PD is a neurodegenerative disorder of unknown etiology that currently afflicts over one million Americans. The pathological hallmark of PD is a selective loss of dopamin-ergic neurons in the substantia nigra pars compacta in the midbrain that projects to the corpus striatum (Greenfield and Bonsaquet 1953). When the loss of dopamine (DA) exceeds 50-80%, Parkinsonian symptoms become clinically evident (Ehringer and Hornykiewcz 1960; Hornykiewcz 1963). The cardinal features of PD include resting tremor, rigidity, bradykinesia, and impaired postural reflexes (Parkinson 1817; Lang and Lonzano 1998).
Since Cotzias demonstrated the dramatic therapeutic effects of the dopamine precursor levodopa on the motor symptoms of PD patients (Cotzias et al. 1967), the prevailing therapeutic strategy has been to restore striatal dopamin-ergic transmission (Lang and Lonzano 1998). Initially, pharmacologic agents such as levodopa, the metabolic precursor of DA, or a direct DA receptor agonist that restores dopaminergic transmission, typically afford substantial symptomatic relief. But with disease progression, increasing difficulties arise. With DA agonists, the ability to provide adequate symptom suppression gradually declines; most agonists require levodopa supplementation within two years of initiation. With levodopa, the problem is not so much a loss of anti-Parkinsonian efficacy as a gain in adverse effects, especially motor response complications (Chase and Oh 2000). Elements of the motor complication syndrome eventually occur with all currently available dopaminomimetic therapies, although latency to onset is longer with the commonly used agonists (Marjama-Lyons and Koller 2001). Notwithstanding the introduction of several new dopaminomimetics since the discovery of le-vodopa, most Parkinsonian patients still become significantly disabled within ten years of symptom onset.
Administering levodopa or other direct dopamine agonists alleviates the severity of Parkinsonian signs. Although levodopa is safe and effective, after a few years of levodopa therapy patients may experience motor complications from repetitive administration of dopaminergic drugs (Marsden 1990). The most common motor complications observed in humans are the involuntary and nonfinalized movements known as dyskinesias, and the reduced duration of the anti-Parkinsonian effect of the therapy, known as "wearing-off effect" (Shaw et al. 1980).
While patients with early PD characteristically enjoy a good response to levodopa, the combination of disease progression and chronic levodopa therapy eventually compromises this benefit in several ways (Marsden 1994). Over the years, the anti-Parkinsonian effect of each levodopa dose lasts for a progressively shorter time, requiring increasingly more frequent levodopa administration. At first, when the shortening of motor benefit occurs in a predictable and gradual fashion, patients are said to have wearing-off fluctuations. Subsequently, when the effect of an individual dose ceases in an unpredictable and abrupt manner, the term "on-off phenomenon" is used. Combined, motor fluctuations and dyskinesias are referred to as motor response complications (MRCs) and occur in over 50% of patients after five years of levodopa treatment (Marsden 1994).
In addition to these fluctuations in motor function, patients also develop involuntary movements called dyski-nesias. When these symptoms first arise, they are usually associated with high levodopa levels and may be prevented or minimized by lowering the levodopa dose. Later on, however, the therapeutic window of levodopa narrows progressively and dyskinesias occur at a plasma levodopa level equal to that needed to induce an anti-Parkinson effect (obligatory dyskinesias). Dyskinesias are most commonly choreiform and occur when plasma levodopa levels are high (peak-dose dyskinesias) or, in the more advanced disease, throughout the levodopa-induced motor benefit (square-wave dyskinesias). They may also be more dystonic or ballistic in appearance and occur when levodopa levels are rising or falling (diphasic dyskinesias).
C. Therapeutic Strategies and Animal Models of Motor Response Complications
In an effort to find ways to prevent or relieve the long-term complications of levodopa treatment, investigators established animal models for the motor complication syndrome (Engber et al. 1989; Papa et al. 1994; Marin et al. 1996), conceptualized and began to characterize the functional consequences of the chronic nonphysiologic stimulation of striatal DA receptors (Mouradian et al. 1989), and began to exploit the therapeutic implications of these findings in primate models (Chase 1998). Recent studies have extended these findings in ways that advance our understanding of mechanisms contributing to the production of motor complication symptoms and enhance our ability to identify novel targets for palliative intervention. In addition, they have begun to delineate molecular mechanisms subserving motor memory and synaptic integration in striatal spiny neurons. Recent observations have also provided added support for the revolutionary concept that symptom relief in PD might be better achieved, not by replacing the deficient neurotransmitter, but rather by preventing or correcting the consequences of dopaminergic denervation at downstream sites. Clinical investigations over the past few decades have tested novel hypotheses generated by preclin-ical research with nonhuman primates and provided initial evidence for promising new therapeutic approaches. These translational studies have also begun to shed light on another problem plaguing late-stage Parkinsonian patients: the pathogenesis of the increasing motor disabilities—such as those involving speech, swallowing, and gait—that resist current dopaminomimetic therapy.
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