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
Unable to display preview. Download preview PDF.
- Anden, N.E. (1970). Pharmacological and anatomical implications of induced abnormal movements with L-dopa. In L-Dopa and Park insonism (Barbeau, A. and McDowell, F.H., Eds), pp. 132–143. F.A. Davis, Philadelphia.Google Scholar
- Barbeau, A., Marsh, H. and Gillo-Joffroy, L. (1971). Adverse clinical side effects of L-dopa therapy. In Recent Advances in Park inson’s Disease (McDowell, F.A. and Markham, C.H., Eds.), pp. 204–237. F.A. Davis, Philadelphia.Google Scholar
- Carlsson, A. (1970). Biochemical implications of dopa-induced actions on the central nervous system, with particular reference to abnormal movements. In L-Dopa and Parkinsonism (Barbeau, A. and McDowell, F.H., Eds.), pp. 205–213. F.A. Davis, Philadelphia.Google Scholar
- Fahn, S. and Breenberg, J. (1972). Striatonigral degeneration. Trans. Am. Neurol. Assoc. 97, 275–277.Google Scholar
- Goetz, C. and Klawans, H.L. (1974). Studies on the interaction of reserpine, d-amphetamine, apomorphine, and 5-hydroxytryptophan. Acta Pharmacol. Toxicol. 34.,119–L30.Google Scholar
- Jonas, W. and Scheel-Kruger, J. (1969). Amphetamine-induced stereotyped behavior correlates with the accumulation of O-methy- dopamine. Arch. Int. Pharmacody. 177 ,379–386.Google Scholar
- Klawans, H.L. (1968). The pharmacology of parkinsonism. Bis. Nerv. Syst. 29 ,805–816.Google Scholar
- Klawans, H.L. (1973). The Pharmacology of Extrapyramidal Movement Disorders. S. Karger, Basel.Google Scholar
- Klawans, H.L. (1975). Amine precursors in neurologic disorders and the psychoses. In Biology of Major Psychoses (Freedman, D.X., Ed.), pp. 259–272. Raven Press, New York.Google Scholar
- Klawans, H.L. and Rubovits, R. (1975). The pharmacology of tardive dyskinesia and some animal models. In Proceedings of the IX Confress of the Collegium Internationale Neuropsychopharma cologicum (Boissier, J.R., Hippius, H. and Pichot, P., Eds.), pp. 58–67. Excerpta Medica, Amsterdam.Google Scholar
- Klawans, H.L., Goetz, C., Westheimer, R. and Weiner, W.J. (1973a). 5-Hydroxytryptophan-induced behavior in intact guinea pigs. Res. Common. Chem, Pathol. Pharmacol. 5 ,555–559.Google Scholar
- Klawans, H.L., Crosset, P. and Dana, N. (1975a). Effect of chronic amphetamine exposure on stereotyped behavior: Implications for pathogenesis of L-dopa-induced dyskinesias. In Advances in Neurology, vol. 9 (Calne, D.B., Chase, T.N. and Barbeau, A., Eds.), pp. 105–112. Raven Press, New York.Google Scholar
- Klawans, H.L., D’Amico, D.J., Nausieda, P.A. and Weiner, W.J. (1976). The specificity of neuroleptic- and methysergide-induced behavioral hypersensitivity. Presented at the American Academy of Neurology Annual Meeting, April, 1976, Toronto, Canada.Google Scholar
- Nausieda, P.A., Crosset, P. and Klawans, H.L. (in press): Effect of chronic dopaminergic agonism on subsequent response to amphetamine and apomorphine. Encephale.Google Scholar
- Ohye, C., Bouchard, R., Boucher, R. and Poirier, L.J. (1970). Spontaneous activity of the putamen after chronic interruption of the dopaminergic pathway. J. Pharmacol. Exp. Ther. 175 ,700–708.Google Scholar
- Tarsy, D. and Baldessarini, R.J. (1976). The tardive dyskinesia syndrome. In Clinical Neuropharmacology (Klawans, H.L., Ed.), pp. 29–61. Raven Press, New York.Google Scholar
- Ungerstedt, U. (1971). Postsynaptic supersensitivity after 6-hydroxy dopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol. Scand. (Suppl.) 367 ,69–93.Google Scholar