Expanding the repertoire of L-DOPA’s actions: A comprehensive review of its functional neurochemistry

Philippe De Deurwaerdère, Giuseppe Di Giovanni, Mark J. Millan
Progress in Neurobiology. 2017-04-01; 151: 57-100
DOI: 10.1016/j.pneurobio.2016.07.002

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Though a multi-facetted disorder, Parkinson’s disease is prototypically
characterized by neurodegeneration of nigrostriatal dopaminergic neurons of the
substantia nigra pars compacta, leading to a severe disruption of motor function.
Accordingly, L-DOPA, the metabolic precursor of dopamine (DA), is
well-established as a treatment for the motor deficits of Parkinson’s disease
despite long-term complications such as dyskinesia and psychiatric side-effects.
Paradoxically, however, despite the traditional assumption that L-DOPA is
transformed in residual striatal dopaminergic neurons into DA, the mechanism of
action of L-DOPA is neither simple nor entirely clear. Herein, focussing on its
influence upon extracellular DA and other neuromodulators in intact animals and
experimental models of Parkinson’s disease, we highlight effects other than
striatal generation of DA in the functional profile of L-DOPA. While not
excluding a minor role for glial cells, L-DOPA is principally transformed into DA
in neurons yet, interestingly, with a more important role for serotonergic than
dopaminergic projections. Moreover, in addition to the striatum, L-DOPA evokes
marked increases in extracellular DA in frontal cortex, nucleus accumbens, the
subthalamic nucleus and additional extra-striatal regions. In considering its
functional profile, it is also important to bear in mind the marked (probably
indirect) influence of L-DOPA upon cholinergic, GABAergic and glutamatergic
neurons in the basal ganglia and/or cortex, while anomalous serotonergic
transmission is incriminated in the emergence of L-DOPA elicited dyskinesia and
psychosis. Finally, L-DOPA may exert intrinsic receptor-mediated actions
independently of DA neurotransmission and can be processed into bioactive
metabolites. In conclusion, L-DOPA exerts a surprisingly complex pattern of
neurochemical effects of much greater scope that mere striatal transformation
into DA in spared dopaminergic neurons. Their further experimental and clinical
clarification should help improve both L-DOPA-based and novel strategies for
controlling the motor and other symptoms of Parkinson’s disease.


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