The History of Dopamine #2: Electrochemical Boogaloo

Eristatismus of Keon wants to know all about your spirit animal.

Science is weird.

One day, someone thought to themselves: I wonder what happens to the urethra of a cat when you inject different substances to its surrounding muscle: and taadaa, we discover neurochemistry!

Obviously that's not the way it happened at all. Well, except someone really did inject stuff into a cat for the specific purpose of observing effects on the urethra. THE URETHRA. OF A CAT. I can't imagine the cat volunteered for this job.

No I'm not kidding.

In further illustration of Langley's generalisation that the effect of adrenalin upon plain muscle is the same as the effect of exciting the sympathetic nerves supplying that particular tissue, it is found that the urethra of the cat is constricted alike by excitation of the hypogastric nerves and by the injection of adrenalin.

—T.R. Elliot

Before we get to that part, we have to talk a little bit about ol' Hippo.

You’re reading Part 2 of The History of Dopamine; Click Here for Part 1!

Back in ye olden times, a guy with the tantalisingly punny name of Hippocrates (c. 460–370 BCE) wrote about his theory of the "4 Humors", which posited the workings of the human body were the result of balance between 4 substances: Blood, Flegm, Black Bile, and Yellow Bile; should the body have an over (or under)-abundance in any one substance, a typical disease of that imbalance would result.

His was not the only school of thought: roughly 70 years later came Erasistratus of Keos (c. 304–250 BCE), who conducted some of the first dissections (and vivisections, i.e. experimental surgery on living creatures) for scientific purposes, alongside friend and fellow physician Herophilus of Chalcedon.

Opposed to the Humoral school of thought, his experiments helped him figure out the heart was a pump, and distinguish the functions of veins and arteries. He even wrote about nerves as part of the system controlling motor movements and capturing sensations!

Hey Hippocrotamus [snicker] the nervous system doesn't transport bile you dumbass! It's obviously a conduit for Pneuma! Oh, and tell your mother I'll see her later tonight! Hit the gas Herophilus (Tires screeching, zooms away)

—How I imagine Erasistratus challenging Hippocrates in rigorous scientific debate, had they been alive at the same time.

Yes, that's right, as modern as it seems from the outset, he believed the nervous system transported what he called the "Pneuma Zootikon", or "Animal Spirit". It wasn't all that different from the humoral theory, as it essentially acted as a substance emitted by the brain, travelling through the "hollow tubes" of the nerves to the muscles, initiating movement.

So close, yet so far.

Then in the 17th century, René Descartes expanded on the Animal Spirits idea, where nerves were pipes and muscles were springs. In his descriptions, the body operated very similarly to a hydraulic machine. Finally, the modern electrochemical theory emerged not long after the Napoleonic era in the 1800s, and we've been stuck with it ever since.

(Though to be fair, it's a pretty good one this time.)

The basic idea is this: so we know that nerve fibres carry electrical impulses from one end to the other as a "signal". The question is: what happens if the signal reaches the end of the fibre, but needs to keep going? What if there is a chain of nerve fibres, one after the other? How does the signal cross over from one fibre to the next?

The answer: chemistry.

"Neurotransmission" essentially means: "The Transport of information through the nervous system". I've often related chemical neurotransmission to a Bluetooth connection, where a signal arrives in one form (electricity), crosses a gap in another form (radio waves in Bluetooth, chemicals in the brain), and is re-assembled in original form (electricity again) on the other side.

However, while the year is 2024 and Bluetooth headphones still can't handle being connected to 2 devices at once, a single neuron can connect to literally hundreds of other neurons, and broadcast signals to millions of other cells.

Between neurons and nerve fibres, organic chemical compounds called Catecholamines are used to carry a signal from one nerve fibre to the next, being flung across a tiny gap called a "synapse" from one cell to the other; the first of these "Neurotransmitters" to be discovered was a little something called Adrenaline.

Returning to the cat thing, this peculiar scientifically-inclined fellow—a man by the name of T. R. Elliot—published in the 1904 Proceedings of the Physiological Society a communication in peculiar scientific detail describing this "scientific" experiment on cats and their urethrae, along with some peculiar novel findings about the role of adrenaline in the nervous system.

He further wrote:

The point at which the stimulus of the chemical excitant is received, and transformed into what may cause the change of tension of the muscle fiber, is perhaps a mechanism developed out of the muscle cell in response to its union with the synapsing sympathetic fiber, the function of which is to receive and transform the nervous impulse.

Then we get the light-bulb moment:

"Adrenalin" might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery.

In other words: there's more to the nervous systems than just electricity. The response from the wider scientific community was perhaps the least-peculiar part: dead silence.

It turns out that there just aren't all that many scientists keen on the study of cat urethrae. This came as a fairly major disappointment to Elliot, leading him to quit the field of Physiological research entirely.

A long time after his death, it was realised that Elliot's nearly-forgotten 1904 writings were perhaps the first explicit descriptions of chemical neurotransmission.

The Scientific Method

"We are all slaves to our memories", wrote Oleh Hornykiewicz, the man of thick-rimmed glasses and a twinkling eye, as part of an Autobiography series covering notable Neuroscientists in the year 2004.

Enrolling at the University of Vienna in 1945, he studied medicine among the bombed-out ruins of a city in the grips of a severe food crisis; one of his teachers literally starved to death in their one-room flat at the end of the war.

He wrote:

Attending the lecture courses turned out to be no simple matter. Like the rest of Vienna, the medical buildings and lecture theatres were half in ruins, and the few intact ones were hopelessly overcrowded. There was a shortage of lab space and teaching staff. Everyone was trying to get his "Dr.med." (M.D.) as fast as possible, to be among the first to compete for the few paid internship positions in the city hospitals. The whole atmosphere--not necessarily conducive to good schooling was that of a "struggle for the survival of the quickest."

It says something about the power of human determination that a university in a place like Vienna in October 1945 was taking enrolments, despite the utter devastation; first from the Nazi political ideology of hate, violence, persecution and industrial-scale murder, and then from the unhinged vengeance of the Soviet Union alongside the righteous might of the Allied Powers on their triumphant march toward Berlin.

It also says something about the man himself that this was his idea of a party gone memorably wild:

I still have a vivid memory of the party at which one of our company made too fast, "spirited" a start, and after about 90 min had to be "revived," not too successfully, by being placed, as he was, in the bathtub filled with cold water.

Hornykiewicz immediately joined the Pharmacological Institute after obtaining his degree in 1951, which was run by his much-admired Pharmacology professor, Franz von Brüke.

At this time, still very little was known about what dopamine actually does, if anything. Then, near the end of the 1950s, came some surprises.

Kathleen Montagu and Arvid Carlsson’s papers—both published in 1957—had discovered quantities of dopamine found in the mammalian brain, alongside other known catecholamines like adrenaline and noradrenaline. Carlsson's work in particular showed that after a dose of Reserpine (which basically depletes the brain of noradrenaline, dopamine, and serotonin all at once), the administration of L-DOPA restored dopamine levels. That had taken them rather by surprise: they had been expecting a restoration of noradrenaline. DOPA and dopamine were still widely considered just precursors of noradrenaline.

Perhaps it did have a special function after all?

It later inspired Hermann Blaschko, a friend and colleague of Hornykiewicz from Oxford in Cambridge, who realised that dopamine must have its own role to play in the biochemistry of the body. It was Blaschko that fatefully encouraged Oleh to pursue this path further.

Hornykiewicz admired Blaschko greatly. He wrote about him fondly in his recollections:

"Although Blaschko based his idea upon observations known to other prominent catecholamine researchers", wrote Oleh, "none of them had come up with the right conclusion”

“This instance very aptly characterizes Blaschko: low key, kind, interested in people, and with an exquisite sense of humor ... in addition to a phenomenal memory, a very precise, penetrating mind, coming up with surprising solutions to seemingly insoluble problems."

Positively gushing!

After 1960, when Oleh and a young Herbert Ehringer shared their results from obtaining and slicing up human brain tissue from deceased individuals—finding dopamine abundant in certain areas of the human brain, while the brains of Parkinsons patients had a notable absence of dopamine—they had also essentially discovered the "killer app" of morgues: fresh human material for medical science and discovery.

The scientific community, having previously insisted there was nothing to be learned from such Leichenöffnung (corpse opening), rotated a full 180 degrees. Now scientists couldn't get enough of the dead! The study of human biology practically exploded in new ideas and discoveries, and morticians suddenly found themselves with living friends!

“Heyyy Jerry, yeah, sure, we’re totally friends now. Say, while you’re here, I need to borrow a spleen…”

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Oh yeah? That's nothing. The local ice rink where I grew up had to put up a sign at the entrance saying: "DO NOT MAKE SNOWBALLS ON THE ICE" after I had instigated a rink-wide snowball fight one time. What can I say? I'm a trend-setter!

(true story)

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Biochemical Miracles

They had clearly shown that Parkinsons disease depleted the brain of dopamine, though they did not yet know what that meant. Was the lack of dopamine the root cause of their symptoms? Was it a red herring?

To synthesise dopamine, one has to go through a series of chemical stages. Starting with the amino acid Tyrosine, special enzymes attach an additional hydrogen and oxygen atom pair in a process called "Hydroxylation", which turns it into L-DOPA. This L-DOPA is then processed by another special enzyme which strips away the carbon-oxygen-hydrogen atom group ("Decarboxylation"), resulting in the dopamine we all know and love.

Great, so to get dopamine production happening in the body, we just need to supply it with some L-DOPA and it should take care of the rest with enzymes. Easy, right?

Not exactly. Administering L-DOPA to a living Parkinsons patient would prove particularly difficult. The (admittedly really dumb but also kinda useful) experiment by Guggenheim of swallowing 2.5 grams of straight DOPA was an omen: taking that much via the oral route in one go made him vomit it all back up again.

Hardly conducive to a good time.

There didn't seem to be many good alternatives. Raw dopamine could not cross the blood-brain barrier, but L-DOPA could. That meant they had to get L-DOPA into the bloodstream. Perhaps, instead of chugging down 2.5 grams of the stuff, Hornykiewicz and another colleague Walther Birkmayer figured it might be better to, oh I dunno, dilute it a bit — everything in moderation, as the saying goes — and try smaller doses administered via I.V. instead of orally.

So in 1961 they were granted access to a cohort of 20 severely afflicted Parkinson's patients, some of whom could not walk, some of whom could not even stand up, and some of whom were in such a bad state they could not even sit up from bed. Hornykiewicz gave Birkmayer their entire stash of L-DOPA — 2 grams — and directions on diluting and administering to the patients. They would give the first patients a single 150 mg dose via I.V. and see what happens.

Well, what happened was quite frankly miraculous.

For a period of about 3 hours following that single dose, it was as though the disease which had nearly paralysed these patients simply up and disappeared. For those 3 hours, they were fully-functional human beings.

One minute, a patient would be bedridden, unable to make voluntary movements, barely able to even speak; the next, they can stand up, walk by themselves with a normal gait and motion, and even run and jump. Their speech was no longer slurred, but became as forceful, articulate and coherent as any other person. No one had ever seen anything like it before. Not since Penicillin had anything been found to have such a profound impact on disease. Gradually, the effect wore off over the following 24 hours. They published their results later that year.

Despite the spectacular success of this experiment, they were presented with a problem that made this difficult to sustain as a long-term treatment. When Barbeau et al. tested an oral preparation on Parkinson's patients in Montreal, it did seem to offer a lot of improvements to their symptoms, but then there was the nausea. Although at smaller doses given intravenously there wasn't any instant projectile-vomiting (I don't really know if it had been projectile, that's just how I like to imagine Guggenheim’s original experiment), nausea was still a concern, and vomiting could occur, and often did.

It was clear that a way needed to be found to get around the gastrointestinal side effects.

Re-enter: George Cotzias! Now our favourite Greek neurologist was back, and this time he brought some friends—Van Woert and Schiffer—and they had a plan.

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To be continued in Part 3! Thank you so much for reading, this is a continuation of my post from last year about Faba Beans, which I have now renamed The History of Dopamine #1. You can check that one out here: