Understanding The Epigenetics of Addiction

Addiction has been a pervasive problem that has plagued human history since we began recording it. Addiction is an issue we are still grappling with, even in developed nations. In the United States, nearly 21 million people have one or more addictions but only 10% of them receive treatment. [1] This costs the US economy north of $600 billion annually and has resulted in 700,000 deaths from overdose between 1999 and 2017.¹ These are abysmal numbers. I will try to shed some light on what some of the causes of addiction are, as well as a brief overview of the neurochemistry of addiction.

Neurochemistry of Addiction

Before we try tackling the chemistry, lets introduce the key brain structure in addiction. Arguably, the most important part of the brain in addiction is the nucleus accumbens (NAc). This is the area of the brain that all drugs of abuse act on in some way.[2] All addictive drugs cause an burst of dopamine (DA) release in the NAc. ⁴ While this is the structure that will be referenced in this article, it should be known that many more areas of the brain play a role in addiction. A comprehensive review can be found here.[3]

Now to introduce one of the chemical messengers in addiction: FosB. FosB has been found to be expressed after exposure to nearly all drugs of abuse. ⁴ After repeated drug exposure, the levels of FosB only increase in the brain. As the levels continue to climb, a person’s sensitivity to natural rewards and drugs increases (as does the likely hood of voluntarily consuming more drugs). ⁴ FosB causes epigenetic changes in the brain, which increase the likelihood that someone will do drugs. This is one of the causes for the vicious cycle of drug abuse.

Causes of Addiction—Epigenetics

I will not try and explain every cause of addiction in this post for two reasons:

1. 1. It will be a very long list
   2. We don’t know what all of the causes are

However, I will provide a brief overview so we can better understand the causes of addiction, both social and molecular. A recent literature review finds 50% of variance in addiction is dues to genetic variation, while the other 50% is due to environmental variance[4]  First, lets explore the genetic variation, but to do this we have to understand some basic epigenetics.

One of the most fundamental aspects of epigenetics, is the ability of a histone protein to become acetylated (i.e. stick a acetyl group onto a histone). Normally, the histone protein tightly binds DNA and prevents it’s transcription into mRNA. However, when the histone protein is acetylated, it loosens up and allows the DNA to be transcribed (see the following image for a visual).[5]

In addiction, histone acetylation occurs after acute exposure to stimulants like cocaine or amphetamine (meth). [6] Interestingly, these acetylations occur near promoters of c-fos and fosB in the nucleus accumbens (NAc). Earlier in this article, we mentioned how fosB  is one of the molecular causes of promoting addiction. Now we know where it is coming from and why.

Conclusion

Drug addiction is still a problem in modern society. We have seen that epigenetic changes occur in the brain after exposure to drugs of abuse. This causes mental and physical changes to the person that increases their likelihood of continuing to consume drugs. Hopefully through studying the science behind what causes addiction, we can develop new treatments and improve on prevention strategies.

Sources

[1] https://www.addictioncenter.com/addiction/addiction-statistics/

[2] Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C., Roberts-Wolfe, D., & Kalivas, P. W. (2016). The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacological reviews, 68(3), 816–871. https://doi.org/10.1124/pr.116.012484

[3] https://www.brainfacts.org/-/media/Brainfacts2/In-the-Lab/Animals-in-Research/Brain-Illustration-Reward.jpg?h=367&iar=0&w=650&hash=F19DD0579346B918C0126E49A1FB7B4D32967584

[4] Reul, J. M. (2014). Making memories of stressful events: A journey along epigenetic, gene transcription, and signaling pathways. Frontiers in Psychiatry, 5. https://doi.org/10.3389/fpsyt.2014.00005

[5] https://www.google.com/url?sa=i&url=https%3A%2F%2Ftheory.labster.com%2Fhistone-acetylation%2F&psig=AOvVaw3ybLsvI2s_wjYfMn32Uz1y&ust=1634161272580000&source=images&cd=vfe&ved=0CAsQjRxqFwoTCPjCv6TrxfMCFQAAAAAdAAAAABAT

[6] Renthal, W., & Nestler, E. J. (2009). Histone acetylation in drug addiction. Seminars in cell & developmental biology, 20(4), 387–394. https://doi.org/10.1016/j.semcdb.2009.01.005

Migraines

Migraines are likely to occur following a concussion for a number of reasons. Whether the concussion was due to an impact or non-impact injury, there has been damage to the brain. Following a traumatic brain injury, the brain is hypersensitive due to the ionic flux and glutamate release. Immediately after an injury to the brain, there is a large release of neurotransmitters and ions. Glutamate binds to NMDA receptors and an increased amount of it will lead to more depolarization in the neurons. Potassium efflux and calcium influx occur which shifts membrane potential. These changes in physiology cause issues for various other cell functions. Figure 1 describes the different types of headaches that can occur following a concussion. The type of headache someone is experiencing can help physicians determine what areas of the brain have been damaged. 

Figure 1: A few of the different types of headaches someone could experience following a concussion. 

Vulnerability to Further Injury 

The sodium-potassium pump must now work harder in order to restore membrane potentials. The Na+/K+ requires ATP, so the body will divert more energy to the damaged brain areas. An increased amount of ATP triggers an increase in glucose metabolism. This increased glucose metabolism will not last for long; there is often a state of impaired metabolism following hyperglycolysis. 

Cerebral blood flow is often reduced following a concussion. The increased demand for ATP along with the decreased blood flow causes further issues in the brain. Energy reserves in the brain are depleted because of the overall lack of energy, oxygen, and mitochondrial function. Metabolic pathways are altered after a concussion and take time to recover. It is unknown how much time is needed for the brain to fully recover following a TBI, but there is a period of vulnerability after it occurs. The altered state of the brain takes time to recover. It is possible for another injury to happen after a concussion and has the potential to cause even worse damage. Figure 2 shows some common areas that are affected after a TBI and what their primary functions are. 

Figure 2: Areas of the brain often damaged during a TBI and what processes they are responsible for. 

Slowed/Altered Cognition 

Damage to the brain following a concussion can lead to a wide variety of symptoms. During a TBI, there is damage to axons. This can occur on a microscale and cause disruption of action potential transport, disconnection, and microhemorrhages. MRI has been used to measure how white matter changes following a concussion. Researchers are able to gain insight into how much axonal damage has occurred by observing white matter. Studies have shown that decreased or damaged white matter after a TBI can lead to a myriad of symptoms such as depression, PTSD, impaired memory, and behavioral changes. 

The parts of the brain responsible for judgment, problem-solving, and arousal are often damaged during a concussion. These physiological changes help explain why many people experience cognitive alterations. People can have increased fear responses and higher levels of depression following a TBI. This video provides a good explanation of common emotional symptoms after a concussion and how to help someone experiencing these changes. 

What is a concussion?

Concussions are also known as mild traumatic brain injuries (TBI). Concussions are an injury to the brain that is caused by a blow or jolt to the head. They can also be caused by a blow to the body that causes the head to move/ shift quickly which in turn causes the brain to shift quickly inside the skull. Due to this shift, there is a disruption to normal brain functioning. The main point is that during the rapid shifting of the brain, neurons are injured due to them being stretched and can potentially be broken. Concussions are more likely to occur in females, as they have smaller, more breakable nerve fibers. 

What happens to the brain during a concussion (mild TBI)? 

• Ionic flux 
  • • Potassium going out, sodium going in → membrane permeability starts to have
      problems due to the mild TBI 
    • Membrane permeability becomes “leaky”: notice images to the right

   

   

• Glutamate release → NMDA receptor 
  • • Excess glutamate release means more glutamate binding to its receptors 

   

• ATP usage increases via excess glycolysis 
  • Injuries to the neurons causes chemicals to leak in and out of the cells
  • When the membrane permeability is “leaky” → attempting to reestablish all the proper concentration gradients 
  • The chemical leaks destabilize the neurons away from their typical state → Large amounts of ATP are required in order to reestablish the proper concentrations gradients 
• Energy crisis 
  • Mitochondria is stressed out and overworked due to dealing with all of the excess calcium so ATP is diminished 
    • ROS increases 
  • Diminished blood flow to this part of the brain due to energy crisis 
• Proteasome activation
  • Calcium also increases proteasome activation → proteasomes help to break down proteins 
    • When cell in a stressed place, it begins the breakdown of things that should not be broken down to begin with
  • There is cytoskeletal damage 
  • Inflammation 
    • Upregulation of cytokines trying to fix some of the damage 
  • Axonal dysfunction

Symptoms of concussion:

• Migraine
• Decreased reaction time 
• Slow cognition 
• Memory impairment 
• vulnerability to repeated injury 
• Hippocampus and cerebral decrease 
• Changes in protein degradation 
• Chronic atrophy

Treatment options: 

• Relative rest 
  • Physical rest; recommended for two days after concussion
  • Mental rest; recommended for two days after concussion 
•  Complete rest 
  • It is important to note that complete rest (such as very low stimulation areas; dark room with little to no brain stimulation) is not recommended
• Avoid physical activity
• When returning to complete activity 
  • Add activities back into daily life routine gradually 
• Medications
  • Tylenol is recommended during concussions for any pain relief necessary 
  • Ibuprofen and Advil are not advised as they do increase bleeding 

Sources: 

Giza, C. C., & Hovda, D. A. (2014). The New Neurometabolic Cascade of Concussion. Congress of Neurological Surgeons. 

Mayo Foundation for Medical Education and Research. (2020, February 22). Concussion. Mayo Clinic. Retrieved November 14, 2021, from https://www.mayoclinic.org/diseases-conditions/concussion/diagnosis-treatment/drc-203

Sandel , E. (Ed.). (n.d.). What happens to your brain when you get a concussion? Concussion Alliance. Retrieved November 14, 2021, from  https://www.concussionalliance.org/what-happens-to-your-brain. 

Kids with autism are seen to spend more time on screens than neurotypical kids which results in lower physical activity. Screen use may be related to poor academic and development performance, sleep problems, obesity, social behavior deficits, and attention problems. The AAP (American Academy of Pediatrics) advises caregivers to not expose children under the age of 2 years to any electronic device. Kids between the ages of 2 and 5 years old can be exposed to screens for one hour a day before displaying developmental factors described previously. (1)

Watching television at the age of 12 months can increase the chances of developing autistic symptoms at 2 years old. Early exposure can increase a child’s chances of autistic behavior by 2%. However, caregivers can decrease the chances by 8.9% from daily one on one play. (2)

Screens act as a stimulant equivalent to caffeine, amphetamines, or cocaine for children. Autistic kids are more vulnerable to addiction and negative impacts compared to neurotypical kids. Factors that cause the vulnerability include:

• • Low melatonin and sleep disturbance
    • Screen time causes a disturbance in circadian rhythms by suppressing melatonin. Melatonin regulates hormones, the immune system, and inflammation.
  • Arousal regulation issues
    • Autistic kids experience overstimulation with increased stress response and emotional dysregulation. Screen use can heighten these symptoms.
  • Inflammation of the nervous system
    • The combination of increased stress suppressed melatonin, and sleep disturbances cause inflammation within the nervous system.
  • Decreases healthy frontal lobe development
    • Reduces the connection of white matter and gray matter in the frontal lobe. This affects verbal competence, aggression, and cognitive abilities.
  • Social and communication deficits
    • Autistic kids experience difficulties identifying social cues like reading body language, having low empathy, and having trouble communicating with others. Screen use inhibits the development of these skills. One study found that screen use and background screens can delay language development.
  • Prone to anxiety
    • Screen use is positively correlated with the risk of developing OCD, social anxiety, high arousal, and diminished coping methods. The amygdala can be seen to change functions when exposed to screens which cause serotonin synthesis abnormalities.
  • Sensory and motor integration
    • Kids with autism are prone to have tics that can worsen due to dopamine release from watching screens.
  • Psychiatric disorders
    • Autistic kids are at higher risk of developing ADHD, tics, anxiety, mood disorders, and psychosis. Screen use is seen to increase the display of such disorders. Individuals with psychosis “may experience hallucinations, paranoia, dissociation, and loss of reality-testing” while actively using screens. (3)

Increased screen time is correlated with melanopsin-expressing neurons and decreasing GABA neurotransmitters which cause autistic-like behavior and decreased cognitive and language development. One study found:

• • kids who were exposed to screen for less than 3 hours per day had language delays and a short attention span.
  • kids who were exposed to screens for more than 3 hours per day had language delay, short attention span, and hyperactivity
    • This shows that any duration of screen exposure produces negative effects on children.

The light projected from screens is detected by retinal ganglion cells (RGCs) which signal the thalamic nuclei and visual cortex for image visual function. Melanopsin is used for non-image visual function. It can be found in the suprachiasmatic nucleus (SCN), ventrolateral preoptic area (VLPO), and limbic regions to help balance sleep patterns, cognitive function, and mood.

Neurotransmitter deficiency such as dopamine, acetylcholine, gamma-aminobutyric acid (GABA), and 5-hydroxytryptamine (5-HT) may cause a spectrum of autism. (4)

Neurotypical Brain ~ Brain with Early Onset ~ Autistic Brain

The structure of an autistic brain can be seen to be different compared to a neurotypical brain such as:

• • An enlarged hippocampus
  • They will have a larger amygdala early in life then a smaller amygdala with age compared to a neurotypical brain
  • Smaller tissue in the cerebellum
  • An enlarged head and brain which will shrink prematurely (before mid-20’s)
  • Excess cerebrospinal fluid (5)

Screen use can worsen these factors due to the topics discussed throughout this blog. In conclusion, screen use can heavily negatively impact children with and without autism.

Resources:

1. https://www.frontiersin.org/articles/10.3389/fpsyt.2021.619994/full
2. https://www.medpagetoday.com/neurology/autism/86051
3. https://www.psychologytoday.com/us/blog/mental-wealth/201612/autism-and-screen-time-special-brains-special-risks
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849631/
5. https://www.spectrumnews.org/news/brain-structure-changes-in-autism-explained/