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].

What is autism spectrum disorder?

Autism spectrum disorder (ASD) is defined as a developmental disorder characterized by difficulties in communication with other people, repetitive behaviors and interests, and that these symptoms negatively impact their ability to function in everyday activities, including work and school. It is defined as a spectrum disorder because types and severity of symptoms can vary. ASD social-related symptoms can look like minimal eye contact, lack of sharing emotion, slow or minimal response, inappropriate facial expressions for the situation, and others. Behavior-related symptoms of ASD include being overly focused on tasks, being upset about changes in routine and transitions, sensitivity to stimuli, and repeating behaviors or phrases. These are symptoms that clinicians look for to diagnose children with ASD. [1]

What causes ASD?

The exact cause of ASD is unknown, but there are genetic and environmental risk factors that are known for ASD. Some genetic risk factors are having a sibling with autism, older parents at birth, low birth weight, and genetic factors like fragile X, Rett, and down syndromes. Environmental risk factors are extensive and include exposure to air pollution and toxic materials, maternal disorders like obesity, diabetes, or immune system disorders, and birth difficulties in which there is a period of oxygen deprivation. [3]

What is happening in the brain?

There are three main theories that scientists have about what is going on in the brain of an individual with ASD. The first theory is that there is E/I imbalance in the brain. This means that there is an imbalance of glutamate and GABA levels. It has been found through studies that the problem in individuals with ASD is that there are lower levels of GABA interneurons and GABA activity. The fact that one comorbidity of ASD is seizures, it makes sense that there is a lack of inhibitory neurotransmission in the brain. Another theory is that there is altered network connectivity in the brain. This means that there is decreased connectivity between brain regions which can explain the behavioral abnormalities in ASD. The third theory is the predictive coding hypothesis which looks at how children with ASD have difficulties adjusting to situations that are different from their expectations. This could explain why children with ASD have more sensitivity to stimuli and why changes in routine and transitions can be difficult. One commonality between these three theories is that they all have a connection with the dopaminergic system, so dopamine dysfunction is thought to be a neurological cause of ASD. [5]

Treatments and therapies for ASD

The most common treatment for ASD is applied behavior analysis (ABA) in which skills are taught to the child through discrete-trial testing and behaviors are shaped through a reward system. There are other treatments that can be used other than ABA like naturalistic developmental behavioral intervention (NDBI) which utilizes the child’s everyday routine and environment for behavioral interventions. Children with ASD often also go to speech therapy, occupational therapy, and physical therapy as needed. There are no common medications that are used to treat ASD due to how much is unknown about what is going on in the brain. [7]

References

[1] (2023, February). Autism Spectrum Disorder. National Institute of Mental Health. https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd. 

[2] Autism Screening and Diagnosis. Dr. Chantal. https://lifecounselor.net/evaluations/autism-screening-and-diagnosis/. 

[3] (2023, April 19). Autism. National Institute of Environmental Health Sciences. https://www.niehs.nih.gov/health/topics/conditions/autism. 

[4] (2022). Autism. Dr. Chhabra Healthcare. https://drchhabrahealthcare.com/disease/autism-homeopathy-treatment/. 

[5] DiCarlo, G. E. & Wallace, M. T. (2022). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and Behavioral Reviews, 133, 1-29. https://doi.org/10.1016/j.neubiorev.2021.12.017. 

[6] Stefanics, G., Kremláček, J., & Czigler, I. (2014). Visual mismatch negativity: A predictive coding view. Frontiers in human neuroscience. 8. https://www.researchgate.net/figure/Simplified-scheme-of-the-hierarchical-predictive-coding-framework-Friston-2005-2008_fig1_266401430. 

[7] CDC. (2022, March 9). Treatment and Intervention Services for Autism Spectrum Disorder. Centers for Disease Control and Protection. https://www.cdc.gov/ncbddd/autism/treatment.html. 

[8] What is ABA Therapy? OCASG. https://www.otagokidsautism.org/therapy. 

What is autism spectrum disorder?

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder where individuals may display deficits in social communication, restricted interests, and/or repetitive behaviors. In the future, subtypes may be formed due to the symptomology and comorbidities that the individual has which may be defined as psychiatric, multisystem, or seizures [1]. Psychiatric comorbidities are typically ADHD or anxiety and epilepsy falls into the seizures category. Multisystem comorbidities in ASD have shown to be between the gut and brain interaction, particularly through functional gastrointestinal disorders (fGID). This may be shown through exacerbated experience of constipation or diarrhea which, in turn, may increase behavioral symptoms [1].

An article by Dicarlo and Wallace explains different genetic and environmental risks that are also associated with ASD. Specific variants have been found to be important, such as syndromic forms which form by chromosomal abnormalities or single gene mutations. Variants known as copy number variants (CNVs) and single-nucleotide variants (SNVs), which differ in how many base differences they create, also contribute to ASD. Lastly, internal and external environmental factors contribute to the development of ASD, specifically toxins and toxic exposures, perinatal conditions, and an overall male-biased prevalence.

What is the science behind this disorder?

Figure 1 below displays some, but not all of the major areas of the brain associated with ASD. Some of these include the striatum, involved in movement and the reward system, amygdala, which regulates fear and emotion, and the hippocampus, the main memory center of the brain. A lot of these regions receive signals from different parts of the cortex [2]. Each of these then work together in different networks and pathways (figure 2) to produce specific responses and actions such as social motivation and behavior, movements, etc. Dopamine (DA), an important neurotransmitter for social aspects of humans is largely involved in these processes. In an article by Mandic-Maravic et al., the DA pathway is shown to be altered in individuals with ASD, resulting mainly in reward dysfunction. The nigrostriatal circuit (NS), which projects toward the striatum, also involves DA. This means that if DA is dysfunctional, the ability to act suitably toward goal-directed behavior is changed [3]. Further, DA is found to have a connection to gastrointestinal symptoms because of its placement in the enteric nervous system, which is a part of the peripheral nervous system [1]. Overall, connection between different sections of the brain is often weaker in ASD, which is especially evident in the DA system.  All of these factors have been taken into account to create theories for the development of ASD.

Fig 1. Regions of the brain

Edit image, resize image, crop pictures and appply effect to your images. (n.d.). Artpictures.Club. Retrieved February 12, 2024, from http://artpictures.club/

Fig 2. Networks and pathways

DiCarlo, G. E., & Wallace, M. T. (2022).

Theories

1. Excitatory-inhibitory balance disruption theory: This theory claims that there are alterations in the ratio of excitatory and inhibitory (E/I) neurotransmission. Different processes such as altered cellular metabolism, receptor function, or neurotransmission uptake may cause the disruption in the ratio. DA plays a role in the disruption as their inputs onto other neurons might change E/I levels. An example of the outcome of this would be if the disrupted balance took place in the striatum, which would alter the function of reward-mediated behaviors [1].
2. Altered network connectivity theory: Distortions in communication in and from the cerebral cortex may also drive different behaviors in ASD. This theory uses fMRI to view increases, decreases, and resting states of connectivity in ASD. Overall, it has been found that there are greater distortions and variability in connectivity maps in people with ASD, meaning their brains are unable to communicate as they should [1].
3. Predictive coding hypothesis: Assumes our brain creates internal models of our external sensory environment that serve as our predictions and perceptions of the world. Individuals with ASD are said to improperly form and fail to update internal models of the environment. This could be the cause to altered social cues and communication as well as an increased reliance on incoming sensory information, leading to their hypersensitivities [1].

While these are all different theories, they are not separate from one another. In fact, they go together very well as each one might lead to the other. For example, E/I balance disruption could lead to altered brain networks [1].

[1] DiCarlo, G. E., & Wallace, M. T. (2022). Modeling dopamine dysfunction in autism spectrum disorder: From invertebrates to vertebrates. Neuroscience and biobehavioral reviews, 133, 104494. https://doi.org/10.1016/j.neubiorev.2021.12.017

[2] Autism in the brain, region by region. (2017, February 27). Spectrum | Autism Research News. https://www.spectrumnews.org/features/legacy-special-reports/autism-brain-region-by-region/

[3] Mandic-Maravic, V., Grujicic, R., Milutinovic, L., Munjiza-Jovanovic, A., & Pejovic-Milovancevic, M. (2022). Dopamine in Autism Spectrum Disorders-Focus on D2/D3 Partial Agonists and Their Possible Use in Treatment. Frontiers in psychiatry, 12, 787097. https://doi.org/10.3389/fpsyt.2021.787097