Deuterium-substituted l-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson’s disease: comparison with the effects produced by l-DOPA and an MAO-B inhibitor

The most effective treatment of Parkinson’s disease (PD) l -DOPA is associated with major side effects, in particular l -DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted l -DOPA (D3- l -DOPA), compared with l -DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3- l -DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO). Therefore, a comparative neurochemical analysis was here performed studying the effects of D3- l -DOPA and l -DOPA on dopamine output and metabolism in 6-OHDA-lesioned animals using in vivo microdialysis. The effects produced by D3- l -DOPA and l -DOPA alone were additionally compared with those elicited when the drugs were combined with the MAO-B inhibitor selegiline, used in PD treatment. The different treatment combinations were first evaluated for motor activation; here the increased potency of D3- l -DOPA, as compared to that of l -DOPA, was confirmed and shown to be of equal magnitude as the effect produced by the combination of selegiline/ l -DOPA. The extracellular levels of dopamine were also increased following both D3- l -DOPA and selegiline/ l -DOPA administration compared with l -DOPA administration. The enhanced behavioral and neurochemical effects produced by D3- l -DOPA and the combination of selegiline/ l -DOPA are attributed to decreased metabolism of released dopamine by MAO-B. The similar effect produced by D3- l -DOPA and selegiline/ l -DOPA, respectively, is of considerable clinical interest since D3- l -DOPA, previously shown to exhibit a wider therapeutic window, in addition may reduce the need for adjuvant MAO-B inhibitor treatment.