Dopamine Replacement Therapy in Parkinson’s Disease: Past, Present and Future

Abstract

Until the 1960s, the only available pharmacotherapy for Parkinson’s disease (PD) consisted in anticholinergic drugs, whose positive symptomatic effects were discovered serendipitously [1]. This category of drugs is particularly effective in alleviating tremor, but also causes significant side effects due to the blockade of muscarinic receptors in the autonomic and central nervous system. The modern era of PD pharmacotherapy started about 50 years ago and was made possible by two scientific breakthroughs. Arvid Carlsson and collaborators discovered that dopamine (DA) was a centrally active neurotransmitter and that DA depletion by reserpine produced a syndrome very similar to parkinsonism in animals [2]. A few years later, Hornykiewicz and collaborators discovered DA deficiency in the brains of PD patients [3] and paved the way for the use of DA precursor, L-3,4-dihydroxyphenylalanine (L-DOPA) as a replacement therapy [4]. L-DOPA had an impressive efficacy on all the motor features of PD (resting tremor, rigidity, akinesia and postural instability) [5] and seemed to provide the ultimate treatment for this condition. It soon became apparent, however, that this treatment was not devoid of complications. Already at the beginning of the 1970s, abnormal involuntary movements (dyskinesia) were reported as a common, dose-limiting side effect of L-DOPA pharmacotherapy [6–9]. Involuntary movements could occur very early after the initiation of L-DOPA treatment, but their incidence and severity increased with time. Along with the clinical use of L-DOPA grew an awareness of its limitations. It is now well established that the response to L-DOPA changes during the progression of PD [10]. As the disease becomes more severe, the need for symptomatic medications becomes larger. Thus, both the total dosage and the