Treatment of Glioblastoma Through EGFR and CREB

Posted on March 21, 2023 by / 0 Comment

Artstract Created by Hailey Puppe

Glioblastoma is an aggressive, fast-growing malignant brain tumor. It has a very low survival rate. Only 5% of those with Glioblastoma will live past 5 years. Treatment usually consists of surgery, radiation, and chemotherapy.¹

There are two main types of Glioblastoma, primary and secondary.

Primary Glioblastoma effects elderly people and represents around 90% of Glioblastoma cases. This is characterized by EGFR amplification and is fast growing and very aggressive. EGFR is epidermal growth factor receptor. Overexpression allows for continual cell growth.
Secondary Glioblastoma effects younger people. First signs of this appears in childhood prior to puberty. Children will often experience excessive headaches. Once children reach puberty, the tumors will die out. Unfortunately, these tumors come back later, prior to 50 years of age. Secondary Glioblastoma has a better response to chemo than primary due to a genetic component that shuts off DNA repair that occurs after damage done by chemo treatment. This allows the tumors to die.

Pathways Involved

In Glioblastoma there are a few things that go wrong in signaling. As discussed previously, EGFR is amplified in Glioblastoma. This leads excess cellular signaling to produce new cells. Some pathways included in this are cAMP, MAPK, and PI3K.

When a ligand like epidermal growth factor bind to the RTK receptor, signaling occurs that activates RAS. In turn, RAS activates RAF, MEF, and then MAPK. MAPK then activates CREB to lead to cell production. In Glioblastoma, MAPK becomes hyperactivated which leads to increased cell production.
When a growth factor binds to the RTK receptor. PI3K is recruited to the receptor and allows for cellular signaling in the cell that leads to CREB becoming activated. In Glioblastoma PI3K amplified and CREB is hyperactivation causes increased cell production.
When a ligand binds to the G-coupled protein receptor, adenylyl cyclase converts ATP to cAMP. cAMP activates PKA which inhibits tumor growth by activating gene transcription. cAMP is lower in Glioblastoma and cannot activate PKA. PDE degrades cAMP in Glioblastoma and tumor growth is not inhibited.¹

Each of these pathways can be targeted for the treatment of Glioblastoma. This figure shows how each pathway is involved in gene transcription and how different medications may effect these pathways.

Possible Treatments

Two major factors involved in increased cell production in Glioblastoma is EGFR amplification and CREB hyperactivation.

EGFR gene amplification is also found in other cancers. Unfortunately, targeting EGFR in cancer treatment has not shown to be effective against Glioblastoma. EGFR inhibitors have helped with other cancers, but trials with Glioblastoma have not shown promise. A specific genetic variant of EGFR, ΔEGFR, is specific to tumors. Treatment with a ΔEGFR monoclonal antibody has shown to decrease tumor growth and increase cell death.²

CREB inhibition on the other hand shows more promise. Other medications that inhibit signaling in RTK receptors leads to decreased CREB activation. This was shown to decrease tumor cells. CREB inhibitors are currently in pre-clinical trials for the treatment of cancer and could be a potential treatment of Glioblastoma.³

Glioblastoma is a very aggressive and difficult disease to treat. Exploring the different pathways involved in Glioblastoma can provide new solutions to treatment. Targeting EGFR and CREB has shown some promise, but different aspects of these pathways need additional discovery.

Uncategorized

Complexity of Glioblastoma – Types, Treatment Options, and More

Posted on March 19, 2023 by / 0 Comment

What is Glioblastoma?

Glioblastoma (GBM) is a fast-growing and aggressive malignant brain tumor. It is a very invasive form of cancer which means it has one of the worst survival rates across all types of cancer. GBM accounts for about 50% of all malignant cancers and the 5-year survival rate is around 6%. It is also estimated that almost 10,000 Americans will succumb to GBM every single year.

The symptoms of GBM can include things like headaches that keep getting worse, seizures, nausea, changes in personality, weakness in one side of body, memory loss and speech difficulty. These symptoms can be seen in MANY other diseases, which makes GBM hard to discover and diagnose. The median amount of time before discovery of the tumor is around 330 days, which allows a lot of time for the tumor to grow to nearby cells of the brain.

Subtypes of GBM?

There are four subtypes of GBM that have been discovered and researched.

Classical
- Over expression of epidermal growth factor receptors and responds best to aggressive treatment.
Mesenchymal
- Over expression of regulatory components of MAPK and PI3K pathways. Responds best to aggressive treatment.
Proneural
- Occurs in younger patients and has an over expression on chromosome 4q12. Less responsive to aggressive treatment, but has longer survival time.
Neural
- No obvious pattern of over expression or mutation. Worst survival rate and no improvement with aggressive treatment.

What is Going Wrong?

MAPK Pathway:

This pathway is activated by a ligand binding to its receptor tyrosine kinase (RTK) which results in a cascade of activation and phosphorylation. RAS activates RAF which activates MEK which activates ERK/MAPK. In GBM, NF1 is being over expressed which is inhibited the activation of RAS, which stops the activation of the molecules after that.

PI3K Pathway:

This pathway is activated by a ligand binding to its receptor tyrosine kinase (RTK) which results in a cascade of activation and phosphorylation. PI3K is recruited to the RTK by the p85 subunit which then activates another subunit p110. The p110 subunit converts PIP2 to PIP3, and PIP3 activates AKT which then activates mTOR, promoting cell survival. In GBM, PTEN inhibits the conversion of PIP2 to PIP3, which stops the activation after that.

cAMP Pathway:

This pathway is activated by aa ligand binding to G-Protein Coupled Receptors (GPCR). Adenylyl Cyclase converts ATP to cAMP which in turn activates PKA to inhibit tumors. In GBM, PDE is inhibiting this pathway meaning it is under expressed, which results in tumor growth.

There are three different pathways involved in GBM, which makes treating it extremely difficult. These pathways are over and under expressed so finding the ‘sweet spot’ for each pathway is a difficult task. These pathways can also cross over into each other adding more confusion when trying to treat GBM.

GBM Treatment:

Because of the complexity of GBM, finding the proper treatment is just as complex. Treatment options include surgery, radiation therapy, chemotherapy, and antibody therapy.

Antibody therapy uses the immune system to help attack cancer cells. Monoclonal antibodies are made in the lab to mimic the bodies natural antibodies. They are infused into the body and are made to attack cancer cells, disrupt the cell membrane of cancer cells, and help T-cells kill cancer cells.

While there are many treatment options to choose from when dealing with GBM, it can can cost a lot of money as well as take an emotional and physical toll on the body. There are many natural ways to try and treat cancer without having to spend most of the time in a hospital bed. Things such as acupuncture, exercise, meditation, cognitive behavior therapy, and music therapies are just a few ways to naturally treat cancer. It is important for the person diagnosed with these types of diseases to consider the ways they want to spend their limited amount of days. Some people may want to try every medical advancement to treat themselves while others may want to find natural ways to spend the rest of their days at peace with themselves. Either way, it is important to understand the statistics of GBM, what is happening in the body, and the options for treatment.

References:

braintumor.org/…ss-day/about-glioblastoma

pubmed.ncbi.nlm.nih.gov/29727799

mayoclinic.org/…glioblastoma/cdc-20350148

cancer.gov/…therapy/monoclonal-antibodies

https://doi.org/10.1016/j.cellsig.2019.01.011

Uncategorized

Addicted Brains Explained

Posted on March 1, 2023 by / 0 Comment

Addiction is defined as having a craving or dependence to a substance, thing, or activity. Addiction can be tied to a natural reward such as sleep, food, etc. whereas it can also be tied to an unnatural reward such as substances. Unnatural addictions such as drugs or alcohol can be life threatening at times and turn into a horrific cycling pattern if trying to withdraw and stop usage.

In the brain there are three areas of the brain an addiction behavior can go through:

The first is the basal ganglia, the portion of the brain that controls the reward response to the substance use and helps to form the habits around substance use.
The second is the extended amygdala that associates with the feelings of discomfort, anxiety, stress that usually follows substance withdrawal.
The third is the prefrontal cortex which controls the ability to have control over the substance usage.

Figure 1: The different areas of the brain affected by addiction. https://www.ncbi.nlm.nih.gov/books/NBK424849/

The overwhelming effects of addiction occurs when this cycle repeats itself and the addiction grows stronger after making those rewarding affects attainable with the substance rather than without.

Studies suggest that individuals with an addiction to substances have a reduction in sensitivity for the brain’s reward system (brain circuits with dopamine receptors). Therefore, once pleasurable or stimulating activities no longer have the same effect as they once did, an individual going through withdrawal symptoms will want to regain the same pleasurable feelings the reward system once provided but only be able to do this through the substance.

At the more neuronal level, during the withdrawal stage there is an activation of the stress neurotransmitters in the extended amygdala. These NTs include corticotrophin-releasing factor (CRF), norepinephrine, and dynorphin. These neurotransmitters have been shown to play a key role in negative feelings associated with withdrawal. Therefore, to get rid of the negative emotions from withdrawal a lot of individuals tend to use the substance again. In other words, the individual is experiencing negative reinforcement every time they use the substance again to rid themselves of the negative emotions and this is how the cycle continues.

Taking a closer look at the brain it is important to understand the difference between an addicted brain versus an unaddicted brain to a substance. In the control brain, VTA dopaminergic neurons project to NAc whereas with the addicted brain neurons there is an increase of dopamine in NAc (Nucleus accumbens) leading to tolerance, sensitization, and adaptation to the substance. In the addicted brain, the VTA neuron appears smaller as the NAc portion is larger in size with more branching, leading to the effects of becoming addicted to a substance and unable to stop.

Figure 2: Image of neurons in the brain from Nestler article (2005).

Overall, addiction starts as a choice and turns into a gray area where the choice of using a substance is no longer there. As there has been some controversy on whether addiction is a disease, in the future when we learn more about addiction and what more is happening in the brain can we decipher if the individual has a choice or if that choice is no longer there once the brain creates tolerance, sensitization, and adaptation to the substance.

References:

Substance Abuse and Mental Health Services Administration (US), Office of the Surgeon General (US), and US Department of Health and Human Services. 2016. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK424849/

Nestler, Eric. 2005. Is there a common molecular pathway for addiction? Nature Neuroscience: Neurobiology of Addiction.

Leyton, Marco. 2013. Are addictions diseases or choices? Journal of Psychiatry & Neuroscience. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692718/

Uncategorized

Addiction on the Molecular Level

Posted on March 1, 2023 by / 0 Comment

Addiction on the Molecular Level

Addiction is a significant issue in today’s society. Addiction is defined as a compulsive and persistent dependence on a substance or behavior that has negative consequences. Some of the most common types of addiction are substance addiction (addiction to drugs, alcohol, and tobacco), natural addiction (addiction to food, binge eating disorder) and behavioral addiction (addiction to gambling, video games, and social media).

Addiction can have a significant impact on an individual’s life as well as the lives of those close to them. It can result in physical and mental health issues, financial difficulties, social isolation, and legal complications. Addiction can also have a negative impact on the larger community by causing crime, violence, and other social problems.

Addiction is particularly problematic in today’s society due to a number of factors. For starters, addictive substances and behaviors are more widely available, thanks to the proliferation of online gaming and social media platforms. Second, there is less social stigma attached to addiction, which may make it easier for people to engage in addictive behaviors without fear of being judged. Finally, many people lack access to effective addiction treatment and support services, making it difficult for them to overcome their addiction and live a healthy life.

Drug abuse can activate several signaling pathways in the brain, leading to the development of addiction. The following are some of the most common signaling pathways involved in drug abuse:

Dopamine pathway: The mesolimbic dopamine pathway, which is a circuit of brain regions involved in reward and motivation, is one of the key pathways identified by Dr. Nestler and his colleagues. This pathway is activated when a person engages in rewarding behavior or takes an addictive drug, and dopamine is released in the nucleus accumbens, a key region of the brain’s reward circuitry. This dopamine release reinforces and motivates the individual to repeat the behavior.
Glutamate pathway: The glutamate pathway is responsible for learning and memory. Drugs of abuse can activate this pathway, leading to changes in synaptic plasticity, which can lead to drug cravings and addiction.
GABA pathway: The gamma-aminobutyric acid (GABA) pathway is responsible for the brain’s inhibitory system. Drugs of abuse can disrupt the balance of GABA signaling, leading to an increase in excitatory signaling, which can lead to drug cravings and addiction.
Endocannabinoid pathway: The endocannabinoid system is responsible for regulating appetite, pain, and mood. Drugs of abuse can activate the endocannabinoid pathway, leading to changes in appetite and mood.

Moreover, repeated drug use or addictive behavior causes the brain to adapt, resulting in long-term changes in gene expression and synaptic plasticity. Dr. Nestler has identified a number of specific molecular pathways involved in these adaptations, such as changes in gene expression of various transcription factors, epigenetic DNA modifications, and changes in synaptic plasticity and neuroplasticity.

While there may not be a single common molecular pathway for addiction, Dr. Nestler’s research has contributed to the identification of some of the key molecular and cellular mechanisms that underpin addictive behavior. This understanding is critical for the development of new treatments and interventions to assist individuals in overcoming addiction and leading healthy, fulfilling lives.

sources:

https://moodle.cord.edu/pluginfile.php/1266921/mod_resource/content/4/Nestler%202005.pdf
https://www.ncbi.nlm.nih.gov/books/NBK424849/figure/ch2.f5/

Health/Hot topics

Addicted to Addiction Medicine?

Posted on March 1, 2023 by / 0 Comment

Opioid addiction is a major problem in the US. According to the CDC overdose deaths involving opioids have increased by over 8 times since 1999. In 2020 an estimated 69,000 people died of opioid overdose. The start of these addictions can vary, often it starts with a prescription for opioids as a pain relief, and will spiral from there into a serious problem.

https://www.cdc.gov/opioids/data/index.html

What is Addiction?

All drugs with potential for addiction work by activating the brains natural reward system, and eventually will rewire that reward system to be preferential to the drug of choice. The mesolimbic dopamine pathway has long been regarded as the reward pathway, and is what is most affected during addiction. Drugs will activate dopamine neurons in this pathway, and with enough use the circuit will adapt to these levels of activation. This adaptation will make natural rewards (food, sex, social interaction, etc.) less rewarding, and the person will seek drug use in order to feel a reward.

Effects of Addiction

With addiction and the changes in the reward pathway comes with it comes something called tolerance and withdrawal. Tolerance in defined as “reduce response to a drug with repeated use” by the CDC. With chronic drug use, over time the brain will adapt its reward system to the amount of drug being taken, and less of an effect will occur. With a dysfunctional reward system a person is driven to take a larger amount of their drug of choice in order to feel a reward, since natural rewards are no longer creating that effect in the brain. Withdrawal is the effects that are felt when there is no drug of choice in the body. Typically the symptoms are opposite of the ‘high’ that the drug causes. Withdrawal often drives people to continue taking the drug, and further the addiction.

How Do We Treat Addiction?

There’s a few ways to go about treating addiction, and often multiple different methods are used together to create an effective plan. Therapy is the most common, to treat the psychological factors of addiction. It is often used with medications to treat the biological factors of addiction discussed above. Medications to treat opioid addiction bind to the same receptors that opioids do in the brain, which can have a few benefits. First it blocks opioids from binding and causing dopamine activation in the reward system. Secondly, binding to these receptors can have relieving effects for cravings and symptoms of withdrawal from opioids. Since they bind to the same receptors, they produce the same effects in the brain.

But wait, isn’t that a bad thing?

Yes and no. It’s not ideal since this is what leads to these medications to also have potential for abuse and addiction. However there are benefits to these medications that make them effective at treating addiction. There are 3 medications that are currently FDA approved: methadone, buprenorphine, and naloxone.

https://www.fda.gov/drugs/information-drug-class/information-about-medication-assisted-treatment-mat

Methadone:

This medication is not used very commonly anymore as it is a full receptor agonist, meaning it produces an effect just as strong as opioids. As you can imagine this is not ideal, and is also highly addictive. The benefit to methadone compared to opioids is that people developed a tolerance to methadone much slower, and the detoxification process from it seemed to be less harsh compared to opioids.

Buprenorphine:

This medication is often prescribed as a combination tablet or dissolvable film with naloxone. It is much more commonly used to relieve cravings and withdrawal symptoms, as it is a partial agonist to the opioid receptor. This means it produces a much weaker effect compared to opioids when bound to the receptor. This makes it less addictive, though there is still a slight potential for abuse. Overdose of buprenorphine is also very difficult to happen and rare to occur, as the drug produces a much smaller effect.

Naloxone:

The third FDA approved drug to treat addiction, and it works in the opposite way that buprenorphine and methadone. Naloxone is an opioid receptor antagonist, meaning when it’s bound it produces the opposite effect, or it stops the effect or opioids. It is used mainly as an antidote for opioid overdose, as it will flood the brain and block all opioid receptors to stop the drug from having an effect.

Uncategorized

Addiction: A Relationship with a Tight Grip

Posted on February 28, 2023 by / 0 Comment

Art abstract by Dhruvika Patel

What is Addiction?

The simplest definition of addiction: a relationship between a person and an activity they do or substance they take that they find themselves losing their self-control over. Most common addictions that seem to cause the most harm are different types of drugs and alcohol. This doesn’t mean that there are not natural addictions as well such as to sugar, exercise, eating, sex, etc. Drugs are, however, the most common and dangerous type of addiction found in the U.S with

This data represents 2023 drug usership. (1)

overdose deaths affecting over 700,000 people in the US since 2000 (National Center for Drug Abuse Statistics). In either case, it is the pleasure that helps drive the need for our brains to keep that relationship strong.

What happens when you want to break up with addiction?

Withdrawal. It is not easy for one to break the relationship they have with a substance they are addicted to. An absence of the substance will cause the person to experience negative emotions as the stress neurotransmitters-CRF, norepinephrine, and dynorphin- in the amygdala begin to get activated. The lack of drugs in the brain can also drop dopamine levels, a major component of the reward system. These changes in the brain result in psychological, physical, and behavioral symptoms. Symptoms may include difficulty sleeping, irritability, mood changes, depression, cravings, tiredness, etc. These withdrawal symptoms are not very easy to live with, making the road to quitting an addiction a very difficult one to take.

Why so attached? LTP & LTD.

If these substances are so toxic, why are you so attached to them? What is one of the major aspects of your brain that keeps you so engaged in this toxic relationship? Long-term potentiation and depression. Long-term potentiation is commonly found in memory formation as your neurons learn and grow and permanently begin changing. That is fine with making new memories, but with addictions, it plays a major role in the formation of reward-related contextual memories. Long-term potentiation is a process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons. Increased depolarization increases the activity of the post-synaptic neuron. To summarize how: post-synaptic activation leads to a calcium influx, and that calcium causes CaMK11 activation to bring AMPA receptors into the post-synaptic membrane. When there are more AMPA receptors inserted into the membrane, the receptor responsiveness increases. Therefore, LTP would cause sensitized behavioral responses.

On the other hand, long-term depression is just the opposite. Synaptic strength is decreased in long term depression as AMPA receptors get removed from the membrane through dephosphorylation. With the removal of these AMPA receptors, the cell becomes less responsive to glutamate. With the lack of receptors, it makes sense that responsiveness would become reduced; hence, the effects of tolerance are seen. It takes more of the drugs to cause the same feeling.

Both changes over time will begin creating very permanent changes in an individual’s brain, which is what makes addiction so difficult to reverse. When this synaptic plasticity changes, it creates long term problems with the brain having new expectations for the receptor activity set by their drug addiction. These long-term changes makes the relationship with drug abuse so difficult to break apart.

Illustration of how long term changes can cause neuronal development not easy to reverse. (3)

Sources:

https://drugabusestatistics.org/
https://jackwestin.com/resources/mcat-content/memory/changes-in-synaptic-connections-underlie-memory-and-learning
doi:10.1152/physrev.00014.2018

Uncategorized

What makes drug addiction a chronic disease?

Posted on February 28, 2023 by / 0 Comment

Addiction to drugs of abuse plagues all corners of America. From needles littering the streets of major urban centres to the hover of prescription opioid abuse in rural areas, it is a growing dilemma. Access to care is stretched and the problem is getting worse.. In fact, a release from the National Centre for Drug Abuse statistics reports that half of reporting individuals (aged 12 and up) have used illicit drugs at least once. There have been 700,000 deaths from opioid overdose alone since 2000. As this crisis has grown, solutions of varying degrees have arisen. Safe-drug use facilities have been proposed to help limit street drug use from an increasingly addicted population while others are working to stop distribution of drugs of abuse in its tracks. However, amongst proposed solutions, some of the fundamental causes of addiction can be forgotten. A review by Eric J. Nestler in Nature Neuroscience back in 2005 dives into what causes addiction at a cellular and molecular level.

The Dopamine System

Otherwise referred to as the brain’s reward circuitry, the dopamine system plays a critical role in why drug addiction can develop. This system can be found in the ventral tegmental area of the midbrain and is also where the dopaminergic neurons within it target areas of the forebrain. A specific pathway is formed in this area called the VTA-NAc pathway. Drugs activate the transmission of the neurotransmitter dopamine within the pathway. When there is continuous activation of the circuit, tolerance to dopamine can occur while at the same time a sensitisation to the neurotransmitter develops. This occurs in combination with withdrawal symptoms that increase drug-seeking behaviour. Sudden withdrawal from use of a drug activates the central corticotropin releasing factor system; this will increase drug withdrawal symptoms. Drug use has also been linked to hypofrontality which is decreased function of the frontal lobe, which is responsible for complex thought processes. Hypofrontality can thus lead to less control over drug-seeking behaviour. With both dysfunction of normal reward signalling in the dopamine system, and increased drug withdrawal, addiction can ensue and magnify itself quickly.

Changes Occur Right Away

Another change occurs to the actual shape of neurons within this system. The neuron is much like a tree. The end of it that receives messages are projections called dendrites that are much like the leaves and branches that make a tree canopy. Drug use and addiction has been shown to affect the morphology of this “dendritic arbour.” Chronic cocaine, amphetamine, or nicotine exposure have shown increases in dendritic arborisation. This increase in the dendritic arbour contributes to drug sensitivity which furthers addiction in an individual. This process changes the actual shape of the neuron and helps demonstrate how persistent addiction can become. The figure below depicts the difference in size between the dendrites of addicted versus non-addicted individuals.

Figure 1. This is from Figure 2 of Nestler (2005) comparing the size difference between addicted and control dendrites.

What Should We Do?

With the addiction crisis we face, all cards need to be put on the table, but this review can help us understand two things that show addiction as a persistent disease rather than that of a mental toughness discussion. Drug addiction affects the brain’s sensitivity to dopamine making drug exposure have higher and quicker highs. It also leads to permanent morphological change to the neurons themselves affecting multiple parts of the brain’s reward pathway. Drug exposure can start the addiction process from the start and needs to be considered when exposing persons to drugs of abuse. The same also comes to the fact that environments contribute to someone’s susceptibility to drug reuse. Environments that systemically cue drug use amongst individuals will make fighting addiction a constant battle. However, armed with this knowledge, we can have empathy for those in their fight against addiction and continue to face this challenge in our future.

“Drug Abuse Statistics,” National Center For Drug Abuse Statistics, accessed 28 February 2023, https://drugabusestatistics.org

Eric J. Nestler, “Is there a common molecular pathway for addiction?” Nature Neuroscience 8, no. 11 (2005), 1445-1449

“Supervised Consumption Services,” Harm Reduction, accessed 28 February 2023, https://harmreduction.org/issues/supervised-consumption-services/

Health/Uncategorized

Addiction: Mental or Physical?

Posted on February 28, 2023 by / 0 Comment

What is Addiction?

Addiction is common and many people may know someone who is addicted to something, their phone, their favorite drink of choice, a drug. In his article, is there a common molecular pathway for addiction, Eric J Nester defines addiction as “a loss of control over drug use.” Addictions are also referred to as substance use disorders. Statistically, more than 20 million Americans suffer from substance use disorders, with the youngest age being only 12. When people think of addiction, the first thing to top into their mind has nothing to do with what they think is going wrong in the brain. Most of the time, someone who suffers from an addiction is just looked at differently, thought to have a hard life, or just labeled “crazy.”

But the brain is altered due to addiction, and once a person becomes so dependent on a drug, there might not be any going back.

So, what goes wrong in the brain?

Drugs of abuse activate the brains reward pathway, the mesolimbic dopamine pathway. Dopaminergic neurons are in the ventral tegmental area (VTA) of the midbrain. These neurons target the limbic forebrain, more specifically the nucleus accumbens (NAc). So, with these things interacting with each other, the VTA-NAc is the most important thing to look at when researching the effect of drugs of abusive on the brain. Drugs activate dopaminergic transmission giving people a feeling of euphoria. The VTA-NAc pathway physically changes when these drugs induce cross-tolerance and cross-sensitization. Cross tolerance is defined as developing a tolerance for one substance that leads to a tolerance of another. And cross-sensitization is when a drug of abuse is taken away from

the person who has been repeatedly abusing the drug and the brain searches for a different way to produce the same effects that the drug did. Simply, in conclusion, drugs of abuse increase dopamine in the reward pathway. Drugs increase dopamine about ten times more than any natural reward does. Because more and more dopamine is produced, the brain builds tolerance to dopamine causing a person to need more and more of the same drug to achieve the euphoric effect that they want. In the figure pictured below, provided by the national institute on drug abuse, everything that I mentioned above can be summarized.

Why should we care?

Drugs of abuse don’t just cause harm to the developed or growing brain, they also greatly impact physical and mental health. According to the CDC, alcohol is one of the most widely abused substances among people in the United States. Alcohol is classified as a depressant, meaning that brain activity is slowed, muscles are relaxed, and neurons can’t communicate effectively in the brain. Alcohol physically alters the brain, causing less communication between neurons, and causing the brain the shrink in comparison to a person who is not dependent on alcohol. Drugs of abuse, including alcohol effect more people around us than we know. Not only do these drugs effect our brains, but they also affect our body. Pictured below are some of the effects on the body from heavy drinking. Many of these are like those of other drugs on the body.

References Used:

https://www.hopkinsmedicine.org/news/articles/new-research-and-insights-into-substance-use-disorder

https://www.yalemedicine.org/news/how-an-addicted-brain-works

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036816/

https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drugs-brain

https://delamere.com/addiction-treatment/alcohol-addiction/effects

https://www.recoveryanswers.org/addiction-101/impact/

Health/Uncategorized

Neuroimaging and Addiction: A Hope for the Future

Posted on February 28, 2023 by / 0 Comment

Artstract from DALL-E2 created by Kailee Vigen

Introduction to Addiction

Millions of Americans ages 12 and older struggle with addiction. These substance problems can exist at any age and may be influenced by one’s social environment, development or upbringing, cognitive function, or genetics. Addiction is often described as a disease, involving physiological and brain alterations that are incredibly difficult to combat or reverse, especially when treatment options are still underdeveloped and not of easy access. So, what is really going on with addiction, and is there a way to universally and effectively treat it?

Drugs of abuse are very diverse in that they each elicit distinct combinations of behavioral and physiological effects. But, these drugs also cause similar effects to each other – they are all rewarding which leads to addiction and they also produce negative symptoms in withdrawal. The question is if there are common molecular and neural pathways of these drugs of abuse that elicit these shared rewarding and addicting actions. And if there are, it could be key for finding effective treatment!

Neurology of Addiction

The ventral tegmental area (VTA) and nucleus accumbens (NAc) circuit of the limbic system is the primary reward pathway in the brain. All drugs of abuse converge on this VTA-NAc pathway which includes dopaminergic neurons in the VTA targeting the NAc which activates dopaminergic transmission in the NAc, producing dopamine-like effects. Regions of the limbic system (hippocampus, amygdala, hypothalamus, frontal cortex) also play a large role in natural addiction reward. It is speculated that there are shared reward pathways and similar anatomical brain abnormalities between drugs of abuse and natural addictions.

Hypofrontality is the loss of executive function (self-control, self-monitoring, planning, judgment, etc.) in the prefrontal cortex (PFC) which exists in addicted individuals. Neuroimaging studies have revealed a pattern of PFC dysfunction in drug-addicted individuals involving decreased input from the “cold functions” (non-drug related, “good” judgment) of the dorsal PFC and increased input from the “hot functions” (drug-related, impulsive judgment) of the ventral PFC as illustrated by the arrows in the figure below. This decreased function contributes to the compulsiveness, cravings, and loss of self-control seen with addiction.

Treatment of Addiction

With the knowledge of shared mechanisms of drugs of abuse and natural rewards, there are safety concerns regarding universal treatment. Thus far, there is no treatment aimed at common drug mechanisms for a range of drug addictions. Current treatments include prescribing drugs such as methadone, suboxone, narcan, or cameral. However, these drugs for treating addiction are also addicting themselves, often making this course of treatment not sustainable.

In a more promising, preventative light, neuroimaging could be used to detect abnormalities in the PFC, as discussed previously, before addiction even occurs! It has been found that PFC dysfunction precedes addiction, leaving some individuals more susceptible to addiction. Knowing that addiction is influenced by social environments, genetics, and certain developmental circumstances, those who have been around addicted individuals in their upbringing or have familial ties to addiction could benefit from early neuroimaging. Having the ability to identify such abnormalities in an individual early on could be beneficial in providing drug addiction preventative efforts!

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462342/

https://pubmed.ncbi.nlm.nih.gov/16251986/

Health

The Pathways of Addiction

Posted on February 28, 2023 by / 0 Comment

What is Addiction?

Addiction is a dependency on a substance or activity, usually drugs of abuse, that is often motivated by the hope of escaping discomfort. This can include drinking an old fashioned every time you start to feel stressed in order to cope or lighting up a cigarette after having a long day. People turn to these drugs of abuse in order because the provide positive emotional responses that make the person feel like they are effectively coping with their negative emotions. But these substances have many negative effects on the brain that can permanently affect its functioning. This is why it is so difficult for people to quit once they have engaged in chronic use. It is also why relapse is so common amongst those suffering from addiction and why it can often take several tries at treatment for them to recover.

Pathology of Addiction

The primary source of addiction stems from the brains reward pathway. This pathway goes from the Ventral Tegmental Area (VTA) to the nucleus accumbens NAc with the primary neurotransmitter being dopamine (DA). Every drug of abuse either directly or indirectly increases DA expression between the VTA and the NAc. This results in positive feelings associated with the activity of taking said substance making you more likely to do it again in the future. When there is chronic use of drugs of abuse this causes permanent changes in these neuronal projections that cause tolerance, sensitization, and withdrawal symptoms.

Chronic use of drugs of abuse impairs the DA system making it more difficult for normally rewarding activates to have the same effect. If you usually love chocolate but then get addicted to cocaine after a while chocolate will no longer make you has happy as it once did. This is partially because of a decrease of tyrosine hydroxylase (TH),which is an enzyme important for DA synthesis, caused by chronic drug exposure. When TH is reduced it contributes to a reduction of DA available for signaling. This means that it will take higher doses of the substance to get the same effect producing tolerance. In a way this is your brain adapting to the upregulation of DA that drugs of abuse causes in an attempt to maintain homeostasis.

Nestler, E. J., (2005). Is there a common molecular pathway for addiction? Perspective: Neurobiology of Addiction 8(11). Doi:10.1038/nn1578

Sensitization is when the brain becomes more sensitive to certain neural projections. In other words it is easier for there to be a strong effect from DA projections. One contributor of sensitization is a protein called Delta-FosB, which accumulates in the NAc after chronic drug abuse. It has been found that as Delta-FosB accumulates in the NAc there is an increase in positive emotional expressions after DA expression. Meaning that it helps DA have a stronger effect to make you feel better.

Finally, there are withdrawal symptoms. Withdrawal is when you feel negative emotional and behavioral effects after stopping the use of a drug of abuse. There are a few factors that play into this phenomenon. The first is the impairment of the DA system due to tolerance. Chronic drug abuse causes changes to how cells function and these either don’t ever go away or take a very long time to recover. This is the case for impaired DA expression, when there is less of DA and the brain is struggling to make more things that normally make you happy no longer have that effect. Only the drug can produce the emotional effect that you are trying to achieve so many people relapse in order to feel better again. This process is aided by the corticotropin releasing factor (CRF) system. CRFs are a neuropeptide that is important for the brains stress response, and also play a role in how the brain copes with stress. During chronic drug use CRFs are released which creates the negative feelings often felt after drug use. When a drug is chronically abused this taxes the CRF system. Once a person decides to stop use of the substance the brain is still trying to release CRFs as part of the coping process for the stress that it is under. But the neurons can’t produce CRFs as fast as they are being released. This means that the brain is physically incapable of coping with the stress that it is under. Resulting in negative emotional and behavioral responses. These negative responses make the brain want to return to use of the substance in order cope with its stress response.

References

Nestler, E. J., (2005). Is there a common molecular pathway for addiction? Perspective: Neurobiology of Addiction 8(11). Doi:10.1038/nn1578

https://www.health.harvard.edu/blog/what-is-addiction-2-2017061914490