THE MEDICAL COUNCIL ON ALCOHOLISM (MCA) AND ITS JOURNAL ALCOHOL AND ALCOHOLISM

Myrddin Evans

Vice President of the MCA and Previous Editor of its Journal, Medical Council on Alcoholism, 3 St Andrew's Place, London NW1 4LB, UK

Received 28 September 1999; in revised form 5 October 1999

INTRODUCTION

Chalkie's Journal arrives with a flourish at the millennium; the dot com world, the century of the human genome, nanotechnology and, through the looking glass, the quantified lives of digital organisms. Dr Herbert Chalke (Chalkie) would have welcomed all developments leading to a better understanding of ethanol addiction and other alcohol problems. He was convinced that biomedical research would eventually provide the insights necessary for effective treatment and prevention. As outlined by Brian Edsall, he founded the Journal and motivated the formation of the Medical Council on Alcoholism (MCA) (Edsall, 1979Go). As one well-qualified to appraise the progress of this act of creative intuition, I can affirm without any doubts that the MCA and its Journal have been a resounding success.

Although I am much inclined to do so, I shall not repeat the memories and tributes presented in my earlier commemorative article (Evans, 1990Go). It is now normal for specialist journals to offer past issues and other material on their website, so that much history of the MCA and the Journal will be readily available to you. We remember with the greatest gratitude the interest and support of three sisters in Scotland, whose beneficence continues through the Robertson Trust. Throughout our short history, I have been amazed by the staunch support given to us by a large number of our most illustrious doctors. Their endorsement and commitment continues in the hands of Sir Leslie Turnberg, Drs E. B. Ritson, P. W. Brunt, J. S. Madden, and P. Abraham, and Professors Philippe De Witte, Roger Nordmann, Kai Lindros, Otto Lesch, and many others.

DEVELOPMENT

What are the four key events in the development of the Journal? To my mind, they are the election of Dr Abdulla A.-B. Badawy as Chief Editor, the selection and adoption of the Journal by the European Society for Biomedical Research on Alcoholism (ESBRA), the appointment of Professor Keith Tipton as joint Chief Editor, and the challenges, opportunities and possible hazards of electronic publishing.

Dr Badawy continues to be active in research, and has a brilliant and capacious mind. He is pivotal to our close relations with ESBRA and many other research societies, and he is well-known to a great number of other researchers. Professor K. F. Tipton, until recently Head of the Department of Biochemistry, Trinity College, Dublin, Ireland, is much respected in research and teaching. He advocates better teaching of kinetics to students: they should be convinced that kinetics is of fundamental importance to functional biochemistry and cellular and molecular biology (McDonald and Tipton, 1999Go). Applications that would benefit include metabolic control analysis, interpreting site-directed mutagenesis studies, understanding drug action, assessing species differences, and ligand binding, cell signalling, and muscle contraction etc. The authors also give a description of simulation programmes in regular use as teaching and self-learning aids, as well as for research purposes. I find these details a useful background to some ideas I shall come to later. Of more interest to some readers is the Chief Editors' welcome to special commentaries on an attempt to find common ground between the alcohol beverage industry, governments, scientific researchers and the public health community in the furtherance of public knowledge about alcohol and the prevention of its misuse (Tipton and Badawy, 1997Go). From this, you may infer that our Editors are tolerant of other pathways to the truth (Medawar, 1991Go), yet I recall that cooperation was recently subject to scientific study of the utmost propriety (Roberts and Sherratt, 1998Go).

In an unsigned feature in Nature (397, 195–200, 1999), Mike Stout is quoted as saying that we are in a transition stage, but electronics will come to dominate because it has all the features and values. With this in mind, it is encouraging to note that our publishers acted without delay in 1998, transferring responsibility for production and hosting of the electronic versions of 160 journals to High Wire. The further development of our Journal's website will require prompt and ample support by the MCA for the Editors' plans. The opportunities are exciting and will intensify and multiply our aims and objectives. It is already apparent that scientists and clinicians tend to consult regularly only a handful of electronic journals in the ‘musts' of their fields. Our Editors will ensure that our website is a ‘must' for alcoholism worldwide.

A DIRECT LINE

I have been looking for a frame, sketch line, or a general explanatory model for what is to follow. A tentative scheme of the neural basis of tolerance by Harold Kalant (1993) was helpful. He stressed that researchers should pay attention to the behavioural, as well as the neurochemical, observations. But in the end I turn again to a meeting I was invited to attend in London in the mid-1960s. It was held in the headquarters of a major medical research funding body.

The Secretary, a courteous scientist of high repute, said he had called the meeting to look at the state of the art in addiction research with a view to supporting suitable projects. He introduced two speakers.

Sir Aubrey Lewis spoke at length, reading from a script. He described the extent of his study of the literature, then stopped, lifted his head, paused for effect, then said, ‘A grim task’. Senior people to his left rocked with laughter, and continued to do so at every quip in what was a reading of a masterly apologia.

Time had run out and Sir William Paton, a leading pharmacologist, spoke briefly, and with some tension. He said that he had taken his brief very seriously and had sought long and hard for a useful contribution, ‘but all I have come up with is a new definition of a drug of dependence. It is a drug that, when taken, gives rise to forces biochemical, pharmacological, social and environmental leading to further taking of the drug.’ The audiences of about 40 people had listened intently, and received this statement with nods and murmurs of approval.

There was a short period of discussion taken up by epidemiologists who made cogent points about the lack of classifications upon which they could base their studies. I shall return to this important point later.

Sir William's definition is complex and stimulating. The ‘forces' have a time course and direction, the input and output are behavioural, and the four large components provide the source of the imagined forces. Viewed as a general covering model, it focuses speculation on how the components are related, could their separate contributions be quantified, and so on.

Having, as it were, encountered these forces in several thousand alcoholics and other addicts, my earnest hope is that we are approaching the time when their sources and tracks can be precisely located. Out of masses of relevant scientific data, which has accumulated in the last 30 years, I chose two or three pointers to further progress.

PERSONAL CHOICE

I shall begin with a reference to the work by Dr Badawy on the effects of alcohol on tryptophan (Trp) metabolism (Badawy, 1988Go; Badawy et al., 1993Go). Most of the early work was done on healthy, locally bred Wistar rats. Briefly, in this rat, acute ethanol administration exerts a biphasic effect on brain 5-hydroxytryptamine (5-HT) synthesis, an initial enhancement followed by inhibition (Badawy and Evans, 1976Go). Both effects are mediated by corresponding changes in circulating Trp availability to the brain, caused respectively by a lipolysis-dependent, non-esterified fatty-acid-mediated release of albumin-bound Trp and a subsequent Trp-mediated activation of liver Trp pyrrolase. If you are put off by this sort of statement, I suggest looking at Figure 1 in the above paper, which gives a clear representation of the results over 10 h. You will notice that brain tryptophan, 5-HT, and 5-hydroxyindol-3-ylacetic acid, rise to a peak in about 3 h, then descend well below the base line before returning to it at about 10 h. The time course clearly shows the cyclical or oscillating character of the individual reactions (Maynard-Smith, 1993Go).

We learn that the initial state of the whole animal needs to be taken into account when planning and interpreting experimental studies, and this conclusion is reinforced by additional studies reported in this paper. Moreover, the reality of species specificity is demonstrated by the failure of ethanol to alter brain tryptophan in the C57BL strain of mouse tested. Dr Badawy has also shown that brain 5-HT is enhanced by chronic ethanol administration, and is inhibited during subsequent withdrawal (Badawy et al., 1980Go).

Other drugs of dependence, namely morphine, phenobarbitone and nicotine, given over 3 weeks, were also shown to enhance rat brain 5-HT synthesis. Including ethanol in another series, these effects of the four drugs were reversed by naloxone (Badawy et al., 1981Go). In a further study, it was shown that the chronic morphine-induced changes in the rat liver and brain Trp metabolism can be reversed as early as 10 min after naloxone administration, and that such biochemical effects coincide with the production of morphine withdrawal under these experimental conditions (Badawy and Evans, 1981Go).

My second choice (Thiele et al., 1998Go) has been hailed as a significant step forward in ‘getting a handle on many aspects of behaviour' (Small and Bloom, 1998Go). In the context of our search for connectivity between the modules in the definition, this is a leap forward. Thiele et al. (1998) describe NPY, a 36-amino-acid neuropeptide, as an inhibitory neuromodulator that acts widely in the brain through Y1, Y2 and Y5 receptors, all of which couple to heterotrimeric G proteins that inhibit production of cyclic AMP. Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that included the NPY gene. Alcohol-preferring rats have lower levels of NPY in several brain regions, compared with non-preferring rats. Because NPY has been implicated in the high ethanol intake of rats selectively bred to model alcoholism, the authors were prompted to determine whether increased alcohol consumption is a general characteristic of animals with reduced levels of, or no, NPY. They produced NPY-deficient (NPY–/–) mice by gene targeting. The results showed that NPY-deficient mice had increased consumption of solutions containing 6%, 10% and 20% (v/v) ethanol, compared to wild-type mice.

NPY-deficient mice were also less sensitive to the sedative/ hypnotic effects of alcohol, despite having similar plasma ethanol clearance rates. Thus, mice that lack NPY consume more alcohol and are resistant to its sedative effects. To further study the relationship between NPY levels and ethanol, they examined transgenic mice that overexpress a marked NPY gene (NPY-OX). There was roughly five times more NPY transgene messenger RNA than endogenous NPY mRNA in the line of mice used. Immunocytochemistry showed that, in the transgenic line, NPY protein was more abundant than normal in many regions of the brain that normally express NPY, including cortex, amygdala and hippocampus, but transgene expression was not apparent in the arcuate nucleus of the hypothalamus or adrenal medulla. These intimidating refinements may be of interest later. When the ethanol consumption patterns and other aspects were examined the results were as follows. NPY-OX mice drank significantly less ethanol at all the concentrations tested, and had lower relative preference for ethanol, compared with wild-type littermates. NPY-OX mice were also more sensitive to ethanol-induced sedation than NPY+/+ (wild-type littermates), even though plasma ethanol concentrations did not differ between genotypes 1 h and 3 h after ethanol administration. Mice did not differ in average body weight, average food intake, or average total fluid consumption.

In the authors' words, ‘a lack of NPY in knockout mice was associated with high ethanol consumption and low sensitivity to ethanol, whereas NPY overexpression in transgenic mice was associated with low ethanol consumption and high sensitivity to ethanol. Our results indicate that alcohol consumption and resistance are inversely related to NPY levels in the brain.’

The lack of NPY transgene expression in the arcuate nucleus of the hypothalamus, a region thought to mediate food consumption, indicates that the effects on ethanol intake are probably not linked to calorie intake. Previous reports had indicated that NPY-deficient mice were anxious, and this may have explained the overconsumption of alcohol. However, the authors showed that the overexpressing NPY mice were no different from wild-type controls in measures of anxiety, such as fear conditioning and the elevated plus-maze test.

In a final glimpse, I turn to a report on cocaine addiction (Kelz et al., 1999Go). The authors refer to previous studies which had shown that acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accum-bens, a region of the brain that is important for addiction. In contrast, chronic exposure does not induce these proteins, but, instead, causes the persistent expression of highly stable forms of delta FosB. It is interesting that delta FosB is also induced in the nucleus accumbens by repeated exposure to other drugs of dependence, including amphetamine, morphine, nicotine and phencyclidine. Ethanol is not mentioned in this paper, possibly because of technical difficulties (see Collins et al., 1991). Referring to the paper by Nestler and Aghajanian (1997), the authors posit that the sustained accumulation of delta FosB in the nucleus accumbens (NAc) indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure. Using transgenic mice in which delta FosB can be induced in the subset of nucleus accumbens in which cocaine induces the protein, they showed that delta FosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of delta FosB appear to be mediated partly by the induction of the AMPA glutamate receptor sub-unit GluR2 in the nucleus accumbens. The authors conclude, ‘While GluR2 is probably just one of the many targets regulated by delta FosB in the NAc, our results support a model in which chronic cocaine exposure results in the gradual accumulation of delta FosB in this brain region, which then causes increased expression of GluR2. An important goal for future research is to understand how increased GluR2 expression in the NAc enhances reward mechanisms. The increase in GluR2 could account for the reduced sensitivity of NAc neurons to AMPA seen after chronic exposure as well as for reduction in Ca2+ flux seen in these neurons. Moreover, inhibition of NAc neurons has been directly related to drug reward. Together, the results indicate that delta FosB may mediate relatively long-lived changes in gene expression that thereby contribute to the development of cocaine addiction.’

It is a very remarkable achievement to establish that chronic administration of cocaine selectively induces delta FosB within the subsector of NAc neurons that project directly to the ventral tegmental area, and to show that this is sufficient to increase an animal's responsiveness to the rewarding and locomotor-activating effects of cocaine. They comment that this finding is consistent with the observation that cocaine is also more reinforcing in 5HT1B -receptor knockout mice, which show a compensatory increase in delta FosB in the nucleus accumbens (Rocha et al., 1998Go). Obviously tryptophan metabolism comes into play in this area, and not surprisingly there is a relating comment in the NPY paper. The authors (Thiele et al., 1998Go) consider that signalling through cAMP may mediate many responses to drugs, and changes in this signalling pathway may mediate drug tolerance and dependence. They find support for this view in a study of cAMP-dependent protein kinase in the nucleus accumbens in cocaine self-administration and relapse of cocaine-seeking behaviour (Self et al., 1998Go).

These and many other connected pointers give me reason to hope for a rapid advance in knowledge of the interface between the pharmacological and behavioural effects of a drug of dependence. The result is likely to be a new pharmacological basis of treatment for the more severely affected ethanol addict.

CLASSIFICATIONS

Progress in biological and social research depends on classifications, which are normally confirmed by international consensus. In the study of alcoholism, an extremely complex and broad domain, classifications have tended to be pragmatic, meant to be merely provisional and heuristic, or made independently of scientific theorizing. In a succinct, but helpful review, Tipton et al. (1993) did not find a clear-cut distinction between state and trait markers for alcohol effects. There were many possible state markers, although these may not all be very sensitive indicators. Up to that time, there was no convincing trait marker for susceptibility to alcohol-related tissue damage or to alcoholism. In that case, they concluded that the arguments about whether only a minority of alcoholics (Type 2) have a strong genetic aetiology, with the remainder being mainly influenced by environmental factors (Type 1-mileu limited) require resolution if the results of experimental determinations with undifferentiated alcoholic subjects are to be meaningfully interpreted. That appraisal has remained virtually unchanged despite the launching of several collaborative initiatives. But perhaps individual effort beats mass observation, and in the summer before the new millennium the Journal gave pride of place to The ESBRA-Nordmann Award Lecture by Odin Van der Stelt. In this address, Van der Stelt (1999) made a compelling case for accepting the P300 or P3 component of the event-related potential (ERP) as a potential vulnerability marker for alcoholism.

COMMUNICATION

The Editorial commitment for the Journal, in time and application, is astonishing and deserving of our utmost support and gratitude. It may seem desirable to extend the Journal's website to accommodate website specials, web debate, special features, previews of accepted peer-reviewed original articles, and so on. Students and subscribers of many science and clinical journals have come to expect ready access to leading science journals, such as Nature and Science. In view of the imminent arrival of new drugs to treat alcoholics, some arrangement with the Cochrane Centre would be valued. But ... overenthusiasm must be curbed, because there are dangers. Costs must be controlled, yet additional staff and editorial time are required. Reports from electronic commerce warn that Internet dilemmas can disrupt businesses as readily as they can transform them. Sub-groups within an enlarged editorial team, taking a lead in developing internet applications, can result in disparate ‘islands' of initiative not tied to the main flow of the journal.

In a more general way, information overload is frequently cited by scientists and clinicians as the biggest problem they experience in using the web. Another issue of concern is how to maintain the peer-review certification process while allowing electronic publishing to disseminate scholarly work widely.

About 6% of web servers have university, college and research laboratory servers (Lawrence and Giles, 1999Go). These authors found that the web contains a diverse range of scientific material, including scientist, university and project home pages, pre-prints, technical reports, conference and journal papers, teaching resources and data bases (for example; gene sequences, molecular structure and image libraries). The high value of the scientific information on the web, and the relatively small percentage of servers that contain the bulk of that information, suggest that an index of all scientific information on the web would be feasible and very valuable. The above authors are critical of the efficacy of the search engines: they do not index sites equally, may not index new pages for months and no engine indexes more than about 16% of the web. New search techniques may delay or even prevent the widespread visibility of new high-quality information. Negative features include: a limited number of sites, insufficient number of pages on a site, bias in favour of ‘popularity’ to rank the relevance of pages and the increasing use of features other than those directly describing the content of pages.

A correspondent responding to this report reminded us that the scientific community has long had a mechanism to categorize information worthy of attention: peer reviewed publications. Another described how members of a clinical discipline had initiated a specific search engine for their purposes.

I am content to leave these matters in the hands of our publishers and Editors, who have earned our highest level of confidence, gratitude and support.

ACKNOWLEDGEMENTS

I am grateful to Mrs Helen Anne Jones for her secretarial assistance and skilful preparation of this typescript.

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