Pathophysiology of drug-induced dyskinesias

The dyskinesias produced by DOPA and prolonged treatment with phenothiazines are so similar that it is tempting to propose a common mechanism for both. The following assumptions are made: (1) Dyskinesias result from excessive inhibition of caudate neurones by dopamine. 1. (2) The mechanism responsible for inactivating excessive extra-neuronal dopamine (mainly reuptake) and intraneuronal dopamine (monoamine oxidase) are impaired in patients with Parkinson's disease. 2. (3) Because of this disturbance, when patients with Parkinson's disease are treated with l-DOPA, excessive levels of dopamine build up at receptor sites resulting in dyskinesias. 3. (4) Long-term use of neuroleptics causes accelerated production of dopamine, which may continue even after the offending drug is stopped. When brain damage, including loss of dopaminergic fibres to the caudate nucleus, coexists, there is disturbance of dopamine inactivation similar to that of Parkinson's disease, resulting in increased extracellular dopamine levels and dyskinesias. The dyskinesias may be exacerbated by discontinuing the neuroleptics because the blocking effect of the latter on dopamine receptors is reversible, while an increased rate of synthesis continues.