Health/Hot topics

Addicted to Addiction Medicine?

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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?

LA Johnson/NPR

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.

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Addiction: A Relationship with a Tight Grip

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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.

(2)

 

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:

  1. https://drugabusestatistics.org/
  2. https://jackwestin.com/resources/mcat-content/memory/changes-in-synaptic-connections-underlie-memory-and-learning
  3. doi:10.1152/physrev.00014.2018
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What makes drug addiction a chronic disease?

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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?

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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/

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Neuroimaging and Addiction: A Hope for the Future

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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

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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

 

 

 

Community/Disease/Health

Addiction: Is It Really A Choice?

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Artwork by Olivia Pederson
Artwork by Olivia Pederson

What is Addiction?

In simple terms, addiction is a loss of control of drug use. The word “drug” doesn’t mean you can only be addicted to actual drugs. There are many things people can be addicted to such as, shopping, drinking, gambling, sex, social media, sugar, and the list goes on. The hot topic along with addiction is whether it is a choice or not to become addicted to a certain something. There are many people on either side of that topic but knowing all of the science and chemistry behind it is the only way to truly argue if it is a choice or not.

People see ‘addicts’ and assume that they have no self-control, no impulse control, and are untrustworthy. When looking at the science and understand just what is happening in the brain during this vicious cycle of addiction, we can see that is goes way further than just making a choice or simply getting short-term treatment.

Statistically, over half of Americans have experienced some type of substance abuse problem within their families. This is only looking at alcohol and drug use, not taking into account the many other types of addiction families can struggle with. The statistics look a little different for recovery of addiction, but that will be talked about at the end.

What is going on in the brain?

Specifically, the most common drugs of abuse are cocaine, heroin, and methamphetamines. These drugs all act by increasing the levels of dopamine in the brain. Dopamine has more to it than just being the “happy” chemical. It is responsible for motivation and reward, which is why an increase is so addictive because it is what the drugs of abuse are providing. These drugs of abuse happen to activate our reward pathway within the brain. This pathway includes the VTA and nucleus accumbens (NAc). Once a drug is taken and the pathway is activated and dopamine is increased the feeling will be reinforced within the brain. This will lead to people wanting to use over and over again to achieve this feeling or “high”.

Addicts will choose this feeling over anything else in their life because eventually their brains don’t feel motivation or reward for any other activity other than using their drug of choice. Even with their drug of choice, they will eventually need to increase the amount they take to keep that high.

These drugs of abuse effect the brain much more than other types of natural rewards (food, social interaction). The brain is overwhelmed with the amount of dopamine that is being released because of the drugs, so it tries to adapt by reducing the amount of dopamine receptors on the neurons. This makes the brain less responsive to the drug but in turn decreases the brains natural reward system. After these changes, a person will need to take more drugs to get to the same level of high that they were at before building up their tolerance.

Part of the brain responsible for reason, judgment, learning, and memory begin to have changes as well. In some spots, the neurons are pruned back whereas in other regions there are more connections, completely changing the shape of the neuron. After all of these changes, the drug-seeking behavior becomes habit and the person becomes addicted.

These changes to the neurons don’t just “go away” after the person quits the drugs of abuse. These changes can last for months or even years! The brain will not immediately return toward normal, which is why relapse and conditioning is an important factor that can effect successful recovery.

Role of Relapse and Conditioning:

Relapse is defined as when a person returns to using drugs or alcohol after a period of sobriety. There are many factors that contribute to relapsing, which can be seen in this image. After the neurons are changed and the feeling and memories of drugs are implanted into someones brain it can be extremely hard to just give it up. The brain is still searching for this increased reward feeling and it isn’t getting it from ‘normal’ daily activities which can make turning back to drugs really tempting.

Conditioning is defined as a higher dose of drugs that can be tolerated when external stimuli is associated with prior administration of the drug is present. Basically, this means that if someone is doing drugs in the same room at the same time everyday they will eventually build up a tolerance because their brain will release the the effects of the drug before it is even taken. This leads to a tolerance, and if the drug is taken with any of the external factors changed it can lead to an overdose.

In the End:

Recovery is much more complex than it is made out to be. There are many factors that play a part in the life of an addict. It is not as simple as quitting cold turkey sometimes. There are memories and outside factors that can effect the ability to remain sober. Being educated on all the facts of addiction can help stop the stigma that it is just a simple choice. It truly goes down to the cellular and molecular level and changes are happening at those levels making it difficult to change behaviors right away. Treatment for addiction can be very expensive and difficult. A lot of people are not even getting the help that they need because they are not sure where to even begin in their recovery journey, or they might not think it will even work. Every person is so unique and it can be hard to find the right treatment and the right length of treatment to fully recover. Also, returning to a routine can be difficult when the external factors are still a part of someones life. Patience and education is key when talking to someone with an addiction or talking to someone about addiction.

 

References:

naatp.org/addiction-treatment-statistics

learn.genetics.utah.edu/…tion/brainchange

pubmed.ncbi.nlm.nih.gov/16251986

statista.com/…/us-families-affected-by-substance-abuse

 

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A New Model for Schizophrenia?

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A New Model for Schizophrenia?

What Is Schizophrenia? - Halza

What is Schizophrenia?

Schizophrenia is a mental illness that is heavily stigmatized. Once diagnosed, it has an impact on both the patients and those around them. The symptoms are so severe and complicated that they are nearly impossible to fully treat. The most commonly used treatments target the positive symptoms of schizophrenia, such as delusions and hallucinations. 

How is Stress Related to Schizophrenia?

Stress is extremely harmful to all populations. The most vulnerable are children who have predisposed genes linked to schizophrenia. They will almost certainly develop schizophrenia if they have a stressful childhood. Early childhood environmental disturbances can disrupt the biological development clock and processes, and can later manifest as brain abnormalities that lead to psychosis.

The Role of Wnt Signaling

In a paper by Singh, Schizophrenia was defined as a neurodevelopmental disorder caused by a wnt pathway malfunction. The underlying pathology and biology of the disease are unclear at the molecular level. In addition to positive and negative symptoms, schizophrenia is associated with cognitive delay and early brain function deficits. 

Frontiers | Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights
Figure 1: On and Off canonical Wnt Signaling Pathways

The authors bring up a novel way to study schizophrenia and its underlying molecular pathway by linking it to the wnt pathway. ​​Beta catenin is a key player in the wnt signaling pathway. In the absence of wnt as a ligand, a destruction complex is active. The destruction complex composed of gsk3beta, axin, apc, and ck1 alpha reduces the cytosolic concentration of beta catenin via proteasomal degradation. The destruction complex dissociates when wnt is present. The subsequent increase in beta catenin activates the nucleus’ TCF/LEF transcription factors, inducing transcription of a target gene. The figure below is a good schematic of this signaling pathway.

The mystery of schizophrenia | Mint
Figure 2: Coronal View of: Schizophrenic brain (left) and normal brain (right)

In the study, the authors point out that in schizophrenia, gsk3beta is overactive due to absence of AKT-its inhibitory regulator. This ensures continued degradation of beta catenin, thereby silencing transcription of TCF/LEF genes. This can cause cellular responses that build up to become development abnormalities in tissues and organs like the hippocampus, hypothalamus, and even the cortex. This hypothesis explains why schizophrenia tends to decrease brain volume as shown in the image here.

In addition to gsk3beta, Singh discusses 3 other pointers that link schizophrenia to wnt signaling:

– In schizophrenia patients, the expression of several Wnt-related genes was significantly reduced in the prefrontal cortex.
– Genetic variations in genes (DISC1) involved in the Wnt signaling pathway may increase the risk of developing schizophrenia.
– Antipsychotic drugs used to treat schizophrenia modulate the Wnt signaling pathway.

All things considered, the connection between schizophrenia and the Wnt signaling pathway is complicated and still not entirely understood. Evidence, however, points to the possibility that abnormalities in the Wnt signaling pathway may contribute to the pathophysiology of schizophrenia, and that focusing on this pathway could be a promising route for the creation of novel therapies.

The medical research field needs more such advances because they are critical to drug and therapy enhancement. Identifying patient populations  with specific biological pathway markers could identify them as the best candidates for medications, resulting in the personal pharmacology needed to treat psychiatric disorders, making treatment more efficient and effective. This type of research could aid in explaining how and why medications work. For example, how and why some antipsychotics that target GSK3 are effective in the treatment of schizophrenia.

https://moodle.cord.edu/pluginfile.php/1239779/mod_resource/content/2/2013%20wnt%20GSK%20and%20schizophrenia.pdf

imgres

 

Disease

What Wnt wrong in Schizophrenia

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What is Schizophrenia:

Schizophrenia is a chronic brain disorder that is characterized by delusions and hallucinations. Delusions are false beliefs that an individual believes to be true. Delusions can be misinterpreting someone’s actions to be something more to the person with schizophrenia. Another symptom is hallucinations, hallucinations are where the individual experiences auditory and visual stimuli of something that does not exist. A majority of hallucinations are linked to hearing voices that are not present. Currently little is known about the cause of Schizophrenia and there are not any definite treatments.

Schizophrenia causes:

Numerous studies have looked at Schizophrenia to determine what causes and no clear-cut definite result has been determined. However, it has been observed that infection in utero has been linked to disrupting fetal brain development and contribute towards the child developing schizophrenia. A marker for schizophrenia at a young age is the delay of reaching cognitive milestones. Additionally, there has been a link between brain size and those diagnosed with Schizophrenia. Those diagnosed with schizophrenia have been observed to have less gray matter due to synaptic pruning and to have a smaller hippocampus and amygdala compared to an individual without schizophrenia.

Research has also looked at the genetics of schizophrenia and found that it is heritable. However, through exome sequencing it was discovered that a chromosomal mutation was responsible for the disease. A mutation on chromosome 14q32 reduces the production of the protein Akt. An imbalance of Akt has been linked to schizophrenia due to the protein’s role in the Wnt pathway.

Wnt pathway:

The Wnt signaling pathway is responsible for neural circuitry development and synaptic plasticity. The Wnt pathway is activated by the binding of Wnt ligands to the frizzled receptor which results in the dissociation of the destruction complex and the decreased phosphorylation of β-catenin. This allows for the accumulation of β-catenin and for the translocation to the nucleus for gene transcription. However, in the absence of the Wnt ligand binding the Axin, APC, CK1α complex is destroyed. The destruction of this complex leads to the activation of GSK-3β and the proteasomal degradation of β-catenin. The consequence of this is that GSK-3β will continue to tag β-catenin for degradation not allowing it to continue to the nucleus. Without proceeding to the nucleus for gene transcription cell differentiation, proliferation, and apoptosis are not able to be carried out.

Schizophrenia treatments

Schizophrenia is characterized by a reduction in β-catenin. Due to β-catenin being produced by the Wnt pathway dysfunction of the pathway is the leading cause of Schizophrenia. Therefore, activation of the Wnt signaling pathway is hypothesized to aid in the treatment of schizophrenia. One treatment method would be to inhibit dopamine signaling on the D2 receptor. Overabundance of dopamine has been recorded as a precursor to schizophrenia and directly activates GSK-3β, in turn degrading β-catenin. Therefore, by inhibiting dopamine Wnt signaling could be stabilized. Another potential treatment is Lithium, lithium directly inhibits GSK-3β since it competes with the binding of magnesium. Lastly, treatments that target metabotropic glutamate receptors could be a potential treatment. Targeting these receptors would increase Akt activation, decrease GSK-3β activation, ultimately resulting in β-catenin accumulation.

Conclusion

Schizophrenia is a life altering disorder that leaves individuals with numerous debilitating symptoms. However, with the help of current research a link between the Wnt signaling pathway and schizophrenia has been found. With this knowledge schizophrenia may be more effectively treated since the dysfunctional pathway is known. By knowing that reduced β-catenin levels due to the dysfunction of Wnt signaling are the culprit for schizophrenia drugs that target the activation of the Wnt pathway, inhibit D2 dopamine receptors, inhibit GSK-3β, or activate Akt are potential treatments for raising β-catenin levels and ultimately treating schizophrenia.

References

  1. Feature image: https://www.tpr.org/bioscience-medicine/2018-12-06/san-antonio-man-working-to-erase-stigma-of-schizophrenia
  2. Pathway schematic: https://jhoonline.biomedcentral.com/articles/10.1186/s13045-017-0471-6
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Treatment of Schizophrenia

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Treatment of Schizophrenia

Schizophrenia is a very consequential mental illness, its effects can alter how someone can think, feel, and act. Often it tends to go untreated. According to WHO only 31.3% of people with schizophrenia get treatment from specialists. You might ask yourself “if help is offered, why don’t people get the help?” Well, it isn’tthat easy.

Pathways Targeted by Anti-Psychotics.

There are four major pathways that anti-psychotics can target. The mesolimbic pathway is altered because people with schizophrenia have too much dopamine. This can cause satisfaction, emotions, and thoughts not be the same. Anti-psychotics lower dopamine transmission.  The mesocortical pathway controls cognition and reward processing. The nigrostriatal pathway controls movement can cause things like tics.  The tuberoinfundibular pathway gets effected by the high dopamine levels by causing too much prolactin. This causes the hysteria and hallucinations.

Most anti-psychotics target dopamine receptors in the brain. They block the receptors so that dopamine isn’t processed that cause the symptoms of schizophrenia. Which again you still might be asking yourself “why don’t they take the treatment?”

What Happens at These Receptors?

Antipsychotics cause D2 receptors to inhibit the enzyme Akt. Akt is responsible for the phosphorylation of GSK3β. Antipsychotics cause the GSK3β to be inhibited.

In medicated schizophrenia patients compared to ones not treated with an anti-psychotic, non- medicated had 5.8% more active D2 receptors.

The dopamine D2 receptor releases clozapine and quetiapine (both are commonly used to treat schizophrenia) more rapidly than it do any of the other antipsychotic drugs.

Perceived Effects of Anti-Psychotics

It inhibits dopamine transmission; it can cause people’s lives to become dull. Sadly, it seems to be a hit or miss acting. Yes, anti-psychotics can stop extreme symptoms, but it also inhibits dopamine transmission for typical everyday life. There are things in life that naturally produce dopamine you don’t even think of. Any sort of action or activity that gives you satisfaction gets dulled while on anti-psychotics. I am not sure about you, but simple things even like selfcare Sunday night to get ready for the upcoming week is something I look forward too. I get so much satisfaction from doing a facemask and crawling into a freshly washed and made bed. While on anti-psychotics, that wouldn’t be rewarding. It can cause people to be a lot less motivated.

Another factor that often gets mentioned is the stigmatism about taking “anti-psychotics.” Think of the word means, I personally think “undoing-the delusion.” As much as I don’t want to say it, but in society it is made to seem if you take anti-psychotics you are “crazy.” Which I can understand how that stigmatism happened due to some cases of symptoms. Yet, if we all had the same unbalance within ours brains we’d be “crazy” too. At the end of the day, we don’t and we can’t undo it for others that do. So truly tagging such negative ideals to something so impacting such a schizophrenia is unfair. Those that deal with it are already just trying to deal with impacts.

The Future of Treatment

As time goes on so does research, more suitable treatment plans are being investigated. A middle ground, not an all or nothing strategy is the goal. Recently an oral compound SEP-363856, has been studied as a medication for schizophrenia. A 2020 study posted to the New England Medical Journal has studied SEP-363856. It isn’t a D2 inhibitor, but an agonist at TAAR1. TAAR1 is a G-coupled protein receptor that has been shown to alter dopamine, serotonin, and glutamate activity. It is currently in phase 3 of clinical testing. Most studies were short, (around 4 months long) yet have shown positive results. The only one thing negative thing I can find so far on this drug is that it may be suitable for mild Schizophrenia cases. Another note on treatment plans I found is that majority of treatment is being done to treat Schizophrenia. There isn’t much being done or real definitive answers to help the physical brain matter of people with Schizophrenia. That not too much can be done for preventative care.

A Peak into Schizophrenia

I found this little youtube video that has a young boy with schizophrenia and his treatment team. I think it is worth the watch. You can read as much as you want to try to understand what symptoms may be like, this video helps me see what it is somewhat like going off of this real life story. It also mentions another treatment plan that is in clinical trial, this one focuses on the auditory system. Which personally blows my mind that so far it seems to be effective. It doesn’t effect dopamine pathways which cuts out the bad effects of anti-psychotics. Instead it helps with auditory hallucinations. It targets the processings within the brain.

 

Sources

https://www.who.int/news-room/fact-sheets/detail/schizophrenia
https://pubmed.ncbi.nlm.nih.gov/32294346/
https://psychopharmacologyinstitute.com/publication/the-four-dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096
https://www.nature.com/articles/s41398-021-01331-9#:~:text=SEP%2D363856%20is%20a%20trace,for%20the%20treatment%20of%20schizophrenia

 

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