“It’s not the side-effects of the cocaine — I’m thinking that it must be love.” — David Bowie
Addiction affects millions of people worldwide, and its hold on people is often baffling, especially if you have never felt the irresistible urge to use some drug. Sure, you like a few drinks from time to time, maybe even a cigarette when you have more than a few drinks, but you’ve never experienced craving so strong it perverts every waking idea. You’ve never felt withdrawal, so impossibly pervasive, it drives you to find relief in the very thing that brought you to a terrible state. Fortunately, you don’t understand.
Maybe you even know somebody that is addicted, and maybe this person can explain her subjective state as she gets high, and maybe she gives you multiple, constructed rationales for continued use, but the underlying reasons, the complexity of addiction, and the neurophysiology of addiction likely remain a mystery to her.
The effects drugs have in the brain cause a reinforcement of the drug-taking behavior that manifests itself as a positive thing to experience again. In cigarette smokers, the first several times smoking usually cause dysphoria, but many smokers remember it as rewarding. Changes in neurobiology after a long time using elicits craving and tolerance which manifest themselves as a strong urge to use and to use a lot, both in quantity and frequency.
Researchers have been investigating the effects of drugs of abuse in the brain for decades and have discovered pharmacological effects of drug use, long-term changes after extended use, as well as several treatment options for different drug types. Even after extensive research, it should be noted there is still some debate as to the nature of addiction. I discussed this in a blog post, arguing that instead of taking sides on whether addiction is a disease or choice, people should recognize the disease-like qualities of addiction as well as the choices a person has as an individual.
(Part 2 is now available and can be found here.)
Pharmacology of Drug Use
Different drugs cause different things to happen in the brain. For example, what happens in the brain when someone takes a line of cocaine? In short, it increases dopamine signaling, which has downstream effects in several brain regions, and it’s important to understand how this happens.
Dopamine has become ubiquitous when people talk about drug use and addiction. It is often conflated with pleasure, but it was first understood in the context of motor movements and is necessary for everyday functioning. The brain is composed of billions of neurons (not to mention, glia, blood vessels, and ventricles filled with cerebral spinal fluid) that make up distinct regions in the brain. Dopamine-producing neurons are highly concentrated in both the basal ganglia and limbic system. These two brain systems overlap somewhat and are important for different processing: the basal ganglia for motor planning, actions, and learning, and the limbic system for motivation, reinforcement, and pleasure. In a sense, both systems are run on dopamine.
Neurons communicate with each other by both electrical and chemical means. When a neuron fires, neurotransmitters (e.g., dopamine, serotonin) are released into a tiny space in between the neurons, called the synaptic cleft. Neurotransmitters released by the fired neuron (presynaptic neurons) attach to receptors on the receiving end of other neurons (postsynaptic neurons), regulating transmission on these neurons. What’s more is that there are mechanisms that take back up the neurotransmitters into the neuron that just released them. These are called transporters, and the process is called reuptake.
Cocaine works by blocking the reuptake process of dopamine, which has the effect of increased dopamine signaling at the synaptic cleft. Neurons on the receiving end of this are flooded with dopamine, causing over-stimulation of neurons with dopamine receptors. Many of these neurons with dopamine receptors release opioids, causing the high associated with drug use. Other neurons may release GABA or glutamate, which inhibits or excites neuronal transmission, respectively. It all depends on the region in which the dopamanergic neurons are terminating in (e.g., there are high concentrations of opioid neurons in the nucleus accumbens but less in the PFC, where there are higher concentrations of glutamate neurons).
After multiple times using cocaine, neurons compensate for the upsurge in dopamine signal by decreasing the amount of available dopamine receptors, so that more cocaine is needed to achieve a similar effect as before, an effect called tolerance.
All of this is more or less agreed upon in the neuroscience community. It’s basic neuroscience; however, there are several theories as to why addictive behaviors are so difficult to stop, and why the brain and body crave drugs after a long-time using.
Theories of Addiction
Addiction has been defined as a maladaptive behavior characterized by persistent drug use in the face of negative consequences. Addiction is considered by many researchers to be a brain disease influencing abnormal behavior. It is driven by decision-making systems and functions similarly to other behaviors. This may be especially true when considering the development of habit-based behaviors. Even though habit-based behaviors are difficult to change, individuals still retain at least some agency in their choices, even though choices may seem limited.
Habits are a normal part of our lives, necessary for survival. Addiction is similar but also more complex. Addiction can, indeed, be characterized by more automatic, habit-based behaviors, but some theories of addiction also imply purposeful, goal-directed behaviors.
In the first part of this theories of addiction series, I’ll discuss two theories. The first, compulsivity, is characterized by more automatic processes driving behavior, and the second, opponent process, can be thought of as more deliberative choice to avoid uncomfortable situations.
Theory 1: Compulsivity
This theory posits that in a subset of drug users, behavior becomes compulsive. Compulsive behavior is characterized by continued use of drugs even in the face of negative reinforcement and is one of the hallmarks of addiction (as discussed above).
Although imperfect, animal models can be useful for studying addiction, especially when investigating the underlying causes in the brain. Researchers developed an animal model of compulsive drug seeking by giving rats access to cocaine for many hours for several days (extended access) and then tested whether they would continue to use even when drug-seeking behavior could result in punishment. The researchers found that after extended cocaine use, a subset of rats exhibited punishment-resistant behaviors, a percentage that is similar to the subset of humans who are susceptible to drug abuse. An intriguing finding, since a compulsive pre-clinical population (i.e., animals) provides a potentially useful tool for studying and finding treatments for addiction.
Now that the researchers have developed a viable model of compulsive drug seeking, underlying brain areas driving this behavior can be studied. New technology, called optogenetics, allows for selective inhibition or excitation of specific brain areas. Researchers took these rodents that were resistant to punishment and found that an area, called the pre-limbic area, was sufficient and necessary for compulsive cocaine-seeking behaviors. In other words, the pre-limbic area was less active in punishment-resistant rats, but when they selectively stimulated the pre-limbic area, these same rats reduced cocaine responses when there was the possibility of punishment.
This is compatible with other research, wherein compulsivity has been linked to deficits in regulatory brain areas, such as the orbitofrontal cortex, pre-frontal cortices, and caudate, areas that are important for deliberative decision making and for inhibiting basic drives and impulses when inappropriate. Generally, reduced functionality in these regulatory regions and increased control in areas important for driving habits, like the dorsal striatum, lead to more compulsive drug seeking.
The implications for people are that compromised regulatory regions could exist for a percentage of people that become addicted (~20%) after extensive use, and behaviors are driven by brain regions associated with habit. Therefore, increasing the functionality of the regulatory brain areas might help decrease drug use. Sometimes this is difficult for long-time users, whose brains have received considerable damage, but stopping the use of drugs can help heal the brain, and there are medical and behavioral interventions that might help.
Even though substance-dependent people face many opportunities to quit and many consequences for not quitting, they may continue to use. At least, as the theory goes, a subset of users will continue to use. The idea is that neurobiology plays a part in maintaining harmful drug use, and that changing neurobiology with medical and/or behavioral interventions will help reduce drug use.
Theory 2: Opponent Process
In stories of drug addiction, you’ll often hear that a person uses in order to avoid the horrible withdrawal period that comes after use, and it becomes a cycle.
But it would be more accurate to say that addiction is more like a downward spiral where each stage is exaggerated, and the cycles become more and more constricted over time.
In addiction science, this is called the opponent-process theory, in which it is thought that individuals abuse drugs due to changes in homeostatic set points. In the diagram below, process A is the pleasurable experience from the drug, but this effect is diminished shortly after use by the B process. The B process is the body’s attempt to restore balance (homeostasis). The A process is more immediately in effect, while the B process develops more slowly and lasts longer, even after the A process has stopped. This results in the after-effects (peak of B), causing withdrawal.
Over time and with enough drug use, the B process becomes larger, as the body and brain adapt to the continued use of drugs. This results in smaller peaks of A (less effective drugs) and larger peaks of B (harsher and longer withdrawal period). The diagram above is a linear representation of what I mean by the downward spiral effect.
Biologically, this effect is thought to be caused by a dampening of dopaminergic (and opiate) signaling and increased stress-inducing neuropeptides (e.g., corticotropin releasing factor, think cortisol).
Offsetting this effect is done by either using more (and more) drugs, or by reducing the amount of stress-causing effects in the body. There are medications available to help reduce the severity of withdrawal for nicotine, opioids, and alcohol, but there is nothing yet for cocaine and other stimulants.
Interestingly, the two theories of compulsivity and opponent process may be thought of as two sides of the same coin. The compulsivity theory suggests more automatic behavior, driven by subconscious processes, whereas avoiding withdrawal (opponent process) is more of a deliberative choice. Of course, it could be argued that avoiding withdrawal, too, is also a type of automatic behavior, an over-exaggerated reflex of sorts. A key take-away is that one person may use more because of compulsivity and another may use more because of avoiding withdrawal.
Even though I’ve only covered two theories, so far, this idea of different mechanisms driving addictive behaviors in different people is eventually where I want to take this series. Various underlying mechanisms means that treatment needs to be personalized, and to complicate matters even more, sometimes it’s a personal choice. For example, I have a friend who is adamant that the withdrawal process is key to long-term sobriety, even though evidence with nicotine replacement and methadone maintenance suggests that reducing withdrawal effects improves treatment efficacy for nicotine and opioid addiction, respectively. I am, generally, of the opinion that if people know that withdrawal isn’t so bad, it will only increase the number of people trying to quit, but of course, the argument could go the other way, too.
I’ll introduce more theories (check out part 2) and talk more about personalized treatment and consistency in the addiction treatment field in future posts.
Paul Regier has a PhD in neuroscience and studies addiction at UPenn. Follow him on Medium and on Twitter @Form_Tell. Feel free to correct him when you think he’s wrong and please respond with your ideas and feedback.