title: Studies on the mode of action of centrally-acting drugs
Creators: name: Pollock, David
Publisher: name: University of Glasgow
Year: 1967

description: This thesis is primarily concerned with the effects of a number of tranquillisers, central stimulants, antidepressives and psychotomimetics upon rat brain nicotinamide nucleotide metabolism. Certain other related aspects of the activities of these drugs, including their effects upon locomotor activity and mitochondrial swelling, are also examined. 

In the introduction the urgent need for understanding the basic mechanisms of action of psychotropic drugs is emphasised and possible experimental approaches to this problem are considered. A survey of the part played by pyridine coenzymes in the main pathways of energy metabolism is given. Justification for the present investigation is mainly provided by certain pharmacological and clinical observations, suggesting possible connections between nicotinamide nucleotide metabolism, altered mental performance and psychotropic drug action. This evidence is reviewed.

Spectrophotometric and spectrophotofluorometric assays for brain nicotinamide nucleotides are described and evaluated. The isolation of the necessary accessory enzyme is described in detail. Methods of measuring the effects of drugs on in vitro mitochondrial swelling, on the in vivo incorporation of radioactive nicotinamide into NAD and upon locomotor activity are outlined. Two ALGOL programmes, devised to permit the statistical analysis of data using a digital computer, are described. 

A number of central nervous system stimulants and psychotomimetics reduced brain NAD levels without affecting the NADH2 levels. The fall in brain NAD levels therefore indicated a change in the total nucleotide content rather than an alteration in the dynamic equilibrium between the oxidised and reduced forms. Tranquillisers had no direct effect upon brain nicotinamide nucleotide levels. Certain central stimulants, which lowered brain NAD levels also apparently accelerated spectrophotometrically-determined mitochondrial swelling. The discrepancy between this latter result and the lack of effect observed in gravimetric measurements of mitochondrial swelling was resolved by microscopy, which revealed that these drugs caused in vitro aggregation. Attempts were made to correlate the drug-induced reduction in brain NAD levels with alterations in the rate of incorporation of radioactive nicotinamide into liver and brain NAD. Behavioural studies showed that the locomotor stimulant effects produced by some of these drugs could be modified by the simultaneous administration of nicotinamide, which also increased brain NAD levels. The time course of the behavioural-stimulant effect did not however, parallel the NAD-lowering action.

In the discussion the experimental methods are critically assessed and the validity and pharmacological relevance of the results discussed with reference to current theories of psychotropic drug action. The particular significance of these results is suggested to lie not in the amount by which brain NAD levels fell but in the fact that any reduction occurred at all, since brain nicotinamide nucleotides are notably unaffected even by procedures, which produce very severe depletion of NAD at the periphery. An examination is made of the various mechanisms by which brain NAD levels could be lowered. The possibility that drug-induced falls in brain NAD levels could arise from a relatively non-specific physical effect upon subcellular structures is examined. The implications of this hypothesis are reviewed and the need for further research to determine the exact nature of the relationship between structure and function at the subcellular level is indicated.