NEOSTRIATAL MECHANISMS IN PARKINSONS-DISEASE

Normal motor function is dependent on the highly regulated synthesis a nd release of dopamine (DA) by neurons projecting from substantia nigr a to corpus striatum. Cardinal symptoms of Parkinson's disease (PD) ar ise as a consequence of a deficiency in striatal DA due to the progres sive degeneration of this neuronal system. Under such circumstances, t he subunit composition and/or phosphorylation state of glutamatergic r eceptors of the N-methyl-D-aspartate (NMDA) subtype expressed on the d endritic spines of medium-sized striatal neurons changes in ways that compromise motor performance. Although levodopa acts, after conversion to DA, to reverse these changes by restoring striatal dopaminergic tr ansmission, significant differences exist between the normally functio ning DA system and the restoration of function provided by standard le vodopa therapy. The nonphysiologic stimulation of DA receptors on stri atal spiny neurons associated with current levodopa regimens now appea rs to contribute to the motor response complications that ultimately a ffect most parkinsonian patients. Current evidence suggests that alter ations in signaling systems linking dopaminergic and glutamatergic rec eptors within these GABAergic efferent neurons induce NMDA receptor mo dification. Functionally, the resultant long-term change in glutamater gic synaptic efficacy leads to alterations in spiny neuron output, fav oring the appearance of motor complications. Although dopaminomimetic replacement strategies that provide more continuous DA receptor stimul ation should alleviate these disabling complications, more innovative approaches to the interdiction of pathologic changes in signal transdu ction components or glutamate receptor sensitivity could ultimately pr ove safer and more effective for the treatment of all stages of PD.