Parkinson's disease (PD) is a common neurologic disorder affecting over 600,000 people in the United States. It is pathologically characterized by a profound loss of dopaminergic cells in the substantia nigra, and its clinical manifestations include disturbances of movement and muscular control such as tremor, rigidity, bradykinesia, akinesia, gait difficulties, and postural instability. Currently, levodopa is the most effective medical treatment for PD. Exogenous levodopa replaces depleted dopamine stores and alleviates PD symptoms. While it is initially effective, the symptoms become refractory after 3 to 5 years of treatment and patients develop worsening on-off symptom fluctuations in which on periods are associated with hyperkinetic movements (e.g. dyskinesias) and off periods with hypokinetic movements (e.g. akinesia, bradykinesia) and gait difficulties. Recent insights into the neurophysiology of PD reveal localized sites of neuronal dysregulation within the brain. The GPi discharge is nearly suppressed during levodopa-induced dyskinesias. Motor fluctuations, on-off phenomena and dyskinesias, usually accompany long-term levodopa therapy. Levodopa-induced dyskinesias, one of the most disabling complications, are comprised of choreic and dystonic involuntary movements which interfere with normal motor behavior and the activities of daily living. The mechanism by which providing dopamine to a denervated striatum produces abnormal movements along with the expected reversal of parkinsonian features remains unknown. According to the current knowledge of the functional anatomy of the basal ganglia, after dopamine denervation striatal cells that project directly to the internal segment of the globus pallidus (GPi) become hypoactive. Conversely, because of the excitatory or inhibitory action of dopamine on different populations of striatal cells, projections to the external segment of the globus pallidus (GPe) are overactive. The overinhibition of GPe cells through this indirect gabaergic striatal output leads to hypoactivity in the GPe output pathway, which also is gabaergic and projects to the subthalamic nucleus (STN). Release of the STN from the inhibitory influence of GPe results in overactivity of glutamatergic STN cells that project to the GPi. Thus, in the parkinsonian state excessive excitatory input from the STN (indirect striatal output pathway) combined with disinhibition through the direct striatal projection results in overactivity of the GPi. Dopamine replacement by levodopa is thought to normalize GPi activity by its action through the direct and indirect striatal output pathways, i.e. by decreasing the activity of STN cells together with an increase in the activity of direct striatal projection cells. Consistent with this concept, neurophysiological studies in parkinsonian monkeys show a reduction in the activity of GPi cells with reversal of parkinsonian features (?on? state) by dopamine agonists8 or levodopa. Moreover, neuronal recording in parkinsonian patients during pallidotomy also shows a decrease in cell firing following induction of the ?on? state by apomorphine administration. If the anti-parkinsonian effects of levodopa are due to decreased activity in the GPi, then levodopa-induced dyskinesias might result from excessively reduced activity of the GPi. There is evidence both for and against this hypothesis. On the one hand, STN vascular lesions (presumably strongly reducing activity in GPi) typically produce prominent involuntary movements in the contralateral side of the body (hemiballismus). Additionally, subthalamotomy reverses akinesia and rigidity with the appearance of transient dyskinesias in parkinsonian monkeys, and it also produces marked contralateral dyskinesias in normal monkeys. On the other hand, pallidotomy selective for GPi greatly ameliorates levodopa-induced dyskinesias. Resolution of this conundrum requires knowledge of the activity of the GPi cells during dyskinesias. To address this issue we used single cell recording of the firing of GPi cells in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-parkinsonian monkeys that developed dyskinesias after chronic levodopa treatment. To avoid the risks associated with pooling activity from different functional groups of cells in the different states, we recorded from individual cells continuously from the ?off? state before levodopa administration, though the ?on? state immediately after the beginning of levodopa effects, and, finally, into the ?on? state with dyskinesias that typically occurs a few minutes after the onset of the ?on? state in monkeys that have undergone chronic treatment. Subsequently, to better link the changes found in the activity of GPi cells during dyskinesias, a second set of experiments was performed using a lower dose of levodopa that, even though producing an ?on? response of similar magnitude, did not elicit dyskinesias. The transition from the 'off' to the 'on' state, with a complete reversal of parkinsonism, was characterized by a decrease (in the majority of cells), no changes or an increase in the firing rate of individual GPi cells; on average there was a 43% decrease of activity. During dyskinesias firing rates fell profoundly in almost all cells, with decrements as low as 97% in individual cells, and 71% drop on the average rate already lowered in the transition from the 'off' to the 'on' state. These changes were seen after some time from the onset of the 'on' state only when dyskinesias were present. The difference in GPi activity between the 'on' state and 'on with dyskinesias' suggests that normalizing parkinsonism critically depends on a fine tuning of the basal ganglia output Dyskinesias, associated with too low firing rates of GPi neurons, seem to result from an imbalance in the GPi discharge.
