PERSPECTIVE
MEDICINE
Arvid Carlsson:
An Early Pioneer in Translational Medicine
Julie K. Andersen
Published 14 October 2009; Volume 1 Issue 2 2ps3
CREDIT: PRESSENS BILD/HENRIK MONTGOMERY/AP PHOTO
[I]t must be recognized that the brain is not a
chemical factory but an extremely complicated survival machine. In order to bring all the
forthcoming biochemical observations into a
meaningful framework it will prove necessary
to emphasize more strongly aspects of neurocircuits and connectivity and to do so both at
the microscopic and macroscopic level.
—A. Carlsson, Nobel Lecture, 2000
Although consciously pursuing translational
research as a major scientific goal might be
novel (1), the practice itself is by no means
new. More than 50 years ago, the Swedish
scientist Arvid Carlsson (Fig. 1) undertook
basic research on the neurotransmitter dopamine that was not only rapidly converted
into clinical investigation but also resulted
within a few years in the first clinical treatment for Parkinson’s disease (PD), a therapy
that is still in wide use today. Carlsson was
well ahead of his time in understanding
the import of viewing basic research with a
translational mindset and, by his example,
helped to lay the foundation for today’s current emphasis on translational research.
What was Carlsson’s contribution to this
“modern” concept? In the late 1950s, he made
the astounding discovery that, rather than
simply being a precursor of the neurotransmitter norepinephrine, dopamine itself is a
neurotransmitter in the mammalian brain
(2) (Fig. 2). This finding was contrary to
long-held dogmas in the field and was initially received with skepticism by many leading
experts. Based in no small part on the rapid
validation of this novel hypothesis by irrefutable clinical data, however, any doubts as to
the pivotal role of dopamine in neurotransmission were soon erased. For the first time,
Buck Institute for Research in Aging, Novato, CA 94949,
USA. E-mail: [email protected]
Carlsson directly demonstrated—via a sensitive fluorescence assay—that dopamine was
present at high concentrations in areas of the
mammalian brain that control voluntary motor movement. Furthermore, he showed that
the depletion of dopamine stores by the antipsychotic, antihypertensive drug reserpine
coincided with increased akinesia (impairment in the ability to initiate locomotion)
and rigidity in rabbits, symptoms akin to
those observed in human PD patients.
This connection with the human disease
was not lost on Carlsson, who proposed that
PD might involve a depletion of dopamine
in areas of the brain important for locomotion, including the basal ganglia. At the time,
reserpine was known to cause movement
impairment, but its mechanism of action
was still a mystery. In a definitive set of experiments, Carlsson showed that the administration of levodopa (l-dopa) (a dopamine
precursor that can cross the blood/brain barrier) to dopamine-depleted rabbits restored
lost motor activities and elevated dopamine
(but not norepinephrine) concentrations in
the brain. His studies demonstrated, contrary to popular belief, that dopamine was a
neurotransmitter in its own right.
TRANSLATIONAL MEDICINE
As far as I can gather from an autobiography
of Hornykiewicz . . . the following had happened. I wish to mention this . . . because it
illustrates how the interaction of different
minds can lead to important progress.
—A. Carlsson, Nobel Lecture, 2000
As a result of Carlsson’s seminal work on
reserpine and l-dopa, Ole Hornykiewicz
undertook studies that led to the use of
l-dopa as a drug to treat PD in humans.
Because he had read about Carlsson’s work
on dopamine, in the late 1950s Hornykie-
Fig. 1. Arvid Carlsson. Carlsson shared the Nobel
Prize in Physiology or Medicine in the year 2000.
wicz decided to measure dopamine and
noradrenaline in the brain of a PD patient
using purification techniques developed
by Carlsson’s group (3). After the laborious
procedure, Hornykiewicz found that the PD
brain samples lacked dopamine. In addition,
Hornykiewicz initiated human studies in
1960 that demonstrated the degeneration of
dopaminergic neurons in the parkinsonian
midbrain (4), forming the basis for the first
experimental use of l-dopa as a PD therapy
in 1961 [performed by Ole Hornykiewicz
and Walter Birkmayer (5)]. For his contributions, Carlsson was awarded the Nobel Prize
in Physiology or Medicine in the year 2000,
along with Eric Kandel and Paul Greengard
(www.nobel.se/medicine/laureates/2000).
Not only did Carlsson’s initial work have
a profound impact on the treatment of PD,
but his subsequent work elucidated how dopamine participates in another neurological
disorder, schizophrenia (6, 7). He realized
that the antipsychotics used to treat schizophrenia often had undesirable side effects in
patients that resembled the motor-related
symptoms that occurred in PD patients and
in his animal subjects after reserpine treatment. These observations led Carlsson to
speculate that antipsychotic drugs might
act by blocking the action of dopamine at
dopamine receptors (8). At about the same
time, early clinical trials of l-dopa treatment in PD patients had revealed that the
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Translational medicine has recently experienced an upsurge in interest and funding, yet
the idea is not new. More than half a century ago, the Swedish scientist Arvid Carlsson
performed basic research on the neurotransmitter dopamine that was rapidly translated
into the first clinical treatment for Parkinson’s disease. For his contributions, Carlsson
shared the Nobel Prize in Physiology or Medicine in the year 2000.
administration of large amounts
of l-dopa resulted in psychoses
similar to those seen in schizophrenia. Together, these findings initiated a line of investigation that ultimately proved
that dopamine dysregulation in
nonmotor regions of the brain
contributes to schizophrenia.
Carlsson also was one of
the first to recognize that the
increase in addictive behaviors
seen in some l-dopa–treated patients was caused by dopamine’s
effects on the motivation and
reward centers in the brain,
linking increased dopamine concentrations with the actions of
several substances of abuse (7,
9, 10). And, in addition to his
pioneering work on dopamine,
Carlsson was instrumental in
uncovering the contribution of
the neurotransmitter serotonin
to depression and anxiety disorders, in a line of research that
lead to the development of new
medications (including Prozac,
the first in its class to be approved for clinical use) for the
treatment of these and related
conditions (11, 12).
Although still in use after 50
years as a frontline treatment for
PD, l-dopa is by no means a perfect drug. Besides resulting in
problematic side effects caused
by its actions in nonmotor brain
regions, l-dopa becomes ineffective in some patients after sev-
Fig. 2. Dopamine as a neurotransmitter. Dopamine (DA, shown as red
circles) synthesis involves the conversion of tyrosine to the dopamine
precursor L-dopa, which is in turn converted to dopamine. Dopamine
is then stored within synaptic vesicles at the nerve terminal; the antipsychotic and antihypertensive drug reserpine blocks the step in which
dopamine (DA) is put into the synaptic vesicle. Activation of the neuron
induces the release of dopamine into the synapse, where it can diffuse
and bind to dopamine receptors (DA-Rs) on a neighboring target cell,
eliciting both motor and nonmotor effects.
CREDIT: C. BICKEL/SCIENCE
REFERENCES
1. S. H. Woolf, The meaning of translational research and
why it matters. JAMA 299, 211–213 (2008).
2. A. Carlsson, M. Lindqvist, T. Magnusson, 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine
antagonists. Nature 180, 1200 (1957).
3. A. Carlsson, A half-century of neurotransmitter research: Impact on neurology and psychiatry, in Nobel
Lectures, Physiology or Medicine 1996-2000, H. Jörnvall,
Ed. (World Scientific Publishing, Singapore, 2003), pp.
303–322.
4. H. Ehringer, O. Hornykiewicz, Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human
brain and their behavior in diseases of the extrapyramidal system (transl. from German). Klin. Wochenschr. 38,
1236–1239 (1960).
5. W. Birkmayer, O. Hornykiewicz, The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia (transl. from
German). Wien. Klin. Wochenschr. 73, 787–788 (1961).
6. A. Carlsson, Does dopamine have a role in schizophrenia? Biol. Psychiatry 13, 3–21 (1978).
7. A. Carlsson, T. Magnusson, T. H. Svensson, B. Waldeck, Effect
of ethanol on the metabolism of brain catecholamines.
Psychopharmacology (Berlin) 30, 27–36 (1973).
8. G. Grunder, A. Carlsson, D. F. Wong, Mechanism of new
antipsychotic medications: Occupancy is not just antagonism. Arch. Gen. Psychiatry 60, 974–977 (2003).
9. J. Engel, A. Carlsson, Catecholamines and behavior. Curr.
Dev. Psychopharmacol. 4, 1–32 (1977).
10. M. F. Piercey, J. T. Lum, W. E. Hoffmann, A. Carlsson, E.
Ljung, K. Svensson, Antagonism of cocaine’s pharmacological effects by the stimulant dopaminergic antago-
eral years, resulting in increased
freezing and involuntary movement (13). l-Dopa also does not
eliminate nonmotor features
of the disease that contribute
to overall disability, including
autonomic nervous system dysfunction, sensory disturbances,
sleep disorders, mood disorders,
and dementia. Some symptoms
(alterations in olfaction and
sleep patterns, and constipation)
are in fact believed to predate
more classic motor features of
the disorder. The greatest shortcoming of l-dopa is that it does
not prevent the progressive
neuropathology associated with
the disease. Nevertheless, Carlsson’s demonstration that l-dopa
can allow patients to regain lost
motor function has permitted
millions of PD patients to recapture their normal lives to a large
degree and to delay, for several
years, the impact of the devastating motor symptoms associated
with this disorder. Carlsson’s
far-ranging scientific efforts not
only led to a fundamental understanding of dopamine’s role
in both PD and psychosis, but
also to the rapid development
of novel and effective therapies
for numerous neurological and
neuropsychiatric disorders. His
contributions have undoubtedly
earned him the title of one of the
foremost pioneers in the field of
translational research.
nists (+)-AJ76 and (+)-UH232. Brain Res. 588, 217–222
(1992).
11. A. Carlsson, Structural specificity for inhibition of [14C]5-hydroxytryptamine uptake by cerebral slices. J. Pharm.
Pharmacol. 22, 729–732 (1970).
12. J. Wålinder, A. Carlsson, R. Persson, 5-HT reuptake inhibitors plus tryptophan in endogenous depression. Acta
Psychiatr. Scand. Suppl. 63, 179–190 (1981).
13. C. W. Olanow, M. B. Stern, K. Sethi, The scientific and clinical basis for the treatment of Parkinson disease. Neurology 72, S1–S136 (2009).
10.1126/scitranslmed.3000149
Citation: J. K. Andersen, Arvid Carlsson: An early pioneer in
translational medicine. Sci. Transl. Med. 1, 2ps3 (2009).
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PERSPECTIVE