Addiction and Brain Damage

Derek Richter

• Publisher: Taylor & Francis
• Year: 2016
• eBook ISBN: 9781315454030
• Edition: 1
• Topic: Psychology
• Subtopic: Addiction in Psychology
• Index: Psychology

Originally published in 1980, recent research had produced new insights into how, at the biochemical level, alcohol and other drugs of abuse can impair metabolic and neuropsychiatric functions. Epidemiological studies were also demonstrating that even moderate drinking or drug abuse can produce significant brain damage.

This book draws together the latest biochemical, physiological and clinical research on these topics at the time. The initial chapters discuss how alcohol can interfere with various functions: the adaptability of metabolic processes as governed by the ability of the liver to synthesise new enzymes, cell membrane transport, nervous transmission and the transport of nutrients into the brain. It is suggested that opiates, and possibly alcohol, may affect the endorphin system by blocking the uptake of specific amino acids.

The second half of the book reports clinical investigations using biochemical studies, psychological tests, EEG investigations and Computerised Axial Tomography (CAT) scanning. It gives the first report of a long-term study by Lishman and co-workers using an improved tomography technique to assess brain damage in alcoholics. These studies give convincing evidence that heavy drinking, even at socially-acceptable levels, can cause serious brain damage in vulnerable people.

PART ONE

BIOCHEMICAL AND PHYSIOLOGICAL MECHANISMS

1 THE EFFECTS OF ALCOHOL ON METABOLIC PROCESSES

Hans Krebs

The chief target organs of ethanol are the nervous system and the liver. From the biochemical point of view the mechanism of action of alcohol on the nervous system is still mysterious in many ways. We are only just beginning to get some understanding of the manner in which ethanol interferes with the function of the nervous system. This applies to the mechanism of acute intoxication as well as to the chronic manifestations such as polyneuritis, the deterioration of personality, delirium tremens and Korsakoff’s psychosis.

By contrast, we do have some biochemical information on the mechanism of the effects of alcohol on the liver. Above all, it is clear why the liver is one of the major target organs. The liver is the only organ which possesses a highly active enzyme capable of breaking down alcohol. This specific role of the liver in disposing of ingested alcohol was discovered by the Danish physiologist, Einar Lundsgaard (1938). He discovered that alcohol is not metabolised by the eviscerated animal but is readily oxidised by the isolated perfused liver. The specific enzyme responsible for the removal of alcohol is alcohol dehydrogenase, an enzyme which has been crystallised and obtained in a pure form. It brings about the reaction:

Ethanol + NAD ➡ acetaldehyde + NADH₂

By a further dehydrogenation the acetaldehyde is converted to acetic acid, and the acetic acid can then be completely burned either in the liver or in a variety of other tissues, particularly in cardiac muscle and kidney. Although some alcohol appears in the breath and in the urine, probably more than 90 per cent of ingested alcohol undergoes complete oxidation in the body. The oxidation of alcohol is an effective source of energy, because it is coupled with the synthesis of ATP.

Why should the occurrence of this reaction of alcohol in the liver be harmful and, in cases of chronic alcoholism, eventually lead to liver cirrhosis? There is something special about the location of alcohol dehydrogenase within the liver cell, in that this enzyme is located in the cytosol, in contrast to the majority of dehydrogenases which are located within the mitochondria. The rapid dehydrogenation of alcohol to acetic acid causes a unique kind of upset of the intracellular chemical balance. The rate of conversion of NAD into NADH₂ causes a shift in the ratio of the concentrations of NAD and NADH₂, primarily in the cytosol where most of the synthetic activities of the liver cells are located (see Krebs, 1968; Krebs et al., 1969). This ratio is of great importance to many metabolic processes because most dehydrogenases share with ethanol the coenzymes NAD and NADH₂ and their effectiveness depends on the relative concentrations of NAD and NADH₂, i.e. the NAD/NADH₂ ratio (referred to as the ‘redox state’ of the NAD-couple).

The shift caused by alcohol in the redox state of this couple is taken to be a major reason for metabolic disturbances in the liver, showing themselves early in the accumulation of fat in the liver of alocholics and ending in cirrhosis. The acetaldehyde formed by alcohol dehydrogenase has also been suspected of being harmful because aldehydes readily interact with amino groups of proteins. However, as the acetaldehyde is rapidly converted to acetic acid, it is doubtful whether its steady-state concentration rises sufficiently to combine with proteins.

Biochemical studies have thus contributed an explanation of why alcohol is toxic to the liver, but this has not led to new ideas about a cure for liver damage.

One of the secondary effects of alcohol on liver metabolism should be mentioned. Under certain conditions, i.e. when alcohol is taken in the fasting state or when carbohydrate intake is low, hypoglycaemia can develop. The mechanism of hypoglycaemia is as follows: the shift in the redox state of the NAD/NADH₂ couple inhibits glucose synthesis in the liver. In the fasting state the sources of glucose are limited. Adequate glucose levels in the blood can be maintained only by the resynthesis of glucose from lactic acid formed during exercise and from protein broken down during starvation. Gluconeogenesis is inhibited by alcohol because the pathway of gluconeogenesis is effective only if the NAD/NADH₂ ratio is within the normal range. Gluconeogenesis, like the opposite metabolic process, glycolysis, depends on reactions involving this ratio. Therefore changes in the ratio also upset gluconeogenesis. The liver is the main site of gluconeogenesis.

As for the effects of ethanol on the second major target area, the nervous system, the mechanism of the damaging action must be quite different from that in the liver because of the absence of alcohol dehydrogenase from nervous tissue.

The older biochemical approaches to organ function (based on the study of enzymes and metabolic pathways of degradation and synthesis of cell constituents) which have been successful in the study of liver diseases have provided only limited answers to the problems of brain physiology and brain pathology. We must therefore explore whether other areas of biochemistry might be helpful.

In recent years new, more subtle effects of ethanol on metabolic processes have come to light. Work by Mørland and Bessesen (1977), Mørland (1979), Badawy et al. (1979), Rothschild et al. (1971, 1975) has shown that ethanol inhibits protein synthesis in the liver and other tissues. Tewari and Noble (1979) have demonstrated inhibitory effects of ethanol on protein synthesis in the brain. The experimental basis of this demonstration is the observation that the incorporation of radioactive amino acids into the tissue protein (which can easily be measured) is inhibited by ethanol. What does this mean?

We know from discoveries made by Schoenheimer and Rittenberg (1938) and Schoenheimer (1942) that many tissue proteins and other macromolecules are not stable; they are constantly being broken down and resynthesised, a phenomenon referred to as the ‘dynamic state of body constituents’. This phenomenon is especially marked in the liver, where an explanation can be offered for the significance of this ‘turnover’. Most liver proteins are enzymes taking part in metabolic processes. These processes are not always the same but depend upon the nutritional state of the organism and other physiological circumstances. When the diet contains much protein then the liver must degrade the excess and either burn it or convert it into fat or carbohydrate, for the body cannot store much protein. When the diet is low in carbohydrate the liver must synthesise glucose by gluconeogenesis.

When the body is exposed to drugs or poisons, for example barbiturates, enzymes are produced which detoxicate the drugs and poisons. The liver cannot at any one time be equipped with all the enzymes it might need in different physiological situations. For this it would have to be a very much larger organ. The liver deals with variable requirements by removing, through proteolysis, enzymes which it does not need in a given situation and by synthesising, from the amino acids released, the enzymes it requires. Thus the dynamic state of proteins is part of a process, adapting the organism to changing physiological circumstances.

Another function of the continuous protein synthesis/degradation is taken to be the elimination and replacement of faulty material. Tissue proteins may become denatured, for example, by the irreversible oxidation of SH-groups, or faulty protein molecules may arise either from mutations or from errors of the translation and transcription of genes. Thus, the turnover of cell constituents serves to maintain a fully functioning cell (Goldberg and Dice, 1974; Goldberg and St. John, 1976).

If ethanol inhibits the turnover of proteins it means that it inhibits the capacity of the organism to adapt itself and to maintain a state of efficiency. Examples of adaptive enzymes are the enzymes for degradation of tryptophan and tyrosine. These are essential amino acids and when the diet is low in protein they must be preserved and not degraded. The body deals with this by getting rid of the enzymes which degrade tryptophan and tyrosine. It is essential that these amino acids are removed when there is an excess. If they are not removed they may give rise to physiologically active substances in excess, such as tyramine and tryptamine. This adaptation of the enzymes is interfered with by ethanol (Mørland and Bessesen, 1977; Mørland, 1974; Badawy et al., 1979; Rawat, 1974).

While, then, for the liver, the significance of the rapid turnover of some proteins can be understood, we cannot yet be quite sure of an analogous explanation for this turnover of cell constituents in the brain. The fact is that protein synthesis does occur in the brain, though not at the same rate as in the liver, and that in brain, as in liver, ethanol can slow down protein synthesis (see Tewari and Noble, 1979; Lindholm and Khawaja, 1979). Presumably in the brain, as in the liver, protein synthesis is an aspect of adaptation. The brain synthesises biologically active polypeptides such as the opioids and also a number of peptide hormones.

There are two aspects of special interest in the present context. The need for these peptides is not constant. Their quantities must therefore vary with time and this is achieved by a rapid turnover. The need also varies in different parts of the brain. In the past it has been difficult, from the biochemical point of view, to account for the mechanism of action of drugs and of toxic agents on the nervous system because such information as was available did not explain the differential effects of the substances in different areas of the brain, as for example, that anaesthetics affect only those areas connected with consciousness, but leave large portions of the brain in a normally functioning state.

I am very hopeful that the exploration of this new field of biologically active peptides, and of the specific receptor sites (see Snyder, 1979; Kosterlitz, 1976) will add greatly to the understanding of the specific neural function.

Finally, let us look at alcohol or drug dependence generally. Regular intake of a drug, or any ‘unphysiological’ substance, can cause habituation. It follows from what I have said that habituation is, at the biochemical level, the adjustment of the enzymic equipment of the tissues to the intake of special substances, and that this adjustment or adaptation involves continual protein synthesis. If this adjustment is not readily reversible when the stimulus is withdrawn, then the chemical organisation of the tissues – or of some tissues – becomes unbalanced, and to restore the balance the stimulus must be provided again. In other words, t...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Original Title Page
• Original Copyright Page
• Table of Contents
• Preface
• Part One: Biochemical and Physiological Mechanisms
• Part Two: Clinical Investigations
• Notes on Contributors
• Index