Recent Advances in the Biochemical Pharmacology of Extrapyramidal Movement Disorders
The biochemical pharmacology of parkinsonism and choreatic dis orders has been reviewed in relationship to recent observations in the synaptic pharmacology of dopaminergic systems. Despite the fact that parkinsonism is usually due to a failure of presynaptic dopamine input into the striatum, an identical clinical syndrome can result from postsynaptic striatal dysfunction. Although clinically identical, these two states differ both biochemically and pharmacologically. Presynaptic parkinsonism is associated with decreased dopamine turnover in the brain and responds to levodopa. Neither of these facts applies to postsynaptic parkinsonism
Denervation hypersensitivity has been proposed as a mechanism in the production of levodopa-induced dyskinesias and neurolepticinduced tardive dyskinesias. The role of chronic dopamine agonism in the former suggests that denervation hypersensitivity is not the only factor and raises the question that the treatment of parkinsonism with such agonists may inevitably be associated with dyskinesias and psychosis
Dopamine and acetylcholine have antagonistic effects on striatal neurons and that the normal function of these neurons depends upon a balance of the influences of these two neurotransmitters.
A shift of this balance such that there is a decrease in dopamine activity results in the signs and symptoms of parkinsonism. In most, if not all, of these patients this decrease is felt to come about as a result of decreased dopamine input (i.e., presynaptic dysfunction).
A shift of this balance such that there is a relative in crease in dopaminergic activity results in choreatic movement disorders. This increase in dopaminergic activity is felt to be due to dysfunction of the striatal neurons (postsynaptic dysfunction). This is felt to be related to primary neuronal disease in Huntington’s chorea and to denervation hypersensitivity in tardive dyskinesias and levodopa-induced dyskinesias.
The occurrence of parkinsonism as a result of striatal cell dysfunction, i.e., postsynaptic parkinsonism.
The role of chronic dopaminergic agonism in the pathogenesis of levodopa-induced hypersensitivity, i.e., agonist-induced hypersensitivity.
Further observation on the development of denervation hypersensitivity within the central nervous system.
KeywordsTardive Dyskinesia Stereotyped Behavior Levodopa Therapy Chronic Levodopa Choreic Movement
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