Damage to the basal ganglia through injury, stroke, or degenerative diseases produces characteristic motor, cognitive, and emotional symptoms. Motor disturbances may present as hyper- or hypokinesias. Hypokinesias may be akinesias (failure to initiate movement) or bradykinesias (reduction in amplitude and velocity of movement). There is evidence that basal ganglia activity is greatest during the planning stage of a voluntary movement, which may explain the akinesia to some extent. Bradykinesia is caused by a disturbance of the equilibrium between direct and indirect motor pathways.
Parkinson's disease (see also p. 370) is a progressive loss of movement accompanied by affective disorders. The etiology of Parkinson's disease is unknown. Most patients do not exhibit symptoms until the fifth or sixth decade. Motor symptoms are akinesia, bradykinesia, oculomotor disturbance (e.g. absence of blinking), so-called cogwheel rigidity, and loss of postural reflexes. Patients exhibit both normal and shuffling gait, have flexed posture and a 'pill-rolling' tremor of frequency 3 to 6 per second. There is evidence that the cause of the tremor is an abnormality of transmission between the cerebral cortex and the motoneuron cell body.
The disease is caused by the progressive degeneration of the dopaminergic nigrostriatal pathway. Symptoms appear when the loss of striatal dopaminergic terminals reaches between 80-90%. At autopsy, the pars compacta lacks neuro-melanin i.e. dopaminergic cell bodies. There is evidence of degeneration in other brain areas including the midbrain raphe nuclei, the nucleus ceruleus and the pars reticulata. Other aminergic (noradrenergic and serotonergic) pathways degenerate as well, but dopaminergic loss causes the symptoms.
This conclusion is supported by the discovery that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a contaminant of illicitly prepared heroin, caused parkinsonian symptoms in 20-year-old users. At autopsy, the pars compacta of the substantia nigra was virtually devoid of dopaminergic neurons.
The aim of treatment is to replace the lost dopamine. This is attempted through the administration of a dopamine precursor, L-dopa, since dopamine will not cross the blood-brain barrier. L-dopa is particularly useful for counteracting the brady-kinesia. The drug does not slow the course of the disease, and, disappointingly, its beneficial effects wane with time. Furthermore, the drug produces side effects. The hypothalamus and other brain areas have dopaminergic inputs, and patients experience nausea, loss of appetite, abnormal blood pressure control, mood changes, and sleep disturbance. Atropine-like drugs have also been used, which suggests that symptoms may be related to overactivity of striatal acetylcholine neurons.
A newer and still unconvincing treatment is the injection or implantation of human or autologous fetal brain tissue rich in dopaminergic cell bodies. Fetal tissues are not rejected. The results of treatment have been disappointing so far. Very recently, there have been reports that injection of a vector containing the human gene for glial cell line-derived neurotrophic factor (GDNF) into the rat mesencephalon protected dopaminergic neurons from the destructive effects of 6-hydroxydopamine.
Tardive dyskinesia is another disturbance of dopamine function in the brain, caused iatrogenically by administration of psychoactive drugs such as phenothi-azines.
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