What is addiction?
Addiction is a dependence on a substance or certain activity like drugs, alcohol, gambling, and more. What characterizes a behavior as an addiction is that the person continues to take the substance or take part in the activity even though it negatively impacts daily life. Addiction has been found to be a brain disease in which the brain undergoes physical changes in its circuitry, so overcoming addiction is not as simple as it may have once seemed.

What does addiction look like in the brain?
The brain first receives information from a rewarding stimulus which is processed primarily in the hippocampus and the amygdala. The ventral tegmental area (VTA) is stimulated which releases dopamine and travels through the mesolimbic pathway to the nucleus accumbens (NAc). A reinforcement signal is then sent to the prefrontal cortex which associates the rewarding stimulus with the pleasure response in the NAc. The role of glutamate is important in the reward system because it regulates dopamine release to the NAc. The continued use of drugs or some other substance or activity makes this reward pathway stronger and the reward pathway takes over the individual’s brain and all attention goes to the drug or drug-related cues.

Role of synaptic plasticity
Synaptic plasticity is the ability of the brain to change the strength of connections between neurons and is essential to the ability of the brain to learn and develop new memories. There are two types of long-term plasticity, long term depression (LTD) and long term potentiation (LTP), both of which occur in the hippocampus and are triggered by NMDA receptors. LTP refers to connections between neurons becoming stronger and LTD refers to the connections becoming weaker. Both are essential for the formation of memories. Synaptic strength is seen in the mesolimbic pathway in people with substance use disorder (SUD) in which the connections between neurons are becoming stronger and LTP has occurred. This is thought to be the reason behind relapse; people with addiction have these pathways being stronger, so it becomes more difficult for the brain to be rewarded by “normal” mechanisms like food, and it becomes much easier to fall back into the habit of taking the substance because those pathways are so prominent. [4]

What does all of this mean?
The brain undergoes major circuitry changes after continuous use of substances which is what contributes to the symptoms of addiction. Someone who has developed an addiction to a certain substance will have a very difficult time overcoming their addiction because the brain has changed long-term and it takes an extensive amount of time to change it again. It is unknown whether or not the brain has the ability to change back to the way it was before addiction, but it seems unlikely that it would ever be the same. Those with addiction typically cannot take that certain substance again without relapsing, so it makes sense that LTP and LTD have long-lasting effects on the brain and it would not be able to return back to pre-drug condition.

 

References
[1] Department of Health and Human Services. (October, 2015). Biology of Addiction. National Institute of Health. https://newsinhealth.nih.gov/2015/10/biology-addiction.
[2] Mozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P., & Haghparast, A. (2022). A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 124. https://doi.org/10.1016/j.pnpbp.2023.110735.
[3] Su, Yun-Ai & Si, Tianmei. (2022). Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder. General Psychiatry. 35. e100724. 10.1136/gpsych-2021-100724.
[4] Stampanoni Bassi, M., Iezzi, E., Gilio, L., Centonze, D., & Buttari, F. (2019). Synaptic Plasticity Shapes Brain Connectivity: Implications for Network Topology. International journal of molecular sciences, 20(24), 6193. https://doi.org/10.3390/ijms20246193.
[5] Niehaus, J.L., Cruz-Bermúdez, N.D., & Kauer, J.A. (2009). Plasticity of addiction: a mesolimbic dopamine short-circuit? The American journal on addictions, 18 4, 259-71. https://pubmed.ncbi.nlm.nih.gov/19444729/ .

What are psychostimulants?

Before understanding the comparisons between medications and psychostimulants, such as cocaine, nicotine, amphetamine, and more, it is important to know what they are and how they function. Psychostimulants have a long history of being banned after years of use due to learning more about their detrimental effects, like addiction. An article by Mozafari et al. discusses the topic of substance use disorders (SUDs), specifically psychostimulant use disorder (PUD) (2023). These disorders are characterized by having a difficulty limiting drug intake and having high motivation for use despite the known negative effects.

PUD ultimately has effects on reward and motivational circuitry within the brain. This includes dopaminergic projections throughout different areas of the brain including the ventral tegmental area and the nucleus accumbens. The release of dopamine from these projections causes a feeling of reward. This makes sense because drugs have a rewarding effect which is highlighted through the individual’s behavior, causing motivation to continue using the drug. To act, the dopaminergic projections modulate glutamatergic and GABAergic transmission, influencing the most abundant excitatory neurotransmitter, glutamate [1].

Glutamate receptors are either ionotropic, which involve NMDA, AMPA, and kainate, or metabotropic (mGluRs), which have eight subgroups. Different receptors play diverse roles in storage, consolidation, and retrieval of memory and learning, changing synaptic plasticity along the way. Long term changes to these receptors occur due to the influx of dopamine and depend on synapse function. Drug use does this by disrupting glutamate homeostasis and inducing long-term depression (LTD), long-term potentiation (LTP), or long-term facilitation (LTF), which all refer to how the receptor is functioning. In the case of long term drug use, these functions may include receptor loss (Figure 1) or forming new connections (Figure 2) [1].

Figure 1. Reduced dopamine levels [2].

Figure 3. New connections of neurons [2].

What does this mean?

Drugs that affect the brains reward circuit such as psychostimulants or certain medications cause a sense of euphoria and a rush of dopamine, which is shown in figure 3. When working properly, these reward systems motivate repeated behaviors like eating or spending time with friends. Instead, the dopamine surge from the drug reinforces the pleasurable feeling, leading to repetitive use [3].

Figure 3. Surge of Dopamine from drug [2].

Comparisons of psychostimulants to medication

Medications are used to make quality of life better, which often makes the patient feel good by relieving symptoms and may give them the urge to take more just like other drugs such as alcohol or nicotine. With continued use of both medicine and psychostimulants, the relief or high that the person feels begins to lower, which is known as tolerance. This is due to the reduction of the reward circuit’s ability to respond to the drug. Unlike all psychostimulants, however, certain medications are more susceptible to addiction than others. Despite this, an article from Health Direct explains that becoming dependent on a prescription drug from taking it over a long period of time may cause withdrawal symptoms and lead to addiction (2023). Overall, the use of medications has the same ability to change the brain’s circuitry and function as psychostimulants if used for a long period of time [4].

Conclusion

Psychostimulants are a group of well-known drugs such as nicotine, cocaine, and amphetamine. Figure 4 portrays how they work by flooding the brain with dopamine through different types of glutamate receptors, especially mGluRs. This influx of dopamine eventually leads to the change in neural reward circuitry through neuron loss or new connections. The tolerance that the individual builds up along with the rewarded feeling of taking the drug influences further consumption. While long-term use of prescription medications is safer than psychostimulants in many areas, they still have the ability to change the brain’s reward and motivation circuitry along with its functions. Because of this, becoming dependent on medications and having withdrawal symptoms after the discontinuation of use is a possibility.

Figure 4. Effects of psychostimulants and medications [Artstract created by Megan Olson].

[1] Mozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P., & Haghparast, A. (2023). A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 124, 110735. https://doi.org/10.1016/j.pnpbp.2023.110735

[2] Drug Use Changes the Brain Over Time. (n.d.). Retrieved March 12, 2024, from https://learn.genetics.utah.edu/content/addiction/brainchange

[3] Abuse, N. I. on D. (2018, June 6). Understanding Drug Use and Addiction DrugFacts | National Institute on Drug Abuse (NIDA). https://nida.nih.gov/publications/drugfacts/understanding-drug-use-addiction

[4] Australia, H. (2023, September 7). Can medicines be addictive? [Text/html]. Healthdirect Australia. https://www.healthdirect.gov.au/medicines-and-addiction

What do you mean this mouse has Schizophrenia? – Mice models in Schizophrenia Research

By: Hannah Olson

You’ve seen the headlines that go, “Mice with Schizophrenia are twice as likely to …”. Obviously, these headlines are based on powerful scientific research and findings, but in the back of my mind I ask myself, “How do mice get Schizophrenia?”. I don’t feel very smart nor scientific when I ask myself that, but these articles really don’t talk about how these mice came to be (granted they are likely talking about the more serious human implications).

Why Do We Need Animal Models?

In an article on this subject by Dr. Bryce from the University of Missouri, titled, “The Mighty Mouse: the Impact of Rodents on Advances in Biomedical Research”, She explains the reasons that mice models are used for research: Historical, Economical, and Physiological. 

Historically, use of human models has been unethical and is now illegal. Other animal models have been developed to use instead of the human models like zebrafish, fruit flies, primates or mice.

Physiologically, primates and mice are ideal candidates because of how closely their brains and bodies are to humans. For example, mice and humans each have around 30,000 genes, and 95% are shared between the two species. Additionally, both human and mouse genomes have been sequenced so geneticists (people who work and study genes) can compare the genes between the two.

Economically, mice are better than primates because of their shorter life cycle and because they need less space and food for care of these animals.

Due to these reasons, mice are one of, if not the most common animal model used in biomedical and psychological research which is where all those headlines originate from.

How Do Mice Get Schizophrenia?

So now we know why we need mice, but how does a mouse get schizophrenia? According to the article by Winship et al. (written in 2019), there are three ways used to induce (give) schizophrenia in a mouse.

1. Drug Induced

Just as it sounds, drug induced models are when a mouse is dosed with drugs to induce schizophrenia-like symptoms. The most common drugs used are amphetamines like methamphetamine or Adderall.

1. Genetic Modification

Mice in this category are genetically modified while the mice are still in the womb. The genes that are modified are not random. A scientist will choose the genes to change based on past information gathered about which genes might cause schizophrenia in humans.

1. Developmental Modification

In these mice, their regular development in the womb is disrupted. This is usually done in one of two ways. Way 1 being stressing the mother whether that be with sleep-deprivation, poor diet, etc. Way 2, the most common, is to inject a drug into the fetal mouse. The drug injection has become so common for inducing schizophrenia in mice that it has become protocol to inject it on day 17 of gestation (pregnancy).

Now we know how mice “get” schizophrenia and why they are important for medical research. 

 

References

 

 [1] Bryda, E. C. (2013). The Mighty Mouse: The Impact of Rodents on Advances in Biomedical Research. Missouri Medicine, 110(3), 207–211.

[2] Photo by Kanashi on Unsplash

 [3] Winship, I. R., Dursun, S. M., Baker, G. B., Balista, P. A., Kandratavicius, L., Maia-de-Oliveira, J. P., Hallak, J., & Howland, J. G. (2019). An Overview of Animal Models Related to Schizophrenia. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 64(1), 5–17. https://doi.org/10.1177/0706743718773728

 

Schizophrenia is a condition that, like many other neuropsychiatric conditions, is not well understood. Because it is not well understood, treating and developing new treatments for schizophrenia are difficult. One treatment mechanism lies in the Wnt signaling pathway. This pathway is mostly observed in nervous system development and neural circuit function. Because of this, some theorize that disruptions in prenatal and/or postnatal brain development could be triggers for schizophrenia.

 Symptoms of Schizophrenia

 Schizophrenia can manifest through a variety of symptoms. Some of these symptoms could be due to reduction in gray matter in the medial and superior temporal lobes as well as the prefrontal cortex that has been shown in patients with schizophrenia. These changes impact interneuron communication and integration [1].

The symptoms of schizophrenia cause it to be one of the leading causes of disability in the United States. According to VeryWellHealth.com, symptoms are categorized as positive, negative, or cognitive. Positive (also called psychotic) symptoms are added to an individuals perception of the world. Positive symptoms occur with delusions, hallucinations, disorganized thinking, or abnormal behavior such as agitation and involuntary or uncoordinated behavior. Negative symptoms occur with a reduction in typical behaviors which includes lack of motivation, interest in daily activities, and emotion, social withdrawal, and difficulty with typical functioning. Cognitive symptoms disrupt memory, attention, and concentration and can manifest as difficulty processing information and making decisions, inability to pay attention or concentrate, and difficulty using information that is heard [2].

Most of the treatments available for schizophrenia can help alleviate some of the positive symptoms of the disease but do not treat the underlying cause. A potential root cause treatment mechanism lies in the Wnt signaling pathway [3].

How Does Wnt Signaling Work?

There are multiple Wnt pathways which have different functions. The canonical or traditional pathway is most related to the development and treatment of schizophrenia and will be discussed in further detail. Each of the Wnt pathways uses Wnt protein as a signaling ligand which begins an intracellular cascade of effects. When there is no ligand binding to the receptor in the canonical Wnt pathway, β-catenin (a transcription factor) is not phosphorylated and as a result is degraded by a GSK destruction complex. When β-catenin is destroyed, it cannot perform gene transcription in the nucleus. In summary, lack of Wnt signaling is correlated to increased GSK and decreased β-catenin [3].

When Wnt is available to bind do a receptor as a ligand, disheveled protein dissociates the GSK destruction complex. This decreases the phosphorylation of β-catenin which allows for it to have increased stability in the cytoplasm of the cell. The stable β-catenin is then transferred to the nucleus where it can initiate gene transcription. Canonical Wnt signaling allows for increased β-catenin levels and decreased GSK [3].

The non-canonical Wnt pathways can also affect neural circuit formation and synaptic plasticity in the central nervous system without the activity of β-catenin, as shown in Figure 1.

Neural Development

Embryonic development is known to be regulated by Wnt signaling which plays a role in tissue polarity, cell fate and movement, and neuronal connectivity. One way that Wnt signaling affects is through synaptic development and synaptic modulation. Typical synaptic development through early childhood is shown in Figure 2.

Wnt Dysfunction in Schizophrenia

Individuals with Schizophrenia tend to have overactive dopamine receptors which oppose Wnt signaling. Dopamine will increase GSK dephosphorylation activation, which will phosphorylate β-catenin, increasing its degradation. In contrast to this, proper Wnt signaling would phosphorylate and inactivate GSK, thereby decreasing β-catenin phosphorylation, allowing for increased β-catenin concentration which acts to promote transcription. To further support this theory, several genetic variations associated with schizophrenia or other neurodevelopmental disorders have been associated with Wnt signaling [3].

Treatment Using the Wnt Pathway

Wnt signaling is a direct or indirect target of many drug treatments for schizophrenia or other psychiatric conditions. Antipsychotic treatments often inhibit D2 dopamine receptors which can decrease GSK activity, allowing the Wnt signal to be more active. Lithium is another commonly used neuropsychiatric treatment that can directly activate the Wnt pathway. By inhibiting GSK, lithium allows more β-catenin to accumulate and perform transcription functions. Metabotropic glutamate receptor (mGluR2/3) agonists can also be used to activate Akt which will phosphorylate/inhibit GSK3 which can result in increased disheveled protein and β-catenin. Each of these effects can be seen below in Figure 3 [3].