Cobbers on the Brain

People with drug addiction not only suffer from the effects of the drug, but also a negative connotation that surrounds addiction. If I were to ask you to imagine someone who suffers from drug addiction, you, like many other people, would create the image of a “junkie” in your mind. This is part of the problem with addiction, one of many problems that will be discussed later. Many people believe that addiction is a choice; little do they know that drugs have the ability to rewire a brain, forcing people to seek those drugs above all else.

The Reward System

Drugs affect the brain’s reward system. Dopamine is the main neurotransmitter involved in this reward and motivation pathway. Drugs cause dopamine release, creating a pleasurable feeling. There are two dopamine receptors that tie in with the addiction dilemma. The first dopamine receptor, D1, is involved with direct activation of the reward pathway, and it has a lower binding affinity for dopamine. The other receptor, D2, is involved with indirect punishment and inhibition of the pathway; it also has a higher binding affinity for dopamine.

Certain brain regions are involved in this reward pathway. In the addiction story, the two major regions are the nucleus accumbens (NAc) and the ventral tegmental area (VTA). The VTA is the site of neurons that produce dopamine, which tells the individual whether a stimulus (drug of abuse) is rewarding or aversive¹. VTA neurons target the NAc, which causes the activation of D1 and D2 receptors creating the rewarding effects of drugs or natural rewards. Under normal conditions, the reward pathway controls an individual’s responses to natural rewards, such as food, sex, and social interactions¹. This pathway is important in determining an individual’s motivation and their incentive drive¹. Stimulation of the reward pathway tells the individual to repeat what it just did to get that reward¹.

But, drug induced stimulation of this pathway could lead to addiction. The VTA-NAc pathway is activated with each drug use². Drugs, such as opiates, bind to receptors and send signals to dopamine terminals to release more dopamine². This dopamine release, then, creates a pleasurable feeling that causes individuals to become addicted to that drug, seeking it out over and over for that pleasurable feeling. Repeated use of drugs cause an over-activation of dopamine and stimulation of the receptors involved, thus impairing the regulatory responses for which the brain is responsible². If the regulatory response is impaired, then it is nearly impossible to stop using the drugs.

Therefore, drug addiction should not be viewed as a repeated choice. You are your brain, and your brain is telling you to seek those drugs for the pleasurable feeling. Each drug has a different mechanism, but they all increase the activity of the reward pathway by increasing dopamine transmission. Drug addiction is truly a disease of the brain, not a choice.

1. http://neuroscience.mssm.edu/nestler/brainRewardpathways.html
2. https://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-iii-action-heroin-morphine/3-morphine-binding-within-reward

“Don’t Do Drugs”

The first time I heard this message I was in kindergarten, and I didn’t even know what drugs were. As I climbed up the elementary school ladder, I slowly began to understand the “basics” of drugs. I eventually came to the conclusion that there were two different “types” of drugs in the world:

• The “good” drugs that you take when you are sick to make you feel better
  AND
• The “bad” drugs that you take if you want to ruin your life

That’s what I was told.

As a child, this thought becomes ingrained in your mind, and how can it not? From the haunting textbook images of individuals before and after taking “bad” drugs to the countless warnings you hear from concerned parents, teachers, and the media, it is no surprise that you begin to develop an image of what a stereotypical drug addict looks like:

You think to yourself…

• Drug addicts have:
  • Rotten/Missing Teeth
  • Wrinkled/Scabbed Skin
  • Dry/Damaged Hair
• Drug addicts are:
  • Criminals
  • Lazy/Unproductive
  • Liars/Manipulators

You begin to tell yourself that there’s no way that you would ever become a drug addict. You’re not “that kind of person.” That’s where you’re wrong. 

Anyone can be a drug addict .

Individuals develop this preconceived notion that they could never become a drug addict, and that even if they try a drug, just once, they won’t get hooked.

The fact of the matter is, no one knows how drugs of abuse will affect them until they try them, and for many, after just once, it’s too late. In fact, one’s genetic makeup accounts for 50% of their risk of becoming an addict. The other 50% chance is the result of one’s environment, specifically whether or not one exposes themselves to drugs of abuse.

So why are drugs so hard to quit?

They change the way your brain works. 

The brain has a specific system that drugs of abuse “manipulate”: The Mesolimbic Pathway

• This pathway is involved in the feelings of reward that often accompany naturally rewarding things such as food, sex, and caffeine.
• This reward comes in the form of the “feel-good” neurotransmitter known as dopamine.
• Dopamine originates in cell bodies within the ventral tegmental area (VTA) of the brain. The axons that release dopamine leave the VTA and terminate in a separate area of the brain known as the nucleus accumbens (NAc).
• In addition to the NAc, dopaminergic axons can also be found in the hippocampus (involved in memory), the amygdala (involved in emotional responses), and the prefrontal cortex (involved in cognitive functioning).

• When an individual experiences something rewarding, the concentration of dopamine within these brain regions increases, and they immediately experience a sense euphoria.
• Drugs of abuse in particular have a way of making this euphoric “high” last for a prolonged period of time.
  • For example, cocaine blocks the re-uptake of dopamine so that it is able to stimulate the reward system for a longer period of time, inducing a more intense “high”.
• Drugs of abuse increase the reward to a certain extent:
  • Whenever a drug of abuse is taken, molecules known as dynorphins bind to specialized receptors in the brain known as kappa opioid receptors.

    

    • The binding of dynorphins to these receptors inhibits the release of dopamine into the reward pathway.
      • Therefore, after repeated exposure to the drug of choice, less and less dopamine is released into the reward pathway, and the “high” decreases.
        • The individual’s brain does not understand this, however, as it has become re-wired to expect the “high” that it has previously experienced.

          

        • The individual will begin to crave the drug of abuse intensely, and will go through withdrawal symptoms if it is not administered.
          • To satisfy the brain, the individual will need to take more of the drug of choice to deliver the same amount of reward….

            ……… and there you have it, you’ve become addicted.

So what’s the take home message?

It’s exactly what you’ve been hearing since you were in kindergarten:

Don’t do drugs.

• Individuals often do not know how drugs will affect them, until it’s too late.
  • No one is “immune” to becoming a drug addict.
  • And once you’re addicted your brain will change itself in a way to ensure that you’ll stay hooked.
    • But, quitting isn’t impossible!

The road to recovery isn’t an easy one, but it is possible. 

There are many resources that you can use to help yourself or a loved one on the road to recovery:

• Substance Abuse and Mental Health Services Association
  • https://www.samhsa.gov/find-help/national-helpline
• American Addiction Centers
  • This link provides a list of local rehabilitation and treatment services by state
    • https://drugabuse.com/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920543/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681/

What is Drug Addiction:

Drug addiction is a medical condition characterized by the compulsive seeking and taking of drugs for rewarding stimulus despite adverse consequences or loss of control over drug use. Drug addiction occurs due to long-lasting changes that occur in the brain from prolonged use, but not everyone is affected in the same way. Genetics account for 50% of an individual’s variability in addiction vulnerability, while the other 50% comes from a wide array of environmental factors. Once an individual becomes addicted, it can be extremely difficult to stop, and the chance of relapse will continue to be present.

Why Are These Drugs So Addictive?

Drugs can be so addictive because they hack the reward pathway in the brain. The reward pathway is a pathway in the brain that enhances certain behaviors that are necessary for survival, such as eating, drinking, sex, and social interaction. Drugs turn these survival needs into drug needs.

The reward pathway involves the transmission of dopamine. Dopamine is release when an individual engages in pleasurable activities and binds to an adjacent neuron in the brain. The binding of dopamine to a dopamine receptor is what gives a pleasurable feeling or rewarding effect, making you want to continue to do that activity. Eventually this dopamine is taken back into the neuron by a molecule called dopamine transporter.

Drugs abuse this system by increasing the amount of dopamine present in the synaptic cleft. Some drug increase the number of action potentials which leads to increased dopamine release, other drugs increase dopamine without the action potential, and some block the reuptake of the dopamine back into the neuron. Whatever the method, they all work to keep the concentration of dopamine high in the synaptic cleft for an extended period, causing the prolonged and intense euphoria described by drug use. These repeated exposures to dopamine surges desensitize the reward system which makes those normal, necessary action for survival no longer a priority as drugs are the only rewarding thing. With continued drug exposure, the reward system continues to become more and more desensitized requiring more drug for the same effect. This is what can eventually lead to overdose.

What Can You Do?

It is important that we remember that individual who deal with addiction are struggling with a neurological illness that so far appears to be irreversible. We as a society need to learn to treat this as any other neurological disease and help those who are struggling as this is far more than just a choice as the brain structure is literally altered. This is why it is important that we avoid street drugs with all costs and take medically prescribed drugs with extreme caution.

The opioid epidemic has become an enormous issue nationally. In the United States, a public health emergency was declared in 2017 in relation to the opioid crisis. Based on data from 2016 and 2017, more than 130 people die each day from opioids, 11.4 million people have abused prescription opioids, and 42,249 people have died from opioid overdose. This issue is harming individuals all over the country and has everlasting effects. In order to combat this issue, there must be more knowledge, less stigma, and a greater understanding of addiction as a whole in order to fight this crisis.

There are many misconceptions about addiction, specifically opioid addiction, including “Why don’t they just quit?” or “Why do something that causes you so much harm when you could just choose not to?”. Even though it may seem easy to choose a life without opioids to an outsider, it becomes less and less of a choice when looking at the brain of an addicted individual. Addiction vulnerability of each individual is 50% accounted for by genetic factors, made up of hundred of genetic variations. The remaining 50% is accounted for by various combinations of environmental factors, causing an individual to be more vulnerable to addiction. Some risk factors that contribute to opioid addiction are:

• “gateway” drugs such as prescription medication, marijuana, alcohol, and nicotine
• anxiety or depression
• other psychiatric disorders
• exposure to abuse or trauma
• family or friends addicted to drugs
• access to addictive drugs
• starting substance abuse at a young age
• poverty

There are many reasons why an individual may be more predisposed to becoming an addict. In addition, there are specific changes in the brain that occur in order to cause specific symptoms of addiction to occur if an addicted individual tries to “quit”, such as craving, withdrawal, and relapse.

These changes in the brain include changes to certain nerve cells due to drug exposure, causing the neurons to respond differently to drugs, changes that occur in response to addiction, such as altered gene transcription, synaptic plasticity, and neurotrophic mechanisms, and changes in key neural substrates or brain regions of behavioral memory. These alterations cause caring and relapse as there are differences in the memory circuits due to addictive drugs.

Since it is clear that addiction is not necessarily a “choice”, the U.S. population as a whole must become more aware of the opioid crisis in order to begin finding solutions.  In order to target the opioid epidemic, there must be a greater awareness of how addiction occurs, what is happening in the brains of addicted individuals, and how to target therapies and treatments to each specific individual. Stated in the facts above, the opioid epidemic is affecting millions all over the nation and must be addressed. By understanding the factors that play in to addiction and gaining knowledge about each addict’s personal situation, treatments and solutions may become more accessible.

https://www.centeronaddiction.org/addiction/addiction-risk-factors
https://www.hhs.gov/opioids/about-the-epidemic/index.html

Addiction is an issue continuously growing worldwide. This disease is most commonly associated with drug use but it can also entail other activities that can have addictive characteristics as well, such as social media, video games, gambling and many other things of that nature. When one becomes addicted to drugs or any activity, the reward pathways in their brain are being altered which is when the addiction sets in.

What’s changing in the brain?

In a person that is not suffering from addiction, the reward pathways reinforce behaviors that are beneficial and necessary for survival (eating, drinking, sex and social interactions). Drugs that are abused or other sources of addiction alter this system so that using the drug becomes a necessary behavior. In the regular function of this pathway, dopamine is transmitted from the ventral tegmental area (VTA) of the midbrain to the limbic system and pre-frontal cortex where it binds to dopamine receptors to give the pleasurable or rewarding effect of these necessary behaviors.

An increase in dopamine levels is what is common to all forms of addiction.  This continuous overstimulation is what causes the prolonged and stronger sensation of euphoria. The constant exposure to this higher level of dopamine desensitizes the reward pathway which then becomes no longer sensitive to the everyday stimuli leading to the drug being the only stimulus to create this feeling of pleasure. The drug then eventually becomes less effective in creating this pleasure feeling and higher doses are needed to achieve the same feeling which can lead to overdose.

D1 and D2 dopamine receptors are affected in this disease. These rapid increases of dopamine activate the reward pathway through the D1 receptors which amplifies the reward pathway. On the other hand, this dopamine surge also activates the D2 receptors which inhibits the ‘punishment’ pathway. Therefore, this doubles the effect by producing reward and also removing punishment.

Due to these changes in the brain, even one time using an addictive substance  can lead to the development of addiction. When the brain changes, it is re-wired to crave these addictive things as a necessity like it should crave food, water and other stimuli required for survival. It is because of this it is a disease, not a decision to continue using these drugs of abuse. Additionally, addicts are likely to relapse because the pathways in their brain have been changed, so re-exposure to the substance of abuse could lead them back down that path of addiction.

Risk Factors

Social and environmental pressures are very common surrounding drug use. It is seen on TV and in movies and even at school for some adolescents . People can become exposed to these substances of abuse through pressure from peers, being bullied and feeling lonely. However, genetic factors, depression, lack of confidence and other illnesses can increase the risk of developing an addiction. About 10% of people who experiment with drugs become addicted at some point. Therefore, it is important to know and recognize the risk factors, because it is so easy to become hooked even if a person only tries something once or twice.

How can addiction be treated?

Addiction is usually treated with a combination of medication and behavioral therapies. There is also a new medical device called the NSS-2-Bridge which is a device that gets placed behind the ear and sends electrical pulses to stimulate certain nerves to help reduce opioid withdrawal symptoms.

Methadone– an opioid agonist which impacts the same type of neurotransmitter and therefore stimulates it in the same way an opioid drug would, but in a more controlled safer way. This is used in detoxifying a person suffering from addiction.

Naltrexone-an opioid antagonist which specifically blocks opioids at their receptors and used in patients who are already detoxified. This medication can also be used to treat alcohol addiction because it blocks the opioid receptors in the reward pathway which helps suppress the craving to drink.

Schizophrenia is commonly portrayed in media as its more severe cases, resulting in illusions of the individual leading to them hearing and seeing things that aren’t reality. The range of Schizophrenia cases vary, however I found the developmental factors of Schizophrenia is rather intriguing. The potential implications of other environmental factors on an individual that could result as an increased risk for developing Schizophrenia. As with most cases individuals see onset of Schizophrenia in their early adulthood. During this period there is an increased amount of the many factors that could result in the potential for transcription of Schizophrenic genetic factors. Some of these factors being stress and substance abuse. These factors act on epigenetic regulation of genes, this results from activation/regulation of genes via environmental factors. The degree of these factors can also be present during conception, for example individuals with older fathers are at a higher risk for Schizophrenia, other pregnancy complications can also increase chances for development of Schizophrenia.

I find this interesting, as for most parents, they attempt to control the environment to the best of their extent. However based on these factors, this increases the amount of parameters out of ones control. The results of epigenetic factors create in major implications for development of Schizophrenia and other major impacts on mental developmental processes. The encoding of various hidden environmentally triggered life changing genes is a startling thought, as there are so many factors that we are unable to control in our lives. There are some factors that can be limited or omitted completely, avoiding substance abuse, and finding outlets for stress are factors that can be directly controlled, thus decreasing potential risk for Schizophrenia.

A Developmental Issue?

While majority of Schizophrenia causation is a mystery to current scientists, the most prominent theory is one of brain development. People with schizophrenia have statistically shown delays in cognitive milestones, have smaller brain size, and are below the general population in cognitive ability. In addition, the majority of schizophrenia’s environmental factors interfere with proper brain development. These can include prenatal infection, prenatal famine, pre-eclampsia, infant infection, low birth weight, and even maternal depression.

Fig 1.  A chart displaying numerous types of environmental factors listed for schizophrenia

Biological Support:

With a new emphasis on brain development, scientists found a strong correlation between decreased Wnt pathway activity and schizophrenia. When active, the Wnt pathway increases cellular levels of a molecule called beta-catenin which activates genes critical for development. When the pathway is inactive, the body naturally creates a destruction complex that breaks down beta-catenin, reducing its concentration, and preventing developmental genes from being expressed. In conclusion, it is important for this pathway to be active during critical developmental periods.

Fig 2. The left column shows the accumulation of beta-catenin when the Wnt pathway is active and the left column depicts the breakdown of beta-catenin when the pathway is inactive.

So What Went Wrong?

There is a molecule in everybody’s brain called Akt that aids in disassembling the natural destruction complex. This means that high levels of Akt increase levels of beta-catenin and result in increased expression of developmental genes. However, postpartum schizophrenic patients were found to have significantly lower levels of Akt in their brains. People with schizophrenia, therefore, have decreased Wnt pathway activity resulting in developmental problems. Most antipsychotics prescribed to schizophrenic patients target the Wnt pathway to alleviate symptoms. They usually increase the activity of Wnt signaling by increasing Akt activity, decreasing inhibitors of Akt, or directly inhibiting the destruction complex formation. While these drugs do a phenomenal job of treating the symptoms they still do not cure or reverse the permanent damage done to their brain.

Problems of Developmental Diseases:

The hard part about developmental disorders, like schizophrenia, is that majority of the damage is completed early in life. The devastation on the brain is then usually cemented after the individual reaches adulthood and brain development has ceased. This means that even if we did know how to treat schizophrenia, the treatment would have to be done early in a patient’s life to catch the developmental periods. This would have to lead to an intensive pre-natal screening and tests made specifically for diagnosing schizophrenia. Unfortunately, these options would probably be incredibly expensive which would prevent them from reaching their true at-risk population.

Another problem is that schizophrenia is usually not diagnosed until the late teens to early twenties making it impossible to catch the disease early. Many of schizophrenia’s positive symptoms, including delusions and hallucinations, can be attributed to normal childhood behavior like imaginary friends and make-believe games. Then in the teenage years, most parents and doctors correlate symptoms to hormone imbalances and puberty. There is also a lot of maturing and development that occurs during this time so many doctors don’t want to diagnose a patient prematurely.

Together these current problems make it hard to intervein early for schizophrenic patients. Future research should focus on finding early warning signs for the disease and its progression throughout early childhood and into adolescence. Majority of our research is only on adults since they are the only ones diagnosed, but much more could be learned from researching younger patients. Additionally, more extensive research must be found about the specific genes affected by decreased Akt activity.