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Individual entry: Arvid Carlsson (1923-2018)

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Individual entry: Arvid Carlsson (1923-2018)

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Arvid Carlsson would be the best individual to guide you through this exhibit, winning the Nobel Prize in Physiology and Medicine alongside Eric Kandel and Paul Greengard in 2000. Born in Uppsala, Sweden, Carlsson was raised by two academically-oriented parents - his father worked as a history professor, and his mother had a Master of Arts and published several books. At 18, he enrolled in the University of Lund to study medicine and pharmacology. Because Lund was a coastal town in southern Sweden, during World War II thousands of Jewish refugees from Denmark and Germany arrived, some of whom were rescued from concentration camps. As a medical student Carlsson was tasked with examining and treating these survivors, and he noted their anguished mental status (1).

While completing his doctorate in pharmacology, the head of the Pharmacology Department at the University of Lund persuaded Carlsson to investigate calcium metabolism using radioactive tracers. This technique would be useful for Carlsson and other neurotransmitter researchers when investigating localization and reuptake within neurons.

After receiving his pharmacology Ph.D. in 1951, Carlsson initially joined the Lund faculty but soon accepted a fellowship with biochemist Bernard B. Brodie at the National Institutes of Health. This fellowship motivated Carlsson to focus on psychopharmacology - moving back to Sweden, he continued researching neurotransmitters and accepted a position at the University of Gothenberg.

In 2000, Arvid Carlsson received the Nobel Prize for demonstrating that dopamine is a neurotransmitter in the brain and developing an assay to quantify dopamine levels among different brain regions (2). Carlsson's studies of neurotransmitter systems extended far beyond the identification of dopamine and its connection to Parkinson's. By administering rats L-DOPA followed by first-generation anti-psychotics, Carlsson established that antipsychotic drugs are dopamine antagonists that act on the limbic and striatal systems (3). Carlsson also studied tricyclic antidepressants and found that they blocked both serotonin and norepinephrine reuptake. Through studying antihistamines, Carlsson and his lab found that certain antihistamines groups were selective inhibitors of serotonin reuptake. Carlsson's lab synthesized zimelidine, one of the first selective serotonin reuptake inhibitors (SSRIs), in the early 1970s. Eli Lilly cited Carlsson's research on antihistamines when developing Prozac (4).

Sources:
(1) https://www.nobelprize.org/prizes/medicine/2000/carlsson/biographical/

(2) Yeragani, V. K., Tancer, M., Chokka, P., & Baker, G. B. (2010). Arvid Carlsson, and the story of dopamine. Indian journal of psychiatry, 52(1), 87–88. https://doi.org/10.4103/0019-5545.58907

(3) Carlsson, A. (1977). Does dopamine play a role in schizophrenia? Psychological Medicine, 7(4), 583-597. doi:10.1017/S003329170000622X

(4) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

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Nigral neurons as illustrated by A. Jules-Bernard Luys, B.C. Giovanni Mingazzini, D. Santiago Ramón y Cajal (1). 

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In 1786, the French anatomist Félix Vicq d’Azyr was the first individual to describe and illustrate the substantia nigra in his most notable work, Traité d'anatomie et de physiologie (Treatise on Anatomy and Physiology). Vicq d'Azyr noted the dark pigment of the structure and described a group of nearby nuclei now known as the basal ganglia (2). Another French neuroanatomist, Jules-Bernard Luys, provided the first images of nigral neurons in 1865, noting that most were projection neurons with large processes. In the early 20th century, the anatomists Torata Sano and Santiago Ramón y Cajal each detailed the subdivisions of the substantia nigra:   the pars compacta was comprised of pyramidal neurons densely packed together, while the pars reticulata was composed of a smaller number of non-pigmented neurons (1).

While neurotransmitters were not known at this time, work at the Salpêtrière Hospital in Paris proposed substantia nigra involvement in Parkinson's Disease. A student of Jean-Martin Charcot, Georges Marinesco and his collaborator Paul Oscar Blocq uncovered a tumor in the substantia nigra of a patient who had suffered from unilateral Parkinson's symptoms. Based on this 1893 finding, other physicians at the Salpêtrière hypothesized that Parkinson's Disease may be caused by substantia nigra lesions (1).

Sources:
(1) Parent, M., & Parent, A. (2010). Substantia Nigra and Parkinson's Disease: A Brief History of Their Long and Intimate Relationship. Canadian Journal of Neurological Sciences / Journal Canadien Des Sciences Neurologiques, 37(3), 313-319. doi:10.1017/S0317167100010209

(2) Tubbs, R. S., Loukas, M., Shoja, M. M., Mortazavi, M. M., & Cohen-Gadol, A. A. (2011). Félix Vicq d'Azyr (1746-1794): early founder of neuroanatomy and royal French physician. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 27(7), 1031–1034. https://doi.org/10.1007/s00381-011-1424-y

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Tyrosine metabolic pathway that produces the 3 catecholamines: dopamine, norepinephrine, and epinephrine.

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In 1910, British chemists George Barger and James Hill synthesized the compound 3,4-dihydroxyphenylethylamine at the Wellcome Pharmaceutical Research Laboratories in London, founded by the pharmacologist Sir Henry Dale (1). While Dale was studying the ergot fungus, he found that the ergot alkaloids ergocornine and ergocryptine appeared to inhibit epinephrine, hypothesizing that epinephrine binds to specific receptors that could be blocked (2). He also described how epinephrine mimicked the stimulation of sympathetic nerves. As dopamine is a precursor to epinephrine, it is likely that dopamine was synthesized during Dale's study of this neurotransmitter. In 1952, Dale suggested the name dopamine to shorten dihydroxyphenylethylamine.

Even though dopamine had been synthesized, it was not considered relevant to neuroscience for five decades because unlike epinephrine and norepinephrine, it does not discernibly affect muscle (3).

Sources:

(1) Marsden C. A. (2006). Dopamine: the rewarding years. British journal of pharmacology, 147 Suppl 1(Suppl 1), S136–S144. https://doi.org/10.1038/sj.bjp.0706473

(2) David O. Norris, James A. Carr. Chapter 8 - The Mammalian Adrenal Glands: Cortical and Chromaffin Cells, Editor(s): David O. Norris, James A. Carr,
Vertebrate Endocrinology (Fifth Edition), Academic Press,
2013, Pages 261-290,
ISBN 9780123948151,
https://doi.org/10.1016/B978-0-12-394815-1.00008-2

(3) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

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Diagram of the dopaminergic synapse (1). Reserpine inhibits DA vesicular transport ("granule"=vesicle). Chlorpromazine inhibits both DA transport and receptor.

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Without advancements in psychotropic drugs, the study of dopamine and other neurotransmitter systems would be hindered by a lack of experimental paradigms. In the study of dopamine and other catecholamines, two classes of drugs were used to study these transmitters and their receptors: a) typical antipsychotics, including reserpine and chlorpromazine; b) monoamine oxidase inhibitors (MAOIs), including iproniazid. The mechanism of action for these drugs was not precisely known when they were introduced in the early 1950s, and so identification of their neuronal effects motivated neurotransmitter research.

Monoamine oxidase is an enzyme found in pre-synaptic terminals and glial cells that breaks down monoamine neurotransmitters, including serotonin, histamine, and the catecholamines. MAOIs inhibit this enzyme, increasing the available monoamine stores (2). In Carlsson's initial study of dopamine, the MAOI iproniazid enhanced the effects of L-DOPA treatment (3), implying that dopamine was present at pre-synaptic terminals.

Typical anti-psychotic drugs were discovered "serendipitously" (4): chlorpromazine was initially developed as an antihistamine and used to prolong anesthesia, while reserpine was initially a tranquilizer before it was introduced into psychiatric hospitals and its effects on serotonin and catecholamine levels were discovered (5). In 1963, Carlsson and Margit Lindqvist demonstrated that chlorpromazine and another antipsychotic, haloperidol, increase dopamine and norepinephrine metabolite levels in the synaptic cleft, suggesting that they inhibit dopamine activity (1). This was confirmed by a 1976 study that showed radioactively-labelled haloperidol and dopamine both bind to the dopamine D2 receptor (6).

(1) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

(2) https://www.nature.com/articles/nrn1883
(3) CARLSSON, A., LINDQVIST, M. & MAGNUSSON, T. 3,4-Dihydroxyphenylalanine and 5-Hydroxytryptophan as Reserpine Antagonists. Nature 180, 1200 (1957). https://doi.org/10.1038/1801200a0

(4) Shen W. W. (1999). A history of antipsychotic drug development. Comprehensive psychiatry, 40(6), 407–414. https://doi.org/10.1016/s0010-440x(99)90082-2

(5) López-Muñoz, F., Bhatara, V. S., Alamo, C., & Cuenca, E. (2004). Aproximación histórica al descubrimiento de la reserpina y su introducción en la clínica psiquiátrica [Historical approach to reserpine discovery and its introduction in psychiatry]. Actas espanolas de psiquiatria, 32(6), 387–395.

(6) Seeman, P., Chau-Wong, M., Tedesco, J., & Wong, K. (1975). Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proceedings of the National Academy of Sciences of the United States of America, 72(11), 4376–4380. https://doi.org/10.1073/pnas.72.11.4376

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In his experiments, Axelrod showed that norepinephrine is inactivated through reuptake. Cocaine & the antidepressant imipramine inhibit the reuptake process (1)

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Evidence for synaptic catecholamine transmission

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Evidence for synaptic catecholamine transmission

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The investigation of neurotransmitters began with epinephrine. American biochemist John Jacob Abel isolated and named the active ingredient of the adrenal extract, which was originally described by Schafer and Oliver in 1894. Following this identification, physiologist Thomas Renton Elliot found that epinephrine mimicked electrical stimulation of sympathetic nerves, theorizing that muscles have a mechanism "'to receive and transform the nervous impulse."'(1)

After Otto Loewi's 1921 acetylcholine demonstration, the field of neuroscience became relatively more accepting of chemical transmission at the synapse. With an observable effect on smooth muscle and a well-understood inactivation mechanism (acetylcholinesterase), acetylcholine was an excellent model for synaptic transmission. Unlike acetylcholine, however, there are multiple catecholamine neurotransmitters, all with several degradation mechanisms. These properties complicated the study of catecholamines and their acceptance as neurotransmitters.

Between 1946-1949, American physiologist Ulf von Euler and British physician William Stanley Peart established that norepinephrine is the more prominent neurotransmitter of the sympathetic nervous system and is released following  stimulation of sympathetic nerves (2,3). However, the mechanisms behind catecholamine degradation were still unclear. Julius Axelrod confirmed the identity of epinephrine and norepinephrine as neurotransmitters through demonstrating a crucial degradation mechanism: retrograde reuptake. He injected radioactive-labelled norepinephrine and epinephrine into rodents and administered cocaine, a compound known to extend synaptic transmission. Compared to controls, rodents exposed to cocaine had lower levels of catecholamines at their pre-synaptic terminals, supporting an intrinsic reuptake mechanism (1).

Establishing the existence of catecholamine transmitters and  investigating their reuptake mechanisms facilitated the recognition of dopamine, as well as the development of selective norepinephrine and dopamine reuptake inhibitors for psychiatric disorders.

Sources:

(1) https://www.cell.com/cell/pdf/S0092-8674(06)00370-9.pdf

(2) V. EULER, U. A Sympathomometic Pressor Substance in Animal Organ Extracts. Nature 156, 18–19 (1945). https://doi.org/10.1038/156018b0

(3) Gaddum, J. H., Peart, W. S., & Vogt, M. (1949). The estimation of adrenaline and allied substances in blood. The Journal of physiology, 108(4), 467–481. https://doi.org/10.1113/jphysiol.1949.sp004350

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Schematic of the Aminco-Bowman spectrophotofluorometer, introduced in 1956 (1).

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Because neurotransmitter release takes place on such a small scale, the ability to detect and quantify transmitter levels was crucial to the discovery of dopamine. The tool developed to carry out this process was the spectrophotofluorometer (sometimes shortened to spectrofluorometer), patented by Robert L. Bowman and Sidney Udenfriend at the National Heart Institute in 1956 (1).

Spectrofluorescence relies on the principle that the wavelength a compound emits is specific to its molecular structure. The process begins by introducing a fluorescent molecule to the compound and exciting the mixture with light. Prior to Falck and Hillarp's use of formaldehyde, tri-hydroxyindole was the fluorescent molecule of choice (2). The molecule first absorbs the light, reaching an unstable higher-energy state, and then emits light energy to return to its more stable ground state. The emitted light has a longer wavelength than the absorbed light (3). Different compounds have different emission ranges, which is used to identify the compound present. The number of emissions measures the quantity of the compound (4).

The spectrofluorometer consists of a light source, which the activation monochromator directs toward the sample compound. On the right, a fluorescence monochromator directs emitted light to the photomultiplier tube, which converts photons into an electrical signal. The photometer measures the signal intensity, while the oscillograph records the wavelength of emitted light (4).

The spectrofluorometer was important to neurotransmitter research because it can detect and quantify small samples of transmitter - as little as one microliter. Carlsson used this device to identify dopamine in the brains of rabbits treated with L-DOPA (5).

Sources:

(1) Udenfriend S. (1995). Development of the spectrophotofluorometer and its commercialization. Protein science : a publication of the Protein Society, 4(3), 542–551. https://doi.org/10.1002/pro.5560040321

(2) CARLSSON, A., & WALDECK, B. (1958). A fluorimetric method for the determination of dopamine (3-hydroxytyramine). Acta physiologica Scandinavica, 44(3-4), 293–298. https://doi.org/10.1111/j.1748-1716.1958.tb01628.x

(3) https://www.thermofisher.com/us/en/home/references/molecular-probes-the-handbook/introduction-to-fluorescence-techniques.html

(4) https://youtu.be/B22ZsUOFM98

(5) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

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Catecholamine compounds across 6 species, as identified by chromatography. Abbreviations: N=noradrenaline, A=adrenaline, X=dopamine (1).

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Katherine Montagu was a researcher working in Hans Weil-Malherbe's biochemistry laboratory at the Runwell Hospital, close to London (2). Building off of previous work on norepinephrine and epinephrine, Montagu investigated the presence of dopamine in the brain tissue of various animals, including humans. Using ethylenediamine dihydrochloride (ED) fluorescence followed by paper chromatography (3), Montagu distinguished between the catecholamines in her sample, attributing the compound that could not be classified as norepinephrine or epinephrine as dopamine. To support this conclusion, she also detected L-DOPA and DOPAC (dihydroxyphenylacetic acid), a metabolite of dopamine. In August 1957, Montagu published her results, becoming the first researcher to identify dopamine within the human brain.

Sources:

(1) Montagu, K. Catechol Compounds in Rat Tissues and in Brains of Different Animals. Nature 180, 244–245 (1957). https://doi.org/10.1038/180244a0

(2) Björklund, A., Dunnett, S.B. (2007) Fifty years of dopamine research, Trends in Neurosciences, 30 (5), 185-187, https://doi.org/10.1016/j.tins.2007.03.004.

(3) https://www.britannica.com/science/paper-chromatography

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Reserpine-treated rabbits before and after L-DOPA administration, 1960 (1).

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In 1956, Arvid Carlsson was accepted to an NIH fellowship under the mentorship of Dr. Bernard B. Brodie. His lab was studying reserpine, a drug with sedative effects recently introduced to treat schizophrenia. With a new instrument, the spectrophotofluorimeter, Brodie demonstrated that reserpine depleted serotonin levels. Carlsson was interested in the impact of reserpine on catecholamine neurotransmitters, which - similar to serotonin - are derived from single amino acids (1).

In a relatively simple experiment, Carlsson demonstrated that reserpine exerts its sedative effects as a dopamine antagonist, confirming its role as a neurotransmitter. His lab injected mice with reserpine, then provided each mouse the precursor to serotonin (5-hydroxytryptophan) or catecholamine transmitters (L-DOPA). Animals who received L-DOPA rapidly resumed normal behavior, while animals who received tryptophan remained drowsy (2). Carlsson replicated this experiment in rabbits, and when examining their brains found that norepinephrine levels in animals treated with L-DOPA did not recover as expected. This surprising result motivated Carlsson and his collaborators to investigate dopamine, the intermediate between L-DOPA and norepinephrine, concluding that dopamine itself mediated recovery from reserpine.

Sources:

(1) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

(2) CARLSSON, A., LINDQVIST, M. & MAGNUSSON, T. 3,4-Dihydroxyphenylalanine and 5-Hydroxytryptophan as Reserpine Antagonists. Nature 180, 1200 (1957). https://doi.org/10.1038/1801200a0

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Basal ganglia circuits in healthy tissue (left) and PD (right). The imbalance between direct and indirect striatal pathways suppresses thalamic output (1). 

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The importance of dopamine identification may have gone unrecognized if not for the development of a treatment for Parkinson's Disease (PD). In the early 1960s, Austrian biochemists Oleh Hornykiewicz and Herbert Ehringer examined the postmortem brains of people with PD and healthy controls to evaluate the distribution of norepinephrine and dopamine. After purifying their samples, they found that dopamine levels in the caudate nucleus and the putamen were markedly decreased in people with PD compared to healthy individuals.

Hornykiewicz subsequently conducted a small study of intravenous L-DOPA to treat Parkinson's symptoms, and found that the compound improved motor initiation within 2-3 hours. L-DOPA was selected due to its ability to cross the blood-brain barrier, unlike dopamine itself. In 1967, the physician George Cotzias conducted a study of oral L-DOPA on 16 individuals with PD, observing improvement in tremor and rigidity but also a dangerous drop in white blood cell count within a quarter of the sample. Cotzias found that the optimal L-DOPA dose was 8 g/day, and clinical trials supported this dose regimen. Early studies in the 1970s indicated that L-DOPA increased dopamine concentrations in the putamen and caudate nucleus by 15 fold. The FDA approved L-DOPA in 1970, and it soon become standard of care for PD (1).

Sources:
Hauser R, A: Levodopa: Past, Present, and Future. Eur Neurol 2009;62:1-8. doi: 10.1159/000215875

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Cell bodies of dopaminergic neurons in the rat substantia nigra, 1973.(1). 

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Visualization of neurotransmitter systems: Falck-Hillarp fluorescence 

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Visualization of neurotransmitter systems: Falck-Hillarp fluorescence 

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While researchers knew that dopamine acted as a neurotransmitter in the brain in the 1960s, without the advancement of immunohistochemistry it was extremely difficult to observe neurotransmitters at the cellular level. In the early 1960s, Bengt Falck and Nils-Åke Hillarp, a collaborator of Carlsson's, developed formaldehyde-induced fluorescence (FIF) to clearly visualize monoamines within neuronal tissue. This method involves a) enclosing brain tissue in a dried protein film, b) freeze-drying tissue, and c) exposing the sample to gaseous formaldehyde for one hour (2). This process creates fluorophores that can absorb and emit light (3). Falck and Hillarp observed the appearance of norepinephrine in adrenergic nerves and serotonin in mast cells, confirming the efficacy of FIF (4). While this method was not the most precise - norepinephrine and dopamine have similar chemical structures and produce similar emission wavelengths - this visualization was crucial for the mapping of neurotransmitter systems.

Sources:

(1) DAHLSTRÖM A. Aminergic transmission, introduction and short review. Brain Res. 1973;62:441–460

(2) https://www.wnc.lu.se/about-us/falck-hillarp-method

(3)https://www.thermofisher.com/us/en/home/references/molecular-probes-the-handbook/introduction-to-fluorescence-techniques.html

(4) https://www.nobelprize.org/uploads/2018/06/carlsson-lecture.pdf

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As dopamine only binds to metabotropic receptors, the identification of G proteins was an important step in the study of dopamine function. The biochemists Martin Robdell and Alfred G. Gilman received the Nobel Prize in 1994 for uncovering the existence and role of G-protein coupled receptors, though Gilman was the one to isolate and name the G protein in the late 1970s (2). In a sample of lymphoma cells, Gilman found that stimulation of beta-adrenergic receptors on lymphoma cells resulted in activation of adenylyl cyclase and increased levels of cyclic AMP (3).

As this video from Michigan State University describes, beta-adrenergic receptors couple with a stimulatory G-protein, Gs. When epinephrine binds to its receptor, a GDP molecule on the protein converts to GTP, and the G-protein activates adenylyl cyclase, which converts ATP in the cytoplasm to cyclic AMP. cAMP binds to the regulatory subunits of protein kinase A (PKA) to activate the protein's functional subunit. PKA can then phosphorylate ion channels, proteins involved in neurotransmitter synthesis and release, and transcription factors (1).

The D1 and D5 receptors also contain Gs, and are present in the striatum, nucleus accumbens, olfactory bulb, and substantia nigra. The D2-D4 receptors contain Gi, which inhibits the cAMP secondary messenger cascade and are involved in the survival of dopamine neurons (4). Understanding G-protein coupled receptors has made it possible to investigate the role of dopamine in attention, emotion, judgment, movement, and disease.

Sources:

(1) https://www.youtube.com/watch?v=BiVNftuI2mo&list=PL003npd2UuCCEZiz8hC2usBKV-4dS2eaE&index=5

(2) https://www.nytimes.com/2015/12/25/us/dr-alfred-g-gilman-whose-work-on-proteins-won-nobel-prize-dies-at-74.html?_r=0

(3) Ross, EM; Maguire, ME; Sturgill, TW; Biltonen, RL; Gilman, AG (1977). "Relationship between the beta-adrenergic receptor and adenylate cyclase". The Journal of Biological Chemistry. 252 (16): 5761–75. doi:10.1016/S0021-9258(17)40089-5. PMID 195960.

(4) Bhatia A, Lenchner JR, Saadabadi A. Biochemistry, Dopamine Receptors. [Updated 2021 Jul 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538242/

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Deep brain stimulation of the subthalamic nucleus (1).

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DBS improves dopamine availability for people with Parkinson's 

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DBS improves dopamine availability for people with Parkinson's 

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Because the pathology of Parkinson's Disease involves loss of dopaminergic signaling, PD has always been closely connected to the study of dopamine transduction. While L-DOPA can improve the tremor and motor rigidity symptoms of PD, it can also induce neuronal apoptosis and does not prevent disease progression (2). In the last couple decades, deep brain stimulation (DBS) has emerged as a more effective intervention for PD. The process of DBS involves placing bilateral electrodes in the basal ganglia, most often within the subthalamic nuclei. An impulse generator supplies current to the electrodes, restoring basal ganglia activity. However, the exact mechanism of how DBS improves PD symptoms and impacts dopamine signaling are largely unclear.

Recent research from the University of Leipzig indicates that DBS improves dopamine availability for individual patients, as measured by dopamine transporter (DAT) levels in the caudate nuclei and putamen. Increase in DAT availability corresponded closely with individual symptom improvement (3), suggesting that DBS elevates dopamine availability and that this mechanism could be targeted to improve DBS.

The decades of research on dopamine transduction have made treatments for neurodegenerative disorders like PD possible. Around 4000 articles on dopamine are published each year (4), bringing us closer to understanding the complexities of this neurotransmitter.

Sources:

(1) Okun, Michael. (2014). Deep-Brain Stimulation - Entering the Era of Human Neural-Network Modulation. The New England journal of medicine. 371. 10.1056/NEJMp1408779.

(2) Gandhi KR, Saadabadi A. Levodopa (L-Dopa) [Updated 2021 Aug 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482140/

(3) Löser, J., Luthardt, J., Rullmann, M., Weise, D., Sabri, O., Meixensberger, J., Hesse, S., & Winkler, D. (2021). Striatal dopamine transporter availability and individual clinical course within the 1-year follow-up of deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease. Journal of neurosurgery, 1–7. Advance online publication. https://doi.org/10.3171/2020.8.JNS192740

(4) Björklund, A., Dunnett, S.B. (2007) Fifty years of dopamine research, Trends in Neurosciences, 30 (5), 185-187, https://doi.org/10.1016/j.tins.2007.03.004.