# data[].attributes.body
The 1970 Nobel Prize Winner of Physiology or Medicine Julius Axelrod was an astound scientists who advanced the field of neuroscience and pharmacology through his findings within the field of humoral neurotransmitter storage, release, and inactivation.

Dr. Axelrod began his career working as a laboratory technician in New York after he had been rejected from medical school¹. He began to pursue a Masters of Science degree in chemistry from NYU where he completed his research thesis on the chemical breakdown of enzymes in cancerous tissue¹. His career took a turn when he began to work under Bernard Brodie where he helped discover that acetaminophen (Tylenol) had better painkiller-mechanisms than the preceding prescriptions being used¹. This led him to continue on a scientific track towards pharmacology and understanding synaptic neuromechanisms in which he obtained his PhD in 1955. Dr. Axelrod then went on to received his Nobel Prize in 1970 for his work regarding the release, reuptake, and storage of epinephrine and norepinephrine¹.

As seen in this photo of him, Axelrod lost sight of his eye in a laboratory accident in 1937 when an ammonia bottle exploded. This incident prompted him to wear a darkened lens over his left eye for the rest of his life¹.

Source:

1. https://academic.oup.com/eurheartj/article/41/39/3778/5944105

# data[].attributes.headline
His Research on Acetaminophen and how it Influenced his Career Trajectory

# data[].attributes.subject
His Research on Acetaminophen and how it Influenced his Career Trajectory

# data[].attributes.body
In 1946, Axelrod joined the Goldwater Memorial Hospital research division where he played an active role in discovering acetaminophen as the active pain-relief chemical in analgesic medications¹. His research led this chemical to become one of the most popular painkiller medications, marketed under the brand Tylenol.

This discovery influenced Axelrod's career towards one dedicated to studying the effects of drug metabolism. He later went on to discover the role of hepatic enzymes and NADPH in metabolizing drugs². His natural research capabilities caused him to pursue a PhD in Pharmacology at George Washington University so he could conduct independent research. Because of the sophistication of his previous publications, he was allowed to advance within the PhD program and graduated in only one year².

Sources:

1. https://www.britannica.com/biography/Julius-Axelrod

2. https://www.nature.com/articles/1300799

# data[].attributes.headline
Personal Interest in the Sympathetic Nervous System and Treating Mental Illness

# data[].attributes.subject
Personal Interest in the Sympathetic Nervous System and Treating Mental Illness

# data[].attributes.body
Axelrod was one of the first individuals to conduct experiments in the United States using LSD, or Lysergic acid diethylamide, and determining how the drug was metabolized in the body. He began his research with LSD beginning in 1954 and continued into 1958, right around the time of controversy when Timothy Leary, a psychologist at Harvard University, began advocating the usage of LSD for mental health¹. Instead, Axelrod was curious how the emergence of new drugs for mental illness actually worked (the chemical mechanisms behind these treatments). He realized that a lot of the prescription drugs for treating anxiety or psychosis were agents of altering consciousness, which caused him to shift his focus on how neurotransmitters physiologically affected mental health¹.

Source:

1. https://profiles.nlm.nih.gov/spotlight/hh/feature/neurotransmitters

# data[].attributes.body
Seymour Kety was a scientist at the National Institution of Mental Health who acknowledged the relationship between metabolism and mental health¹. He also coined the term “father of modern biological psychiatry” after his work where he used oxygen flow as a rate of metabolism in individuals with and without schizophrenia¹.

It wasn’t until Axelrod attended a seminar at the NIMH in 1956 where Kety presented the research of Humphrey Osmond and Abraham Hoffer when Axelrod became interested in how neurotransmitters played a role in mental illness. Osmond and Hoffer’s work showed that Vitamin B helped relieve the symptoms of schizophrenia in patients, which also led to the finding that the hormone adrenaline may be “imbalanced” in these individuals¹. This caused Axelrod to begin his study on norepinephrine and the enzyme, monoamine oxidase (MAO), and understanding its role in the synaptic cleft of those with schizophrenia¹.

Sources:

1. https://profiles.nlm.nih.gov/spotlight/hh/feature/neurotransmitters

# data[].attributes.headline
What was originally assumed about MAO inhibitors prior to Axelrod's work

# data[].attributes.subject
What was originally assumed about MAO inhibitors prior to Axelrod's work

# data[].attributes.body
Monoamine oxidase (MAO) inhibitors were introduced as an antidepressant treatment in the early 1950s. This class of drugs were the first antidepressant medications prescribed to those with depression and other nervous system disorders, however, they were not commonly described due to the side effects¹. There was also little understanding of how they operated in the synaptic cleft. It was originally thought that MAO inhibitors disabled the MAO enzyme, one that is responsible for allowing neurotransmitters “to work” properly, that allowed the neurotransmitters to maintain function within the post-synaptic cleft². We now know thanks to Axelrod (later to be discussed in this padlet), that MAO enzymes do not “deactivate” the neurotransmitter, but actually have a different role in the synaptic cleft².

Sources:

1. https://www.ncbi.nlm.nih.gov/books/NBK539848/#:~:text=Monoamine%20oxidase%20inhibitors%20(MAOIs)%20were,and%20depression%20with%20atypical%20features.

2. https://profiles.nlm.nih.gov/spotlight/hh/feature/neurotransmitters

# data[].attributes.body
Ulf von Euler was a scientist from Sweden who worked with Henry Dale’s on the study of acetylcholine in the intestine in London¹. It was in 1946 while working with Dale that Euler had discovered and published his isolation and identification of norepinephrine as a neurotransmitter¹. He had originally discovered this chemical through its similarities to acetylcholine and how it was not only active in the brain and intestine but also modulated the activities of these muscles¹.

von Euler established that norepinephrine was the predominant postganglionic neurotransmitters for the sympathetic nervous system, which laid the foundation for Axelrod to demonstrate how it operated and was removed from the synaptic cleft¹. von Euler also shares the Noble Prize with Axelrod due to how influential his research was to Axelrod’s discovery.

Sources:

1. https://www.sciencedirect.com/science/article/pii/S0025619611649483

# data[].attributes.headline
Discovery of COMT and Catecholamine Metabolism

# data[].attributes.subject
Discovery of COMT and Catecholamine Metabolism

# data[].attributes.body
While still pursuing his interest in understanding the relationship between drug metabolism and mental health, he started his research towards his award-winning discovery by learning more specifically about catecholamine metabolism¹. In 1959, Axelrod isolated and purified the enzyme, currently known as catechol-O-methyltransferase (COMT), that inactivates dopamine through methylation. This advancement in understanding drug metabolism and how it relates to mental health provided other scientists with the techniques to isolate several other metabolic methyltransferase enzymes. It also led Axelrod to focus on how norepinephrine specifically is inactivated in adrenergic neurotransmission¹. Because the termination of adrenergic transmission was slower than that of dopamine, Axelrod theorized that there was another mechanism that broke down norepinephrine besides inactivation¹.

Sources:

1. https://www.remedypublications.com/open-access/the-story-of-julius-axelrod-1912-2004-a-testament-to-commitment-5497.pdf

# data[].attributes.headline
Axelrod Discovers Neurotransmitter Reuptake Cycle in the Synaptic Cleft

# data[].attributes.subject
Axelrod Discovers Neurotransmitter Reuptake Cycle in the Synaptic Cleft

# data[].attributes.body
The research that awarded Axelrod the Nobel Prize of Physiology or Medicine in 1970 was a compilation of all of his prior research curiosities and pursuits.

Axelrod worked with Seymour Kety to obtain a small supply of labeled epinephrine (more on why that is important for research in this padlet), to investigate catecholamines in individuals with schizophrenia¹. They discovered the uptake mechanism in the synaptic cleft by identifying tissue with large amounts of unmetabolized labeled epinephrine that was directly related to the density in which adrenergic sympathetic nerves innervated the organ¹.

By 1961, Axelrod had concluded that neurotransmitters do not stop working once they reach the post-synaptic nerve, but instead are captured (reuptaken) by the pre-synaptic nerve terminal, stored, and used again for later neurotransmission². His research shows that the concentration of catecholamines remains at a consistent level within tissues because they are not degraded, but continuously "synthesized, released, metabolized, and recaptured"².

Source:

1. https://www.remedypublications.com/open-access/the-story-of-julius-axelrod-1912-2004-a-testament-to-commitment-5497.pdf

2. https://profiles.nlm.nih.gov/spotlight/hh/feature/neurotransmitters

# data[].attributes.headline
Applying the Reuptake Process Theory to other Drugs

# data[].attributes.subject
Applying the Reuptake Process Theory to other Drugs

# data[].attributes.body
After discovering the process of how norepinephrine re-uptakes into the synaptic cleft, Axelrod went on to learn more about how other drugs blocked this uptake process (similar to MAO inhibitors). He studied cocaine, amphetamine, and other sympathomimetic amines that specifically blocked norepinephrine from reuptake¹. He found that cocaine, known vaguely at the time to cause super-sensitivity in catecholamine neurotransmitters, blocked the reuptake of these neurotransmitters into sympathetic nerves and caused them to accumulate in the synaptic cleft². Additionally, he saw how amphetamines release dopamine and block the post-synaptic terminal from receiving it. Axelrod showed how these recreational drugs have involvement solely in the norepinephrine reuptake cycle.

Sources:

1. https://www.nature.com/articles/1300799

2. https://www.remedypublications.com/open-access/the-story-of-julius-axelrod-1912-2004-a-testament-to-commitment-5497.pdf

# data[].attributes.body
In the 1960s, Axelrod and other scientists began to uncover multiple antidepressants' mechanisms by applying his norepinephrine reuptake process theory. In 1964, after the publication of his article "A Sensitive and Specific Assay for the Estimation of Monoamine Oxidase," he concluded that some antidepressants on the current market inhibit the MAO enzyme, block the neurotransmitter norepinephrine, or possess a combination of inhibition and neurotransmitter stimulation¹.

The were able to discover this by injecting labeled norepinephrine directly into the brain through the lateral ventricle. Previously, it was hard to study norepinephrine's role in the central nervous system due to the blood-brain barrier. Through this technique, they were able to monitor the accumulation of norepinephrine in the context of different antidepressant medications³. It was understood that norepinephrine is responsible for antidepressant mechanisms, which later led to the proposition that serotonin may also have a role in depression³.

This research suggests that mental states were a result of "complicated physiology and brain chemistry," rather than the result of psychological or environmental factors². Axelrod had laid down the foundation for the development of selective uptake inhibitors (SSRIs) that block the reuptake of the neurotransmitter serotonin.

Source:

1. https://profiles.nlm.nih.gov/spotlight/hh/feature/neurotransmitters

2. https://profiles.nlm.nih.gov/spotlight/hh/feature/prize

3. https://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/axelrod-julius.pdf

# data[].attributes.body
Axelrod’s receivement of the Nobel Prize in Physiology or Medicine made him a public figure in the world of biomedical science and research. While still maintaining and developing new ideas in his research laboratory surrounding drug metabolism and neurotransmitters, he made an effort to “translate the complexities” of his research to a larger audience¹. He published an article in 1974 that described all the functions of the known neurotransmitters, and continued to attend presentations and interviews to discuss new discoveries in psychopharmacology¹.

He also became an advocate for political and social issues outside of research because of his well-known reputation.

Source:

1. https://profiles.nlm.nih.gov/spotlight/hh/feature/prize

# data[].attributes.headline
Axelrod's Research and its Impression on Current Antidepressant Medications

# data[].attributes.subject
Axelrod's Research and its Impression on Current Antidepressant Medications

# data[].attributes.body
Axelrod's understanding of MAO and COMT inhibitors, reuptake, and building the foundation for the development of SSRIs has influenced the current treatments available for depression today. In 2019, the FDA approved two new antidepressants called brexanolone and esketamine that have differing mechanisms than SSRIs¹.

Brexanolone is a medication used to reduce the symptoms of postpartum depression by raising the levels of GABA, a neurotransmitter responsible for inhibiting neuronal activity¹. Its mechanism of action for raising the amount of GABA in the synaptic cleft is by restoring dysfunctional GABA and its transmembrane channels while also being a positive allosteric modulator of its receptors². While previous antidepressant medication was focused on delaying reuptake of neurotransmitters by the presynaptic terminal, this treatment acts to improve receptivity of the neurotransmitter by possessing the qualities to directly bind to its neurotransmitter receptors.

Sources:

1. https://www.healthline.com/health/depression/newest-antidepressants#brexanolone

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477036/#:~:text=Mechanism%20of%20Action&text=of%20postpartum%20depression.-,Brexanolone%20enhances%20the%20inhibitory%20effects%20of%20GABAA%2C%20restores%20dysfunctional,fluctuates%20during%20pregnancy%20and%20postpartum.