior in early recovery.
For those who know their brain biology, one objection to this model is that the mPFC also feeds into the nucleus accumbens which should lead to satiation and reduce hunger. However, that presumes that the nucleus accumbens is healthy. Other articles on this site have reviewed how components of goal directed circuitry, which contains the nucleus accumbens, are diseased and less functional. I am making an assumption, but I suspect the will reduce the ability for the accumbens to cause satiation. The end result is that hyperactivity of the mPFC leads to a net increase in hunger. The stress of this leads to an increase in impulsive behavior.
This is a common component of all addictions: both substance and behavioral. It also explains why naltrexone has benefit is a wide range of addiction