The pathogenesis of motor fluctuations in individuals with PD receiving levodopa has been the subject of much speculation, but little certainty, over the years. Both peripheral and central mechanisms have been hypothesized. Both may actually be active, but it appears that most often the predominant mechanisms driving the pathogenic process are within the CNS. Evidence has begun to accumulate that with PD progression the dwindling number of surviving nigrostriatal dopaminergic neurons are unable to maintain the normal synaptic atmosphere of constant dopaminergic stimulation; instead the environment becomes one in which dopamine receptor stimulation is intermittent, characterized by pulses of dopaminergic stimulation coincident with levodopa administration. It appears that this pulsatile stimulation may, in turn, incite a cascade of changes within the postsynaptic striatal spiny neurons that produces sensitization of glutamate receptors and altered motor responses (125,126). If this is correct, providing and maintaining a synaptic environment of more constant dopaminergic stimulation from the beginning of treatment might forestall the development of the postsynaptic alterations and delay or prevent the appearance of motor fluctuations. This has led to the proposal that a COMT inhibitor, such as entacapone, may be administered along with levodopa and carbidopa right from the initiation of therapy (127,128). Jenner and coworkers reported that in marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, initiation of treatment with frequent doses of levodopa combined with entacapone resulted in less frequent and less severe dyskinesia than that which developed in animals treated with comparable doses of levodopa alone (129). Studies are currently underway in humans, and if a reduction or delay in the development of motor fluctuations with such treatment is demonstrated, the role for COMT inhibitors in the treatment of PD may expand dramatically.
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