Recent advances in the treatment of L-DOPA-induced dyskinesia.

Parkinson's disease (PD) is a degenerative movement disorder resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta. The most widely used treatment for PD is administration of the dopamine precursor L-DOPA, although this eventually results in uncontrolled involuntary movements (dyskinesia) that can be more debilitating than the underlying disease itself. The causes of L-DOPA-induced dyskinesia are unclear, but probably involve non-physiological pulsatile stimulation of dopamine receptors or non-physiological dopamine release (eg, from serotonergic nerve terminals) in the striatum. In any case, this signaling leads to an imbalance in the activity of two basal ganglia pathways, the 'direct' and 'indirect' striatal output pathways, that are characterized by distinct neurochemical architectures. The wide range of neurotransmitter and neuromodulatory receptors present on these two striatal output pathways offers a huge range of potential therapeutic targets. Two main strategies for the treatment of dyskinesia exist: the use of drugs that can be given as an adjunct to L-DOPA, reducing the occurrence of dyskinesia without impairing its antiparkinsonian effect, or therapies with equal antiparkinsonian action as L-DOPA that do not elicit dyskinesia. Novel treatments for dyskinesia in clinical/preclinical development include A(2alpha) receptor antagonists, alpha(2) adrenoceptor antagonists, mu-opioid receptor antagonists and subtype-selective NMDA antagonists. Future research strategies are likely to focus on the molecular mechanisms underlying the emergence of dyskinesia and may lead to the development of agents that can prevent or reverse the cellular changes underlying this phenomenon.