Abstract Dublin, June 2001

Dopamine: A Cinderella Story

Arvid Carlsson, Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden

In 1956, following a most inspiring and fruitful sabbatical at the Laboratory of Chemical Pharmacology, National Institutes of Health, Bethesda, Md, USA, headed by the renowned Dr. Bernard B. Brodie, I discovered together with colleagues at my home University of Lund, Sweden, that the antipsychotic agent reserpine could induce a depletion of noradrenaline in tissues, including the brain. The following year we discovered that the sedation and hypokinetic syndrome induced by reserpine in experimental animals could be reversed by the injection of DOPA. However, this reversal took place despite the failure of reserpine to restore noradrenaline levels. We thus turned our attention to dopamine, then considered to be an in itself physiologically inactive precursor to noradrenaline. After developing a sensitive and specific method for the detection and quantitative determination of dopamine we could show in 1958 that the reversal of the reserpine-induced syndrome was closely correlated to the accumulation of dopamine in the brain. Moreover, we discovered that dopamine occurs normally in the brain in amounts markedly exceeding those to be expected from a precursor, and that its stores were depleted by reserpine, and this led us to conclude that dopamine serves a function in its own right in the brain. In October, 1958, I reported, at the First International International Catecholamine Symposium, Bethesda, Md, that dopamine is mainly concentrated to the basal ganglia. This, together with our earlier findings and the clinical observation that reserpine is capable of faithfully mimicking Parkinson's syndrome, led us to propose at this meeting that dopamine is involved in extrapyramidal functions and that dopamine depletion can induce the Parkinson syndrome, and finally, that the administration of DOPA can reverse this syndrome by restoring the dopamine levels.

Our contention that dopamine plays an important role in brain function was at first, for example at a meeting in London in 1960, rejected by the leading authorities in catecholamine research. This was partly due to the reluctance of pharmacologists to accept the idea that dopamine could possess any significant physiological activity per se. Not until a few years later, when our research group could demonstrate the cellular localization of dopamine, noradrenaline and serotonin, was our claim that these amines serve as important neurotransmitters in the brain, generally accepted.

Already within a few years after our presentation at the above-mentioned Catecholamine Symposium, data from studies in humans, published by researchers in Japan, Austria, and Canada, supported our animal Parkinson model. Finally, thanks to the studies of Cotzias and coworkers in 1967, could L-DOPA be introduced as a clinically useful remedy in the treatment of Parkinson's disease.

Another important line of research deals with the role of dopamine in schizophrenia In 1963 we proposed that the major antipsychotic agents, in contrast to the monoamine depleting drug reserpine, acted by blocking receptors for carecholamines, and possibly also receptors for serotonin. The "dopamine hypothesis of schizophrenia" originates from this work. Recently this hypothesis, which was for a long time supported only by pharmacologic evidence, has received direct support, in that evidence for an elevated dopaminergic tone in drug-naive schizophrenic patients has been presented by several research groups. On the other hand, evidence for an involvement of other neurotransmitters as well has come forth. Nevertheless, dopamine still appears to be strategically involved in psychotogenesis.

A major drawback with the present treatment of schizophrenia seems to be that blockade of dopamine receptors involves the risk of serious side effects induced by hypodopaminergia, leading to motor disturbances and even more severely, dysfunction of the reward system with anhedonia and depression, as well as loss of cognitive functions. To circumvent this problem we have developed a new pharmacological principle leading to stabilization of the dopaminergic system at a normal baseline level. Treatment with dopaminergic stabilizers would be expected to alleviate symptoms of hyperdopaminergia without entailing any risk of hypodopaminergia and should also be able to combat negative symptoms. Preliminary clinical data with one such agent (OSU6162) in patients with neurological disorders and schizophrenia will be presented.