FRANCESCO BIBBIANI and JUSTIN D. OH
Chronic levodopa treatment of Parkinson disease (PD) patients ultimately produces motor response complications (MRCs) that include response fluctuations and dyskinesias. Similarly, in MPTP-lesioned nonhuman primates, administering dopaminomimetics produces many of the features of the human motor complication syndromes. Recent nonhuman primate studies suggest that MRCs from the pulsatile nonphysiological stimulation of dopaminergic receptors on striatal spiny neurons increase the sensitivity of corticostri-atal glutamatergic synaptic transmission. Changes to the glutamatergic signaling pathways and adenosinergic and serotonergic pathways both intrinsic and extrinsic to the stri-atal dopaminoceptive medium-spiny neurons also may contribute to the pathogenesis of motor dysfunction in advanced PD. As a result of these alterations, basal ganglia output changes in ways that favor the appearance of Parkinsonian signs and motor complications. Conceivably, safer and more effective therapies for PD can be provided by drugs that target signaling molecules within striatal neurons or those that interact extracellularly with nondopaminergic receptors such as A-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA), adenosine, and serotonin.
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