L‐dopa in parkinsonism

T e n years of experience with L-dopa ( L-3,4-dihydroxyphenylalanine) has clearly shown that this agent is by far the most effective treatment presently available for Parkinson’s disease.’-6 The rationale for the use of this catechol amino acid rests upon the observation that dopamine, the precursor of which is dopa, is depleted in the corpus striatum of parkinsonian patients7 The reduction in striatal dopamine stores appears to be a consequence of the degeneration of dopaminecontaining nerve terminals, the pigmented cell bodies of which reside in the pars compacta of the substantia nigra. It has generally been assumed that the administration of dopa, which, unlike dopamine, readily penetrates the bloodbrain barrier, improves neurological function by replenishing dopamine stores in residual terminals of the nigrostriatal neuronal system. The concept of replacement therapy through precursor loading may well prove correct but presently poses some theoretical difficulties. If the only function of dopa were to replenish dopamine stores, a correlation between clinical response and severity of disease would be expected. Yet, in patients with advanced disease in whom there are relatively few residual dopaminergic neurons, the cljnical efficacy of Ldopa does not appear to be substantially diminished.8-’2 An explanation of this paradox is suggested by our recent preliminary studies that show that at high concentrations Ldopa may enter noncatecholaminergic cells, undergo decarboxylation to dopamine, and subsequently be liberated in response to depolarization, per-