Cobbers on the Brain

What is Addiction?

Addiction is a condition that is caused by an individual using a substance or behavior for the rewarding effects that compel them to continuously repeat the activity despite it being harmful to them. Common substances that induce addictive effects include opioids, cocaine, nicotine, and alcohol, and behaviors such as gambling and video games can be addictive. These substances and behaviors have been scientifically proven to activate pathways in the brain related to reward and reinforcement, and most of them involve the neurotransmitter dopamine. Addiction also affects the brain’s executive functions, so some people who suffer from the disorder may not realize that they are harming themselves or others around them.

The cause of addiction stems from the first initial use of the substance or behavior, but there are many other factors that contribute to the continual use and eventual addiction. Genetic and biological factors contribute to the susceptibility of individuals to the condition, but social, psychological, and environmental factors have been shown to be the most powerful contributors. As many doctors like to say, with any disease, genetics loads the gun, but environment and behaviors pull the trigger.

A Link Between Stress and Addiction

There is an interesting link between stress and addiction. Stress is a known risk factor of addiction along with risk of relapse. The correlation has been assumed for decades, and has recently been proven scientifically through sophisticated human brain imaging and cross examination with other laboratory methods. These studies have shown a correlation between stress and craving and their link to the brain regions responsible for reward and addiction risk.

Stress – The Good and the Bad

Stress is a very broad term that needs some defining before we dive deeper into the link between it and addiction. Stress is defined as a process involving perception and response to a harmful or challenging event or stimulus. Stress responses are meant to be an adaptive response to regain homeostasis. Examples of stressors include loss of relationship, death of a family member, food deprivation, insomnia, and binge use of psychoactive drugs.

Stress is mostly associated with bad and harmful situations, there is also “good stress.” Good stress refers to stimuli that are moderately difficult to deal with, and if the individual handles the situation well, they generate a feeling of mastery, and are usually perceived as pleasurable. However, as intensity of the stimuli increases and is prolonged, the less control an individual has on the situation, and usually the sense of accomplishment and mastery decreases. This can increase the stress response, which as we will see, increases the susceptibility for addiction or relapse.

Three Groups at Risk

The most widely accepted and common association between stress and addiction is that drugs are used as a coping strategy to deal with stress or to self-medicate. There is sufficient evidence to this theory, and it can be categorized into three types. The first type involves adolescents experiencing negative life events such as loss of a parent, parental divorce, or a single parent family. The second type involves trauma and maltreatment, such as childhood sexual and physical abuse. The third type includes lifetime exposure to stressors and the impact is has cumulatively. These stressors are mostly unpredictable events, such as victims of gun violence, loss of parent, or natural disaster. Unsurprisingly, it has been found that the more of these uncontrollable events an individual experiences in their life, the more likely they are to become addicted to a substance or relapse, despite factors such as race, gender, or family history of drug abuse.

Brain Pathway Disfunction

Scientists have also studied neurobiological mechanisms explaining the effect stress has on addiction. Drugs of abuse such as alcohol, nicotine, and opioids all activate dopamine pathways, which is associated with higher craving. Additionally, stress exposure increases dopamine release. Because both stress and drug abuse both activate similar brain pathways, they both result in changes to neuronal synapses, enhancing the effect of each.

A Vicious Cycle

The link between stress and addiction creates a vicious cycle because they both feed into each other. The more stressed someone is, the more likely they are to abuse drugs, and drug abuse itself creates a very stressful environment for the body. They best way to avoid addiction is simply to never try drugs in the first place, but that can be easier said than done with social pressures and acceptance of drug use in pop culture. In our increasingly fast paced world, stress is tough to avoid, so staying stress and addiction free really comes down to making healthy decisions in all aspects of life.

Images:

https://www.google.com/search?safe=off&biw=1082&bih=565&tbm=isch&sa=1&ei=WXrrW-uCJY6ksAXRxqmYAw&q=stress+and+addiction&oq=stress+and+addiction&gs_l=img.3..0j0i24l4.236183.238454..238624…0.0..1.163.1953.14j6……1….1..gws-wiz-img…….0i67j0i8i30.W3_prnFKycU#imgrc=LojOaK9Nh8DJbM:

https://www.google.com/search?q=dopamine+and+addiction&safe=off&source=lnms&tbm=isch&sa=X&ved=0ahUKEwiz7e7a3dLeAhVxmK0KHY4WC-cQ_AUIFCgC&biw=1082&bih=614#imgrc=eo551pZVRyzTIM:

At the end of class the other day a friend was telling me about her time working in an ER in which she helped many overdose patients. Almost all of them would say something along the lines of “it wasn’t supposed to do this.. It normally doesn’t do this..” After many days receiving these answers she finally asked one of the patients, “so if it wasn’t supposed to do this, what is it supposed to do?” “Help me forget.”

Humans turn to vices daily, using them to help mitigate our lives. These can be healthy or harmful depending on the vice and reasoning behind it. Addiction can stem from any activity that generates a pleasure response in your brain. This is called the reward pathway. It involves the release and transmission of dopamine from the ventral tegmental area (VTA) to the limbic system and frontal cortex where it binds to its receptors. Once bound to the receptor this reward takes place teaching us the actions and situations surrounding the stimulus. Naturally, this pathway enhances certain behaviors necessary for survival such as eating, drinking, sex and social interaction.

Drugs however don’t play by the rules. They take over the system, not only increasing the levels of dopamine but physically changing the brain. Depending on the drug, different areas are affected in different ways primarily by changing the density of receptors (decreasing D2 receptors), blocking re-uptake of dopamine, or triggering the release of excess dopamine. They all work in the same way, increase the dopamine present to therefore prolong the euphoria. This has now changed the behaviors from survival to drugs. Every need is now encompassed by and inferior to the need for drugs.

There is a great lack of self control in drug addiction. Even when the drug is no longer pleasurable and enjoyable the abusers must continue. This lack of self control stems from the reduced concentration of D2 receptors in the brain which regulate the frontal areas responsible for self control. It becomes compulsive and impulsive. This is not the same as an addiction to your phone where you still truly have control over the actions. They truly have lost all control, yet as a society we act as though they are still fully functioning and can stop at the drop of a hat. We have unrealistic expectations for those suffering from abuse. As a society we must change the narrative surrounding this, likely needing to categorize addiction as a mental illness rather than just a personal problem. It not only destroys them but those around them as they slowly lose the one they love to drugs.

When people first hear the term “gateway drug” most people probably think of marijuana, but other common examples include, alcohol, nicotine, and prescription drugs. These are all substances that can increase your probability of further drug use.

Most people do not wake up in the morning and impulsively decide to try heroin, cocaine or other hard drugs. There is a gradual exposure to addictive substances, people, and environments which lead to heavy drug use and addiction. A study between 2001 and 2004 said that marijuana use significantly increases the chance of abusing opioids later in life. Another research article by Yale in 2012 also said that marijuana users are 2.5 times more likely to abuse prescription medicine. While marijuana use is generally accepted in society, it chemically sets up the brain for addiction later in life. I will further investigate the chemical changes in the brain by marijuana to highlight its gateway properties.

Fig. 1: A list of the three most common gateway drugs and additional risk factors for addition

Background on Addiction: Reward Pathway

All drugs are known to affect the brain’s natural reward pathway. This circuit begins in the ventral tegmentum area (VTA) of the midbrain and projects to cells of the nucleus accumbens (NAc) where the neurotransmitter dopamine is released (Fig. 2). An Increased amount of dopamine in the NAc is associated with the euphoria like feeling you get when you do pleasurable things like eating dessert, having sex, or taking drugs. Evolutionarily, the pathway’s purpose is to reinforce behaviors that are beneficial to survival. However, drugs overstimulate and abuse this circuit causing long-term changes in the brain including tolerance and withdrawal. There also is the formation of incredibly strong memories that make it hard for drug users to disassociate familiar environments and people from the urge to use drugs.

Fig. 2: An overview of the Reward Pathway

Gateway Drugs and their Role in Addiction

Marijuana, like every other addictive drug, increases the amount of dopamine in the NAc and activates the reward pathway. However, chronic use of marijuana can actually reduce the size of cells in the VTA which leads to reduced function. The reward pathway is then impaired resulting in less dopamine in the NAc and therefore, tolerance of the drug. Tolerance is then a slippery slope because people start experimenting with higher doses or new drugs to feel the same euphoric effects. The shrinkage of VTA neurons is also directly related to their hyperexcitability when in the presence of morphine. The smaller cell size decreases the number of cell proteins required for inhibitory mechanisms resulting in hyperexcitability of the VTA and increased euphoria. These mechanisms explain why Marijuana users are more likely to abuse prescription painkillers or experiment with other drugs.

Now What?

While this blog focused on marijuana, other gateway drugs such as nicotine, alcohol and prescription drugs follow some of the same concepts to elicit drug abuse. This is a considerably important topic with the legalization of marijuana now in 10 states across America. It is crucial to know that while drugs like marijuana and nicotine are legal to use, it does not mean that they have no consequences. It is also is important to state that gateway drugs do not condemn a person to drug abuse since many factors like genetics and exposure very between people. As a final remark, it is crucial for the public to be aware of the risk factors associated with gateway drugs since they do generate long-term changes in the brain.

Sources:

http://webcache.googleusercontent.com/search?q=cache:http://www.castri.org/Cannabis-Opioids.pdf

Marijuana as a Gateway Drug: Facts vs. Policy

https://www.drugabuse.gov/news-events/nida-notes/2018/03/why-marijuana-displeases

It’s very easy for someone who does not have addiction issues to sit and wonder why addicts are unable to just stop doing their unhealthy behaviors. Why does he always eat junk food? Why is she constantly smoking crack? And a common one for me, why can’t Hannah stop shopping? The thing is, addictive behavior is an illness in the brain. While 50% of the risk for addiction comes from external factors, the other 50% is genetically transferred from generation to generation.

How does genetics play a part in addiction?
Transcription factors, such as CREB and ΔFosB, affect the brain’s reward regions (eg. VTA, the ventral tegmental area, and NAc, nucleus accumbens), which then potently influences behavioral memory.

Let’s talk transcription factors!

CREB
Considering the impact of drugs on the brain, stimulants and opioids activate CREB in many of the regions that are important for addiction and behavioral memory. CREB can be activated by cAMP, Ca2+, and growth factor pathways, but it is unknown which of the three that drugs play a role in the NAc. When CREB is activated by drugs in the NAc, it displays a negative feedback mechanism and CREB reduces the person’s sensitivity to the rewards of the drugs, which is called tolerance. The addict, still searching for the high they once had, has a negative emotional state when they experience withdrawal. Why does CREB do this to our behavioral memory? CREB acts on the two different types of NAc medium spiny neurons, primarily the D1 dopamine receptor. When the D1 dopamine receptor becomes activated, there is an increased influx of glutamate. The overwhelming response of glutamate arriving makes it difficult for any type of signal to be processed fully and completely, giving the drug users a euphoric high that they’re looking for in order to ignore all the problems in the world. And this makes them feel good! Why would they want to stop that?

ΔFosB
When using drugs, all Fos transcription factors are induced. However, ΔFosB is a little special. ΔFosB is a shortened version of the FosB gene. Because it has unusual stability, it can accumulate over repeated drug use. Its stability is also what allows for ΔFosB to remain in the body for weeks after the person has stopped using drugs. Like CREB, ΔFosB is selective for D1-type NAc neurons, which increases a person’s sensitivity to not only drugs, but also any type of rewards. The roles of ΔFosB and CREB split when it comes to dynorphins. Dynorphins are neuropeptides that bind to kappa opioid receptors found within the amygdala, hippocampus, and hypothalamus. Because they are in these regions, it’s valid to assume they play a part in memory, emotions, and learning. Dynorphins are believed to activate neural pathways that can then change neural plasticity. Repeated activation of this pathway can lead to social isolation and aversion towards people. While CREB induces dynorphins, ΔFosB suppresses them, which contributes to ΔFosB’s pro-reward effects. This ALSO is why drugs are so addictive.

However, it isn’t just drugs that are causing this process leading to addiction to happen. Anything that stimulates the D1 dopamine receptors are at potential risk to forming an addiction.

It’s hard to “just quit”. It is a process of rewiring the brain to unravel addictive behaviors. With these two genetic factors, it’s clear to see that addiction is not a choice. It is important to reserve biases about those with addiction and rather be a safe place in which an addict can express their thoughts and feelings.