Dopamine miracle: From brain homogenate to dopamine replacement

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Abstract

Let me first express my gratitude to Professor Andrew Lees for asking me to come to London and give a lecture with the intriguing title: “The Dopamine Miracle: From Brain Homogenate to Dopamine Replacement.” When accepting the invitation, I thought it indeed very appropriate to speak of dopamine in London. As I shall presently show you, it was in this country, and in great measure here in London, that this at first inconspicuouslooking substance entered the stage of biological research. Dopamine was first synthesised in 1910 by George Barger and James Ewens in the Wellcome laboratories at Herne Hill, London. In the same year, and in the same place, Henry Dale (later Sir Henry) examined dopamine’s biological activity and found it to be a weak sympathomimetic, adrenaline-like, substance. It also was Henry Dale (Fig. 1) who, many years later, in 1952, suggested the name dopamine for the full chemical name 3,4-dihydroxyphenylethylamine or the shorter, but misleading, 3-hydroxytyramine. (For references related to the early dopamine history, see Hornykiewicz, 1986 .) In the 30 years following its synthesis, nothing spectacular happened to dopamine. In 1938, however, the pharmacologist Peter Holtz in Germany discovered the enzyme dopa decarboxylase and showed that in mammalian tissue homogenates, especially kidney, it produced dopamine from levodopa ( L-dopa). Based on that discovery, a year later in 1939, Hermann Blaschko at the Physiological laboratories in Cambridge postulated the still valid biosynthetic pathway for catecholamines, which assigned dopamine the modest role of a metabolic intermediate in the synthesis of noradrenaline and adrenaline. As a metabolic intermediate, dopamine could be expected to occur in many catecholaminecontaining tissues. Indeed, beginning in about 1950, reports started to appear about the occurrence of small amounts of dopamine in many peripheral tissues, such as adrenal medulla, heart, adrenergic nerves, and others. By themselves, these observations did not add up to anything important. However, they gave Blaschko, now in Oxford’s pharmacology department, the idea that dopamine might have an own physiological role in the body. In a lecture given before the Swiss Society of Physiology, Biochemistry and Pharmacology in the Fall of 1956, Blaschko asked the question, “What is the physiological significance of dopamine?” Putting the fragmentary information together, he concluded: “In chromaffin tissue, only very small quantities of dopamine occur; this suggests that in this tissue, like a true metabolic intermediate, it is not stored. Schümann has recently shown that in adrenergic nerves this appears to be different. Here the amounts of dopamine found are comparable with those of noradrenaline. This suggests the possibility that dopamine has some functions of its own which are not yet known”. 2