ABSTRACT
Although serendipity has enriched the therapeutics of Parkinson’s disease (PD) with drugs like the antiviral compound amantadine, most of the important advances have followed the route of drug discovery based on rational pharmacology. Several important breakthroughs in modern neuroscience served to guide PD drug development. The finding with the greatest impact was Arvid Carlsson’s recognition of dopamine’s function as a transsynaptic neurotransmitter in the striatum and elsewhere in the central nervous system (CNS) (1). These laboratory observations subsequently led to levodopa’s utilization as a precursor for correcting the PD brain’s striatal dopamine deficiency. Another research contribution that helped to expand treatment options for PD was the discovery of specific dopamine receptor subtypes and the key role of the D2 receptor subtype in mediating the relief of parkinsonian features (2,3). Recognition of dual anatomical and functional circuits originating from the striatum (the direct and indirect outflow pathways) has sparked the search for neuromodulatory systems beyond the dopaminergic nigrostriatal pathway, which might be utilized for therapeutic advantage in PD. These systems involve glutamate, enkephalin, dynorphin, and adenosine, among other substances that act upon neuronal circuitry “downstream” from the dopaminergic nigrostriatal synapse (4). Serendipity has continued to play a role in finding new ways for treating PD, as shown by the recent demonstration that amantadine, beyond its symptomatic relief of primary parkinsonian features, can also act to suppress levodopainduced dyskinesias (5).
