On the Mechanism of the Antiparkinsonian Action of l-DOPA and Bromocriptine: A Theoretical and Experimental Analysis of Dopamine Receptor Sub- and Supersensitivity
Further advancements in the development of antiparkinsonian drugs are highly dependent on a better understanding of the biochemical changes present in the “supersensitive DA receptors”. The present paper stresses also the importance of the development of behavioural models for studies on supersensitive DA receptors (rotational behaviour in 6-OHDA lesioned rats) and on intact DA receptors, i.e. rotational behaviour in KA lesioned rats. The relevance of heuristic models for DA receptor sub– and supersensitivity is underlined. The pharmacological findings with bromocriptine indicate that its ability to reduce the on-off phenomenon in patients could be due to its longlasting and rather constant activation of supersensitive DA receptors, and its partial DA agonist activity at DA receptors not linked to adenylate cyclase. The concept is introduced that to understand DA receptor sub-supersensitivity it is of help to postulate variations in the numbers of coupled DA receptors as an important factor. The behavioural experiments with elymoclavine further underline this view by indicating increases in the working ränge at supersensitive DA receptors although the amount of agonist is reduced.
Furthermore, the concept has been introduced that the DA receptor supersensitivity development does not depend only on the deficit of the transmitter but possibly also on the deficit of a presynaptically released trophic factor. This factor could play a critical role in the control of the biochemical machinery of the postsynaptic cell, e.g. receptor synthesis, formation of catalytic units and of Compounds which can enhance the coupling between receptors and the biological effector.
The introduction of 1-DOPA in the treatment of Parkinson’s disease was a major break-through in neurology (Birkmayer and Hornykiewicz, 1962; Cotzias et al., 1967). The 1-DOPA therapy could be further improved by combining the 1-DOPA treatment with a peripheral decarboxylase inhibitor (see e.g. Birkmayer et al., 1974; Rinne, 1978). With the combined treatment it became possible to avoid peripheral side-effects of DOPA treatment since peripheral formation of,dopamine (DA) was blocked. In this way only a central accumulation of DA could occur. However, in recent studies it has been noticed that following a 5–7-year treatment with 1-DOPA, the original marked improvement of rigidity, hypokinesia and tremor was reduced or disappeared in a substantial number of parkinsonian patients (see Ludin and Bass-Verrey, 1976; Marsden and Parkes, 1976, 1977; Hornykiewicz, 1974; Rinne, 1978). Furthermore, half of the patients on long-term treatment with 1-DOPA develops on-off phenomena. This phenomenon means that the patient has an on- period characterized by marked hyperkinesias followed by an off- period characterized by marked hypokinesia. The off-period can last for a variable number of hours. Against this background it has been of substantial interest to observe that the dopamine receptor agonist, bromocriptine (CB 154), seems capable of reducing the number of patients exhibiting on-off phenomena on 1-DOPA treatment. Furthermore, bromocriptine produces a further improvement of the motor functions in parkinsonian patients, further reducing rigidity, hypokinesia and tremor (see Calne et al., 1974, 1978; Lieberman et al., 1976, 1979; Marsden and Parkes, 1976, 1977; Parkes et al, 1976).
In the present paper we have tried to increase the understanding of these clinical results by studying the pharmacology of 1-DOPA, bromocriptine (Hökfelt and Fuxe, 1972; Fuxe, 1973; Fuxe et al., 1974; Corrodi et al., 1973; Johnsson et al., 1976) and elymoclavine (see Fuxe et al., 1978 a) and by considering some theoretical aspects on DA receptor sub- and supersensitivity.
KeywordsDopamine Receptor Kainic Acid Ergot Alkaloid Parkinsonian Patient Dopamine Receptor Agonist
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