Neuropharmacological Effects of Certain Agents which Interfere with Cell Metabolism

Abstract

A study has been made of the neuropharmacological effects of two classes of compounds which can interfere with cell metabolism. Following their injection into the cerebral ventricles of either the conscious mouse or rat, both 2,4-dinitrophenol and pentachlorophenol, which uncouple oxidative phosphorylation, and the cardiac glycosides ouabain and digitoxin, which inhibit the sodium pump, produce marked changes in general behaviour and in the ability of the animals to regulate body temperature. After central administration the phenolic uncouplers produce a loss of righting reflex similar to that seen after pentobarbitone given by the same route of injection. This leads to a re-examination of an earlier hypothesis that a possible mechanism of hypnotic action of the barbiturates involves uncoupling oxidative phosphorylation. The pharmacological profiles of the phenols and the barbiturates do, however, differ in several respects. A biphasic effect is apparent after central administration of the cardiac glycosides. Ouabain produces a central nervous depression in small doses, whereas higher doses are excitatory, convulsant and lethal. The depressant effects show a number of similarities to those seen after peripheral administration of several drugs which interfere with aminergic systems, although the effect on brain amine levels of these compounds, which have similar pharmacological activity, is variable. Whereas the central excitant actions of the cardiac glycosides may involve noradrenergic mechanisms, their depressant actions seem to involve a dopaminergic component. In view of the ability of both the phenolic uncouplers and the cardiac glycosides to produce effects on the central nervous system and to interact with a number of other drugs, the possible therapeutic implications of these findings are discussed. Although not postulated as a mechanism of action common to all centrally acting drugs, a primary interference in cellular energy metabolism may provide explanations for a number of hitherto inexplicable drug actions.