In
Parkinson's disease patients, a prolonged half-life of
dopamine formed from
L-DOPA may reduce the risk of developing
L-DOPA-induced side-effects.
Deuterium substitutions in the
L-DOPA molecule are expected to yield
dopamine with an altered half-life because C-D bonds are more stable than C-H bonds. Therefore we tested, in the rat, the neurochemical and behavioral effects of different types of
L-DOPA with
deuterium substitutions at the alpha-
carbon and/or the beta-
carbon. By means of microdialysis, we found that
L-DOPA with 3
deuterium substitutions (D3-L-DOPA) enhanced
dopamine output in the striatum more effectively than
L-DOPA and all the other
deuterium variants. Moreover, D3-L-DOPA produced a more pronounced stimulation of locomotor activity in reserpinized rats compared to conventional
L-DOPA. In contrast beta,beta-D2-L-DOPA was less effective than
L-DOPA in raising striatal
dopamine levels and was ineffective at restoring locomotor activity in reserpinized rats. These results demonstrate that the introduction of
deuterium at different positions in the
L-DOPA molecule dramatically changes its behavioral and neurochemical profile and suggest that
L-DOPA treatment of
Parkinson's disease may be improved in this way.