On the mechanism of the antiparkinsonian action of 1-DOPA and bromocriptine: a theoretical and experimental analysis of dopamine receptor sub- and supersensitivity

Abstract

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 range 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.