Cobbers on the Brain

The endogenous cannabinoid system has opened new ways for understanding how our bodies work, over the years more research has been conducted in understanding the system. The Endocannabinoid system has two receptors CB1 and CB2. CB1 is the most common type of receptor, it is found in the CNS in areas of the hippocampus, neocortex, and brainstem, as well as other parts of the body such as the eyes and the testes. CB1 receptors are in synapses, which is where nerve cells connect. CB1 receptors interact with substances such as THC which arises from marijuana, synthetic drugs, and natural compounds produced by the body. THC plant contains over 60 different compounds that can activate CB1 and CB2 receptors, the most well-known being ∆9-THC, exposure to THC can lead to various effects in humans such as pain relief, relaxation, and discomfort.3 They’re several consequences that arise from the overuse of THC, some short-term effects are for instance when an individual smokes this, it will pass through the lungs into the bloodstream and from there travel to the brain and other organs. The high that people experience from THC is due to different parts of the brain being activated with the CB receptors and this causes changes that cause altered senses, changes in mood, and alterations in mood.1 Long-term effects include breathing problems for those who smoke it, if used while pregnant this may impact the child’s memory and problem-solving, and overusing THC can worsen symptoms in individuals who experience schizophrenia, paranoia, and temporary hallucinations.2 The CB2 receptor is found in specific parts of the brain, it is mainly related to the immune system, however in the brain CB2 receptors are found mostly in the microglia which are immune cells that play a role in inflammation. In the past, research into the involvement of CB2 receptors in drug addiction was limited. However, there has been a growing body of research shedding light on their roles in alcohol, nicotine, and cocaine addiction.3 Emmanuel Onaivi conducted research on CB2 and was one of the first to find how the receptors link to alcohol addiction, he used mice in this study and found that when given a CB2 receptor activator the mice would drink more alcohol, especially when they were stressed, when the CB2 gene was removed the mice showed a higher need for alcohol and would consume more of it. However, in involuntary drinking experiments, CB2-/- mice drank less alcohol which is an indication that more research is still needed to understand alcohol’s role. Research on cocaine found that Activating CB2 receptors in mice reduced the effects of cocaine and decreased their motivation to use the drug while blocking these receptors reduced relapse after stopping cocaine use, and reduced cocaine’s rewarding effects. Additionally, changes in CB2 receptor levels in the brain were associated with cocaine exposure and addiction development in both mice and rats. Research on Nicotine found that Activating CB2 receptors in rats reduced nicotine intake but increased motivation for nicotine while blocking these receptors had little effect on nicotine-seeking behavior. In mice lacking CB2 receptors, there was less preference for nicotine and reduced motivation to use it, and blocking these receptors decreased nicotine self-administration and withdrawal symptoms.4

What is the Endocannabinoid System and How Does it Work with Cannabis?

1Abuse, N. I. on D. (2019, December 24). Cannabis (Marijuana) DrugFacts | National Institute on Drug Abuse (NIDA). https://nida.nih.gov/publications/drugfacts/cannabis-marijuana

2Cannabis/Marijuana Use Disorder. (n.d.). Yale Medicine. Retrieved April 12, 2024, from https://www.yalemedicine.org/conditions/marijuana-use-disorder

3Kendall DA and Yudowski GA (2017) Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front. Cell. Neurosci. 10:294. doi: 10.3389/fncel.2016.00294

4 Navarrete, F., García-Gutiérrez, M. S., Gasparyan, A., Navarro, D., & Manzanares, J. (2021). CB2 Receptor Involvement in the Treatment of Substance Use Disorders. Biomolecules, 11(11), 1556. https://doi.org/10.3390/biom11111556

For many years, it’s been understood that obesity triggers a chronic, low-level inflammation throughout the body, which leads to various health problems like type 2 diabetes, high cholesterol, heart disease, and even brain-related issues. Interestingly, the brain plays a significant role in this process by regulating our appetite and metabolism. Genetic factors also play a role, with many obesity-related genes affecting brain function easy access to foods with unhealthy and high-calorie foods not only affects a person externally but also has internal consequences. Research has found the hypothalamus becomes inflamed. This inflammation disrupts the brain’s ability to regulate energy balance and contributes to insulin resistance, making it harder for the body to manage blood sugar levels. The hypothalamus plays a crucial role in regulating our metabolism and appetite, it contains different types of signals such as leptin and insulin which regulate our food intake. When a person consumes a high-fat diet, the hypothalamus is triggered and doesn’t respond as well to insulin and leptin, which are both hormones that regulate sugar and control appetite, saturated fatty acids interfere with normal signaling of insulin and leptin which then leads to positive energy balance and weight gain, the inflammatory pathways in the hypothalamus become activated leading to insulin and leptin resistance. This resistance leads to weight gain and other metabolic issues.2 Leptin, as we know, regulates appetite and energy balance, when you eat a high-fat diet it leads to an increase in fat stored in the body, which then turns to higher levels of leptin being released in the bloodstream, leptins role is to tell our brain to eat less and burn more energy which then helps us maintain a healthy weight, when a person consumes a high fatty diet this leads to leptin resistance, even though the brain levels are high the brain becomes less responsive to its signals when the body becomes resistant it doesn’t do a good job in telling the brain to eat less, which can lead to more eating and weight gain.3 When a person eats a lot of high fatty diet this can make cells less sensitive and when the cells don’t respond the body makes insulin to try to compensate for it, however over time this can mess up how the body controls hunger which makes a person want to eat more high fatty foods.1 TNF-α is a protein that responds to inflammation or infection, it promotes leptin and insulin resistance by activating certain signaling pathways. When the central nervous system is exposed to low levels of TNF- α this can impair leptin and insulin function in the hypothalamus. TNF- α also increases the production of PTP1B which is a protein that that negatively regulates insulin and leptin signaling. Elevated levels of PTP1B, particularly after long-term high-fat diet consumption, impair insulin signaling by directly inhibiting key molecules involved in the process. Deleting PTP1B specifically in neurons has been shown to improve metabolic health and reduce weight gain.

1 Ilyas, Athif, et al. “The Metabolic Underpinning of Eating Disorders: A Systematic Review and Meta-Analysis of Insulin Sensitivity.” Molecular and Cellular Endocrinology, Elsevier, 28 Oct. 2018, www.sciencedirect.com/science/article/abs/pii/S0303720718302867.

2Jais, Alexander, and Jens C Brüning. “Hypothalamic Inflammation in Obesity and Metabolic Disease.” The Journal of Clinical Investigation, U.S. National Library of Medicine, 3 Jan. 2017, pubmed.ncbi.nlm.nih.gov/28045396/.

3Mendoza-Herrera, Kenny et al. “The Leptin System and Diet: A Mini Review of the Current Evidence.” Frontiers in endocrinology vol. 12 749050. 24 Nov. 2021, doi:10.3389/fendo.2021.749050

Every year millions of students get concussions, instead of resting and following precautions to stay home, these students go back to school in as little as a few days, in part due to not wanting to get behind on school assignments, and having other stresses in life that can affect these students concussions can occur due to almost anything, walking outside and tripping on the sidewalk, playing sports and falling off a bike. These are all unpreventable and can happen at any given time. When a person experiences a concussion, it triggers responses throughout the body, the ions rush and release a chemical known as glutamate, due to this certain ions like potassium leave the cell while sodium and calcium enter the cell; this messes up the balance, this imbalance triggers more reactions in the body and specific ion channels start to open, all of this leads to disturbances in the brain and this is why people experience symptoms after a concussion. When a person gets a concussion or gets injured, the body tries to fix things by using up all the energy to restore the balance of the ions and cell function. However, this can lead to a shortage of resources and an increase in certain substances such as ADP. Sometimes the brain needs more energy than the blood flow provides this creates a mismatch and disrupts calcium levels inside the cells. The injury also changes how cells handle oxidation, creating harmful molecules and altering metabolic pathways, which can lead to longer-term issues and make the brain more susceptible to further damage, after this rush of energy the brain’s ability to use glucose is messed up for about a week, this causes learning and behavior problems, especially amongst adults. Concussion is a type of mild traumatic brain injury. Axons are long extensions of nerve cells and are very sensitive to being stretched when a brain injury occurs the outer layer of axons becomes open and is then vulnerable to damage, this causes a disturbance in the axons causing problems with their functions and leading them to break apart. Research on animals shows that their cells can still survive after the axonal breakage but most likely cannot function normally. Other research has suggested that some dietary supplements can help reduce this damage and/or change how quickly it happens. Inflammation in traumatic brain injuries is a topic that is not highly talked about, for many reasons, in severe cases of TBI inflammation is marked by the activation of microglia, it was also found that mild TBI can trigger inflammatory responses.2 In the past, people believed brain inflammation couldn’t happen because of the blood-brain barrier. But now we know it can occur with conditions like concussions. It involves immune cells being drawn in and brain cells like microglia and astrocytes getting activated. High levels of GFAP indicate astrocyte activation in people with brain injuries. Understanding how inflammation works in concussions is tricky. It can help healing, but too much can be bad. Figuring out how to manage inflammation in concussions is still being studied.1

https://theconcussionblog.com/category/rehabilitation/

1Giza, Christopher  C, and David A Hovda. “The New Neurometabolic Cascade of Concussion | Request PDF.” The New Neurometabolic Cascade of Concussion, Fundamental Principles, 1 July 2014, www.researchgate.net/publication/10598081_The_New_Neurometabolic_Cascade_of_Concussion.

2Patterson, Z. R., & Holahan, M. R. (2012). Understanding the neuroinflammatory response following concussion to develop treatment strategies. Frontiers in cellular neuroscience, 6, 58. https://doi.org/10.3389/fncel.2012.00058

Over the years anxiety has affected millions of people around the world. Occasional anxiety is normal as it occurs occasionally this type of stress includes family problems, health, or money. When a person has an anxiety disorder that is when the problem arises. This type of anxiety in most people doesn’t go away, their symptoms can interfere with their day-to-day living. Some symptoms of Generalized anxiety disorder are feeling restless, wound-up, or on edge and Having headaches, muscle aches, stomachaches, or unexplained pains. Anxiety can be treated by types of Psychotherapy such as cognitive behavior therapy or medications such as antidepressants.2 Stress is one of many factors of anxiety. Psychologically stressful events trigger strong physiological, behavioral, and cognitive responses, with anxiety levels playing a key role. Higher anxiety leads to stronger memories of stressful situations, increasing the risk of conditions like PTSD. Researchers investigated how anxiety affects brain mechanisms involved in memory formation using three approaches: exposing rodents to novel and bright environments, manipulating GABAergic signaling with drugs, and studying the effects of voluntary exercise. They found that anxiety levels influenced molecular responses in dentate neurons, with heightened anxiety leading to increased stress-related molecular changes. Heightened anxiety levels can greatly affect how our brains respond to stressful events, potentially leading to conditions like PTS. Anxious individuals tend to form stronger memories of traumatic experiences. Research focuses on the role of anxiety in altering molecular processes in specific brain regions, particularly the dentate gyrus, which is important for memory formation. By studying how anxiety influences these molecular pathways, the paper sheds light on how PTSD might develop after traumatic events.4 GABAergic tone refers to how GABA receptors behave, in anxiety it has been shown that GABAergic tone is reduced.3  GABA works to counteract the effects of natural stimulants such as increased heart rate or adrenaline rush by inducing a state of relaxation in the brain, when the tone is low the body finds it difficult to relax such example would be in stressful events. Glutamate and GABA need to be balanced in the brain, if there is too much glutamate this causes anxiety, migraines, restlessness, etc.[1] If an imbalance does occur, there are medications available to treat it, Valium, Xanax, and Klonopin are three of the known drugs used to combat this, they act as GABA A receptors and increase the actions of GABA, they do so by binding on a different location that GABA doesn’t bind in, and this increases the action of the GABA receptor, this is known as the allosteric effect. Which has a primary role of opening receptors and allowing negative ions to enter, this decreases the chance of firing an action potential and promotes a state of calmness among the individual experiencing anxiety, depression, etc.5

1About GABA and Glutamate. (2018, December 30). https://pmhealthnp.com/about-gaba-and-glutamate/

2“Anxiety Disorders.” National Institute of Mental Health, U.S. Department of Health and Human Services, www.nimh.nih.gov/health/topics/anxiety-disorders. Accessed 25 Mar. 2024.

3Cauli, O., Mansouri, M. T., Agusti, A., & Felipo, V. (2009). Hyperammonemia Increases GABAergic Tone in the Cerebellum but Decreases It in the Rat Cortex. Gastroenterology, 136(4), 1359-1367.e2. https://doi.org/10.1053/j.gastro.2008.12.057

4Reul, Johannes M.H.M. “Making Memories of Stressful Events: A Journey along Epigenetic, Gene Transcription, and Signaling Pathways.” Making Memories of Stressful Events: A Journey Along Epigenetic, Gene Transcription, and Signaling Pathways, Frontiers, 9 Jan. 2014, www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2014.00005/full.

5Huang, J., Xu, F., Yang, L., Tuolihong, L., Wang, X., Du, Z., Zhang, Y., Yin, X., Li, Y., Lu, K., & Wang, W. (2023). Involvement of the GABAergic system in PTSD and its therapeutic significance. Frontiers in molecular neuroscience, 16, 1052288. https://doi.org/10.3389/fnmol.2023.1052288

Addiction is a treatable, chronic medical disease involving complex interactions among brain circuits, genetics, the environment, and an individual’s life experiences. [1] Addiction has been a part of cultures for as long as people have been using addictive substances. The most common ones are caffeine, nicotine, and alcohol. [2] Addiction affects the brain and affects how a person’s life circumstance influences the use of addiction, it involves factors such as cultural, psychological, and genetics of a person. Many individuals who become addicted, struggle in knowing when to stop. When a person takes a drug, it affects their “reward circuit “This induces feelings of euphoria and triggers a surge in the neurotransmitter dopamine when a reward system is functioning properly, individuals engage in essential behaviors such as eating nutritious food and spending time with loved ones, when dopamine levels increase it strengthens the association between taking drugs and the feeling of joy they produce, consequently individuals are more likely to be involved in these behaviors despite the possibility of bad outcomes all due to dopamine making them feel good. When a person continuously takes drugs, their brain will start to adapt to the drug and adjust by making cells in the reward system less responsive to it, individuals won’t feel the same way after taking the drug multiple times this becomes known as tolerance. Some individuals during this time will increase drug intake, in an attempt to experience a “high” such as before, the changes in the brain can cause pleasurable activities to decrease such as eating and spending time with others, long long-term effects can affect learning, judgment, decision making and memory of an individual. [3] Drug abuse is increasing and it’s important to understand what abuse means and its relation to addiction. Abuse is when a drug or prescription is used in a way that is not intended, abuse can start in any way, and at first, individuals may not be aware of this, such example would be grounding up pills and snorting and/or injecting the pill to get high. The problem with doing this is that these prescription drugs “most often misused include opioid painkillers, anti-anxiety medicines, sedatives and stimulants.”[4] Consequences of abusing prescription drugs can lead to serious life-threatening risks, and ultimately death. Mu Receptors (mu-opioid) receptors are GPCRs, they regulate many functions in the brain, and they are mainly found in the central nervous system. Mu receptors are part of the body’s endogenous opioid system, which regulates pain, reward, and addictive behaviors. [5] When opioid molecules attach to mu receptors on brain cells in the LC (locus coeruleus), they reduce the release of neurotransmitter NA (norepinephrine), causing effects like drowsiness, slowed breathing, and low blood pressure—common signs of opioid intoxication. But with continued opioid use, the LC cells adapt by becoming more active. So, when opioids are around, this increased activity balances out their effects, and the person feels normal. However, when opioids aren’t present, the LC cells release too much NA, leading to symptoms like restlessness, anxiety, cramps, and diarrhea. [6] The FDA has approved medications to treat addiction, but that doesn’t eliminate it, but they’re also resources out there for individuals experiencing addiction, with advancements in technology, hopefully, scientists are medical professional can find more treatment options for this addiction crisis we are facing.

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

[1] “What Is the Definition of Addiction?” What Is the Definition of Addiction? , American Society of Addiction Medicine, 2024, www.asam.org/quality-care/definition-of-addiction.

[2] Crocq, M.-A. (2007). Historical and cultural aspects of man’s relationship with addictive drugs. Dialogues in Clinical Neuroscience, 9(4), 355–361.

[3] NIDA. “Understanding Drug Use and Addiction DrugFacts.” National Institute on Drug Abuse, 6 Jun. 2018, https://nida.nih.gov/publications/drugfacts/understanding-drug-use-addiction Accessed 20 Mar. 2024.

[4] “Prescription Drug Abuse.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 25 Oct. 2022, www.mayoclinic.org/diseases-conditions/prescription-drug-abuse/symptoms-causes/syc-20376813.

[5] Volkow, Nora D et al. “The addicted human brain: insights from imaging studies.” The Journal of clinical investigation vol. 111,10 (2003): 1444-51. doi:10.1172/JCI18533

[6]  Herman, Timothy F. “Mu Receptors.” Mu Receptors, U.S. National Library of Medicine, 30 July 2023, www.ncbi.nlm.nih.gov/books/NBK551554/#article-25311.s6.

Autism Spectrum Disorder (ASD) is a developmental disability characterized by variations in brain structure and function. While some individuals with ASD have identifiable genetic conditions, the underlying causes for many remain elusive. Scientists hypothesize that ASD arises from a combination of factors, both genetic and environmental, which collectively alter typical developmental pathways. [1] Prenatal toxins are one of many factors that affect ASD. Infants born to mothers with Pre-Gestational Diabetes Mellitus (PGDM) or Gestational Diabetes Mellitus (GDM) may experience mild developmental challenges post-birth. These difficulties can impact both fine and gross motor skills, potentially increasing the likelihood of learning difficulties and attention deficit hyperactivity disorder (ADHD), a common neurological issue in autism spectrum disorder (ASD). The adverse effects of maternal diabetes on fetal brain development may stem from heightened intrauterine oxidative stress, epigenetic alterations in gene expression, and other yet unknown factors. Although maintaining good diabetes control during pregnancy can mitigate these risks, it may not eliminate them. Research indicates a correlation between maternal rubella infection and a heightened incidence of ASD, whereas infections such as Toxoplasma, Parvovirus, and Tic bone do not appear to be associated. These changes may contribute to the development of conditions like autism spectrum disorder (ASD) as the child grows. [2] Inflammation is another factor that links or contributes to ASD, inflammation affects the immune system and certain proteins called cytokines, which play a role in the body’s response to infection. Scientists are studying how this inflammation affects the brain using both animal models and lab experiments. They want to understand how these immune responses impact the development of autism. When a pregnant woman gets sick, her body releases certain chemicals. These chemicals activate special immune cells in her body, which then release more chemicals. These immune responses not only affect the mother but also reach the placenta, a special organ in the womb. The placenta has its immune cells, and when it detects these chemicals, it starts making more of them. This can cause harm to the placenta and let these inflammatory chemicals enter the baby’s developing body. The baby then starts making similar chemicals. Eventually, these harmful chemicals can reach the baby’s brain and cause swelling and other problems. [3]  Environmental Factors such as exposure to metals, pesticides, and other contaminants can also contribute to the possibility of the child having autism. Researchers found that the high consumption of fish, especially for those living in the Republic of Seychelles because the fish contain mercury, exposures for those living in the Republic of Seychelles this is because the fish contain mercury, exposures to other metals such as lead, arsenic, zinc, or manganese are also in this category. [4] Various theories effectively explain the understanding of Autism. The E/I imbalance theory suggests that a decrease in GABAergic neurons can lead to seizures. In the brain’s striatum, medium spiny neurons (MSNs) receive signals from the thalamus and dopamine-producing neurons from the substantia nigra. These MSNs become active just before initiating movements. Changing how dopamine affects these MSNs could upset the E/I balance in the striatum, potentially causing symptoms of ASD. This is significant because the striatum is crucial for choosing actions and behaviors related to rewards. The altered network connectivity theory suggests that there’s a problem with how brain cells communicate. More severe symptoms of ASD are linked to larger distortions in how brain areas connect between the two hemispheres. The predictive coding hypothesis proposes that our brains predict what we expect from the world around us and adjust when things don’t match up. This might relate to why individuals with ASD prefer routines and repetitive behaviors—they may have different expectations about their environment.

https://doi.org/10.3390/ijms222111516

[1] “What Is Autism Spectrum Disorder?” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 9 Dec. 2022, www.cdc.gov/ncbddd/autism/facts.html.

[2] Ornoy, A., et al. “Prenatal Factors Associated with Autism Spectrum Disorder (ASD).” Reproductive Psychology, Prenatal factors associated with autism spectrum disorder (ASD), 26 May 2015, www.sciencedirect.com/science/article/abs/pii/S0890623815000751?via%3Dihub.

[3] Zawadzka A, Cieślik M, Adamczyk A. The Role of Maternal Immune Activation in the Pathogenesis of Autism: A Review of the Evidence, Proposed Mechanisms and Implications for Treatment. International Journal of Molecular Sciences. 2021; 22(21):11516.

[4] “Autism.” National Institute of Environmental Health Sciences, U.S. Department of Health and Human Services, 19 Apr. 2023, www.niehs.nih.gov/health/topics/conditions/autism#:~:text=Air%20pollution%20%E2%80%93%20Researchers%20found%20early,as%20likely%20to%20develop%20ASD.