The Molecular Wake-Up Call It Is 50 Years Since Arvid Carlsson Showed Dopamine to Be a Neurotransmitter

NEWS FEATURE NATURE|Vol 447|24 May 2007 The molecular wake-up call It is 50 years since Arvid Carlsson showed dopamine to be a neurotransmitter. Alison Abbott profiles a chemical and its champion. hey were conscious but you wouldn’t know it: able to perceive the world around them but powerless to look Taround, sniff the air or to cry out. So when the young scientist injected them with a chemical called l-dopa, he witnessed what seemed to be a miracle. They stirred, opened their eyes and began roaming around as if nothing had happened. This may sound familiar from the book Awakenings1 — the true story of how, in 1963, the neurologist Oliver Sacks used l-dopa to spectacularly revive patients with sleeping sickness who had been ‘frozen’, speechless and motionless, for more than 40 years. But the unwritten and equally startling pre- quel took place in Lund, Sweden, several years earlier. The protagonists were rab- Catatonic rabbits were revived by bits; their saviour a young Swedish phar- dopamine in a 1957 experiment led macologist called Arvid Carlsson. by Arvid Carlsson. In his experiment, Carlsson showed that dopamine — the chemical manufac- embrace new techniques and fight tured from levodopa, or l-dopa — acts as for controversial ideas, as Carlsson a neurotransmitter in the brain, passing in Carlsson’s home has done throughout his career, remains essen- signals between neighbouring neurons. town of Gothenburg, Sweden, to cel- tial to success. “He was one of my heroes when Injection of l-dopa restored the propagation ebrate the 50th anniversary of his formative I was a young neurology resident,” says William of electrical signals in the brains of rabbits that paper on the awakened rabbits2. Langston, head of the Parkinson’s Institute in had been rendered catatonic, allowing the ani- During the past half century, Carlsson and Sunnyvale, California. “What impressed me mals to move. But the pharmacological estab- dopamine have followed intertwined paths. was his brilliant deductive reasoning.” lishment was scornful of Carlsson’s claim. At a Researchers now understand that the way Carlsson is a polite, soft-spoken and humor- London meeting in 1960, the foremost experts dopamine works is subtle and complex, and ous gentleman with a hallmark bow tie. He in neural transmission made it clear that they its mechanisms of action are central to the grew up in a family of academics in Lund that didn’t believe him — dopamine was thought to function of many neurological and psychiatric focused on the humanities but, in what he refers be the metabolite of another neurotransmitter drugs. And Carlsson, now a sprightly 84-year- to as a minor act of rebellion, he chose science rather than one in its own right. old, still spends hours pondering the mysteries over the arts because he thought it more useful Within years the critics were silenced. of brain chemistry. But he feels marginalized in to society. He is also single-minded and uncom- Dopamine was shown to be a pivotal chemical Gothenburg and, last year, the institute estab- promising, features that no doubt contributed in the neural circuits that drive pleasure and lished in his name closed prematurely after bit- to his success as a scientist against stiff opposi- addiction, as well as in illnesses such as Parkin- ter feuds about funding. tion — and perhaps also to his later problems. son’s disease, for which l-dopa quickly became The field of biomedicine has also evolved Carlsson calls himself a lucky man, and says a first-line treatment. It remains so today. In during this time, and much has changed. “We his first stroke of luck came when he arrived 2000, Carlsson shared the Nobel Prize in Physi- used slide rules and manual calculators back in the lab of chemist Bernard ‘Steve’ Brodie at ology and Medicine for his discovery. And next then, so statistical calculations were quite time the National Institutes of Health in Bethesda, week neuroscientists will gather at a meeting consuming,” Carlsson says. But a willingness to Maryland, in the summer of 1955. Brodie’s lab 368 NATURE|Vol 447|24 May 2007 NEWS FEATURE pioneered studies with reserpine, one of the But when Carlsson examined dominated the brain itself. “It’s very first drugs to be introduced for the selec- the revived rabbits’ brains hard to imagine now, but when tive treatment of schizophrenia, and hence one after injecting l-dopa he saw I was an undergraduate stu- of the hottest molecules for pharmacologists of a lot of dopamine and very dent at Cambridge [in the late the day. Reserpine injections made rabbits cata- little noradrenaline. At this 1950s] we were taught categori- tonic, but how the drug worked was a mystery. point it dawned on him that cally that there was no chemi- dopamine could be a neuro- cal transmission in the brain Direct measures transmitter in its own right, a — that it was just an electrical At the time, pharmacologists typically tested memory that still summons machine,” recalls pharmacolo- the potency of neurotransmitters with assays astonishment to his face. gist Leslie Iversen, professor of their biological activity — for example, Within months his gradu- emeritus at the University of applying them to a piece of animal gut under ate students Åke Bertler and Oxford, UK. tension in an organ bath to see how much Evald Rosengren had found In this setting, Carlsson’s they could contract or relax the muscle. Bro- that dopamine is normally ideas went down like a stone. die’s team instead developed the spectrophoto- concentrated in areas of the The meeting unceremoniously fluorimeter, a machine able to measure how brain known to be involved “I won the Nobel Prize rejected his interpretation of much neurotransmitter was synthesized from in movement, such as the 40 years after my his data and, to his mortifica- 3 fluorescently tagged precursors. This allowed basal ganglia . Knowing that discovery. Einstein tion, the single comment in the the researchers to measure the precise level of high doses of reserpine cause discussions praising his work a compound extracted from tissue rather than side effects that are similar won one some 20 was excluded from the sympo- an indirect measure of its activity, and later to some of the movement years after his. So I sium book. “The Ciba meeting became a standard instrument in biological difficulties experienced by guess my work was might have been the oppor- labs. When Carlsson returned to Lund after his patients with Parkinson’s dis- tunity to tell the world how five-month visit to Brodie’s lab, the first thing ease, Carlsson proposed that twice as complicated.” things really were, but there he did was order a spectrophotofluorimeter. “I this disease might be caused — Arvid Carlsson was uniform hostility from the didn’t want to be confined by the indirectness by a lack of dopamine. community,” says Iversen. of bioassays,” he says. Carlsson stuck to his guns, Carlsson’s work with this device showed Sparking opposition and data began to amass to a point that made that reserpine completely drains the stores of In late 1958, Carlsson travelled across the denial impossible. Later in 1960, for example, several neurotransmitters in the brain. Loss of Atlantic to explain his ideas to a symposium in the Austrian pharmacologist Oleh Hornykie- one of these was causing the rabbits to become Bethesda. There, his story was well-received. wicz published studies on postmortem brains catatonic — the question was, which one? “But this was not the case when I presented my from patients with Parkinson’s disease, show- Carlsson reasoned that he could answer this results at the Ciba meeting in London,” says ing the absence of dopamine in the basal gan- question by adding back the missing neurotrans- Carlsson, who is still clearly a bit hurt. glia4. And a few years later, Annica Dahlström mitter to rabbits that had been frozen with reser- The prestigious 1960 Ciba Symposium on and Kjell Fuxe at the Karolinska Institute in pine — the crucial awakening experiment. The Adrenergic Mechanism attracted all the key Stockholm, Sweden, showed that in the healthy blood–brain barrier prevents the neurotrans- European players in the field. At the time, a brain neurons in this region contain high levels mitters noradrenaline and serotonin from pass- vigorous debate was going on between the of dopamine5. ing into the brain from the blood, so Carlsson ‘soups’ — who thought that nerve transmission In 1961, neurologist Walter Birkmayer, work- instead injected precursors of these molecules occurred through chemicals — and the ‘sparks’, ing together with Hornykiewicz, injected the that can enter the brain and are then metabolized who argued that it was all electrical. The soups first Parkinson’s patients with l-dopa to dramatic into the relevant neurotransmitter. One of these had more or less won their case for neurotrans- effect, allowing previously immobile patients to precursors was l-dopa, which is converted into mission outside the brain but, owing to lack move freely6. Carlsson recalls the penchant of his dopamine and then, in turn, into noradrenaline. of experimental evidence, the sparks’ view still collaborator Tor Magnusson for testing drugs openly on himself — something that would be Arvid Carlsson regarded with horror today. Expecting to see collects his some kind of neurological effects, Magnusson Nobel prize in hooked himself up to intravenous dopamine, 2000, more but, says Carlsson, “all we saw was emesis!” than 40 years Many other aspects of practising science were after showing different then. Fax and e-mail did not exist, and dopamine to be a all papers were read in the library rather than on neurotransmitter. a computer.

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