Saccade responses to dopamine in human MPTP-induced parkinsonism.

Depletion of dopamine content in the substantia nigra resulting from 1-methyl-4-phenyl- 1,2,5,6-tetrahydropyridine (MPTP) toxicity produces parkinsonism. Management of 3 patients with MPTP-induced parkinsonism required drug holidays during which there was a state of dopamine depletion followed by dopamine replacement. We used this opportunity to study the effect of the selective loss of pars compacta dopaminergic cells on vertical and horizontal saccade (fast) eye movements. During the drug holidays, visually guided saccades were hypometric and had long latencies but retained a normal saccade velocity-amplitude relationship. Dopamine agonists or precursors improved the accuracy and reaction times of saccades in all directions, but not their velocity. Two of the three patients also had intermittent blepharospasm during dopamine depletion. During the episodes of blepharospasm, saccade responses became slow eye movements. MPTP causes a dopaminergic-responsive disorder of saccade initiation that is similar to idiopathic parkinsonism. The inhibition of voluntary eyelid opening during MPTP-induced blepharospasm further increases this impairment of fast eye movements and altered saccade velocity, presumably via the pars reticulata of the substantia nigra. Hotson JR, Iangston EB, Langston JW. Saccade responses to dopamine in human MPTP-induced parkinsonism. Ann Neurol 20:456-463, 1986 The compound l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a newly recognized neurotoxin 1291 that selectively kills dopaminergic cells in the pars compacta of the substantia nigra [4, 8, 301. In humans, exposure to the street drug form of MPTP causes a Parkinson’s disease symptom complex with bradykinesia, rigidity, tremor, and postural instability. In some patients there is also apraxia of eyelid opening and reflex blepharospasm E3, 291. Patients with MPTP-induced parkinsonism have few of the additional problems accompanying the other forms of Parkinson’s disease symptom complex such as multisystem involvement, aging, or dementia 1 13, 15, 17, 19, 331. Therefore, interpretation of movement abnormalities in patients with MPTP-induced parkinsonism involves few additional confounding variables. Management of these patients, however, is complicated by the early appearance of dyskinesias and hallucinations after treatment with dopamine precursors and agonists. Drug holidays are required to reduce the dopamine-induced complications. This clinical requirement for drug holidays creates the unique situation of dopamine depletion followed by replacement in humans with presumed selective loss of pars compacts cells. It has also recently been established that saccaderelated cells in the superior colliculus are tonically inhibited by cells in the pars reticulata of the substantia nigra, an output of the basal ganglia [21, 22). This inhibition appears to be mediated by y-aminobutyric acid (GABA) [23, 241. GABA agonists injected into the superior colliculus restrict saccadic eye movements, whereas GABA antagonists facilitate their initiation. GABA agonists injected into the pars reticulata of the substantia nigra also facilitate saccadic initiation, presumably by blocking its tonic inhibition of the superior colliculus. It is unknown, however, whether selective dopamine loss in the pars compacta also reversibly alters saccade initiation via this pathway. For these reasons, we used the clinical opportunity offered by the drug holidays in MPTP-exposed patients to study the effects of selective dopamine depletion on visually guided saccades. During the study, we also found that MPTP-induced dopamine depletion caused severe blepharospasm accompanied by restriction of saccade responses in two patients. A brief report of these observations has been presented 1261.