Fifty years of dopamine research.

This year marks the 50th anniversary of the discovery of dopamine as a putative independent neurotransmitter in the nervous system. The amine 3-hydroxytyramine (‘dopamine’) had earlier been identified as an intermediary in the synthesis of noradrenaline and adrenaline from tyrosine. In 1957,ArvidCarlsson,MargitLindqvist,TorMagnussonand BertilWaldeck, inLund [1,2], andKathleenMontagu,working in Hans Weil-Malherbe’s laboratory at the Runwell Hospital outside London [3],made the seminal observations thatwould lead to theunravelling in subsequent years of the role of dopamine as a transmitter in the CNS, independent of its role as a precursor in the synthesis of noradrenaline and adrenaline. In 1957–1958, Carlsson and co-workers made the intriguing observation that the akinetic effects of reserpine could be reversed by an intravenous injection of the dopamine (and noradrenaline) precursor 3,4-dihydroxyphenylalanine (DOPA) andwere correlated to a recovery of dopamine, but not noradrenaline, content in the brain, suggesting that depletion of dopamine, rather than noradrenaline or 5-hydroxytryptamine (5-HT, or serotonin), was the cause of the akinetic state in reserpine-treated animals. The following year, Carlsson’s students Å ́ ke Bertler and Evald Rosengren [4], and Sano and collaborators in Japan [5], reported that the bulk of dopamine in the brain was located in the striatum (a structure containing little noradrenaline) [4,5], thus providing further support for the hypothesis that this new, putative transmittermight have a central role in the control ofmotor function [6]. As described byOlehHornykiewicz in his review of these early events [7], it was the 1959 paper of Bertler and Rosengren that stimulated him, together with Herbert Ehringer in Vienna, to embark on a series of further studies of the distribution of dopamine inhumanpost-mortembrains,which showed that the dopamine concentration is markedly and consistently reduced in the caudate and putamen of patients with Parkinson’s disease (PD) [8]. Thesefindings led to thefirst trials of L-DOPA in PD patients by Walther Birkmayer and Oleh Hornykiewicz [9] in Vienna and by André Barbeau, Ted Sourkes and Gerald Murphy [10] in Montreal. The real breakthrough, however, camefive years later, in 1967,when George Cotzias in New York developed the clinically efficacious,high-doseoralDOPAtreatment that is stillused today [11]. More detailed, personal accounts of these early discoveries are provided in reviews by Carlsson [12] and Hornykiewicz [7]. For the first decade after its discovery, there was little interest in dopamine. A search in the PubMed database