FUTURE PLANS AND GOALS IN RESEARCH: THE OKLAHOMA CENTER FOR ALCOHOL A N D

DRUG-RELATED STUDIES

Alfonso Paredes

Department of Psychiatry and Behavioral Sciences University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73190

On the contemporary scene, scholarly inquiry is often the target of irrational fears and suspicions.l It is therefore appropriate to quote a few statements that justify our commitment to research endeavors: “The reason for suggesting that the canons of science should be respected is not just the critics’ game, but rather something said out of regard for lessons of history which teach that in the treatment of sick people when the standards of scientific proof have not been demanded enthusiastic therapeutic claims have been commonly made, have commonly had a vogue, commonly done harm or little good, and commonly gave the way of purging, bleeding, or crippling.”* In a figurative sense, purging, bleeding, or crippling indeed occur when substantial resources in manpower and money are used in allegedly rehabilitative tasks, the rationale, effectiveness, and harmlessness of which have not been documented through serious scientific efforts.)

The Oklahoma Center for Alcohol and Drug-Related Studies was created to gain new knowledge relevant to the use and abuse of alcohol, to the nature, prevention, and control of alcoholism, and to the diagnosis, treatment, and rehabilitation of the alcoholic patient. The Center was to bring to bear upon alcohol-related problems the contributions of other disciplines in biology, medicine, and the behavioral sciences. Recently, the scope of this original mandate has been broadened to cover the study of other addicting drugs. The Center has several teams of investigators. Each team is free to approach the subject matter from their own perspective and to apply their own scientific tools and conceptual framework. An expected requirement is that in any investigation conducted at the Center, the standards of scientific methodology must be strictly followed.

A brief outline of some of the research undertakings of the Center should make apparent the design of our plans and project directions and goals that we hope to attain. Not all of the activities of the Center have led to progressive clarification of issues; sometimes we found ourselves on a dead-end street. For example, one of our earliest studies was aimed at developing an animal model of alcoholism. African guinea hogs were selected for this purpose. Only two herds of these animals exist in the Western Hemisphere; the animals are descendants of those brought to this country with the slave trade. They are genetically homogeneous and have a weight range similar to that of humans. Like man, the animals are inclined to overeat. We had hoped that these hedonistic hogs could be induced to drink alcohol to excess. Our expectations did not materialize. Only a prolonged exposure to the ardent Oklahoma sun in the heat of summer and the absence of water to drink led the animals to accept an alcoholic beverage, beer. The beer-drinking hogs became intoxicated, their gait was wobbly, and they seemed to ignore fear: if slapped, they did not show an aversive reaction. The experiment, however, had to be terminated, because a few intolerant hogs, which refused to drink, cannibalized the ears and tails of the hogs that became intoxicated.4

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More rewarding results have been obtained from studies on the effects of alcohol on the neuropsychologic mechanisms of rats. These animals are particularly well suited for detailed analyses of the behavioral properties of the drug alcohol. For example, state-dependent learning, a phenomenon that might help us to explain some of the occurrences during alcoholic blackouts, has been investigated at the Center by a series of elegant studies conducted by Dr. F. Holloway and his associates. The experiments have demonstrated the importance of the response initiation-inhibition parameter of certain avoidance conditioning tasks in the produc- tion of state-dependent dissociative effects with alcohol.5 The effects of various doses of alcohol on operant performance were also examined in rats under conditions of cued and noncued tasks.6 Other studies in the same laboratory have investigated the influence of alcohol on the recovery of deficits of central nervous system function caused by brain lesions. Findings suggest that the effects of alcohol on recovery of nervous function are related to the site of central nervous system damage that produced the initial loss of function. This information is of importance in the design of future studies in humans. Alcoholics often have suffered traumatic brain damage unrelated to the direct action of alcohol; alcohol use might affect in specific ways the recovery of deficits in function produced by trauma. The studies mentioned also have suggested the possibility of using alcohol as a diagnostic aid in the detection of subtle central nervous system lesion^.^ Investigations have been projected to assess the long- lasting toxic affects of alcohol on the central nervous system. It is becoming increasingly apparent that the toxic effects of the drug on the brain persist long after the use of alcohol has been discontinued. Animal models are ideal to investigate this aspect, because in a short span of time, it is possible to study phenomena that otherwise would take several years to elucidate in humans.

A new and exciting chapter of research has been opened by Dr. J. Holloway at the same laboratory. She is investigating the interaction of ethanol with other drugs. Interactions are important to understand, because people often indulge in more than one drug at a time. Her interests not only cover the study of additive, hyperadditive, and antagonistic interaction effects, but she also has raised the possibility that more complex events may occur. Other chemicals might affect the positive reinforcing qualities of the drug alcohol. This idea has important implications. Modern man is exposed to a myriad of chemicals never before encountered in history; it might well be that these chemicals interact with the effects of ethanol to augment the addicting properties of this drug.8

Williams er al. have focused their studies on other important areas. It has been well established that alcohol impairs human performance in many skills; however, there is very little specific information that identifies which information-processing operations are affected by alcohol. A series of studies by Williams et al. have indicated that output operations, such as response selection-organization, are more affected than information input operations, like stimulus preprocessing and encod- ing. These types of studies will eventually determine the locus or loci primarily affected by the drug. The same data should help to elucidate the neuropsychologic events that provide the background for drug-induced states of consciousness and the effects induced by these events, such as sleep deprivation brain damage or psychopa- thology.9 Other practical applications of data generated by this research will be in the design of devices, such as interlocking systems, that prevent a n intoxicated person from starting an automobile.

Another scientific contributor to the Center is Lester. His work has focused on the acute and chronic affects of alcohol on the bioelectric activity of the brain in man. In sleep studies, he has found that after single doses of alcohol, the onset of sleep is brisk, the latency of slow-wave (SW) sleep (stages 3 & 4) is reduced, and the first

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episode of stage rapid eye movement (REM) is shortened. These transient altera- tions are accompanied by loss of high-frequency p rhythms and a gain in abundance and synchrony of activity in the a-rhythm range. During the second half of the night, rebound of stage REM sleep usually occurs. However, most of the effects of alcohol on sleep stages and electroencephalogram disappear after .subsequent days of exposure to alcohol. This work has therefore documented, at a neurophysiologic level, the long-range compensation and adaptation phenomena associated with the repeated use of alcohol.10 In investigations that used alcoholic subjects, Lester has found support for the notion that alcoholism might be associated with premature aging of the brain. This is suggested by the fact that nondrinking alcoholics exhibit less stage-4 sleep; in other words, they show a decrease in high-voltage SW sleep. Chronic alcohol abuse seems to impair the cortical mechanisms responsible for the continuous generation of high-voltage SW in the brain. A related and intriguing finding was that in alcoholics, small doses of alcohol had a “normalizing” effect on the sleep profile. That is, alcohol reduced the frequency of arousals, the periods of time awake and potentiated low-wave sleep. It might well be that the alcoholic unknowingly ingests alcohol to bring his biologic sleep profile to normal. It is possible that by drinking, the alcoholic is trying to treat his own insomnia.“

Parsons et $ l . , also from the Center, have published what is perhaps the most comprehensive series of studies on alcohol and brain damage available in the literature.I2-lh According to his research, alcoholics exhibit specific deficits in cognitive tasks that involve visual-spatial, abstracting behavior, and temporal-spatial integration. The deficits are similar to those of patients with brain damage; however, the nature of the deficits suggest that the right side of the brain is more affected than the left and that the frontal lobe and frontal limbic circuits might also be more affected than other parts of the brain. In support of this hypothesis, it was found that scores on verbal tests of intelligence, such as Shipley Hartford, were not impaired in alcoholics (verbal functions are governed by the left hemisphere), whereas on tests of visual-spatial cognitive functions, such as the Ravens Progressive Matrices, alcohol- ics showed measurable deficits (these functions are governed by the right hemis- phere). In repetitive tasks, alcoholics demonstrated difficulty in maintaining sets (a finding suggestive of frontal lobe damage). These data indicate that in alcoholics, areas of the brain responsible for “nonconscious” or background activity are affected; therefore, the person might never be subjectively aware of these brain changes. The alcoholic is a brain-damaged person who is unaware of the damage that he has experienced. Rehabilitative techniques for the alcoholic will have to take into consideration the knowledge generated by Parsons’ studies. It is remarkable that most programs have ignored the existence and implications of these neuropsycho- logic deficits.

Several intriguing findings have emerged from the laboratory of Jones, another of our researchers. He has found that a t identical blood alcohol concentrations, performance tasks in human subjects show greater deficits during the period when the blood alcohol concentration is ascending than in the descending segment of the same curve. It seems that a drinking person gradually adapts to the blood alcohol concentrations to which he is exposed. The deficits are more pronounced during the ascending period of the blood alcohol curve, when the adaptation has not yet 0ccurred.17~~R Other factors that seem to contribute to deficits in performance include the speed at which a person drinks, with the fast drinkers performing more poorly.19 Personality variables also have an influence; for instance, the performance of extraverts is affected to a greater extent than that of introverts.20

For a long time, women have been neglected in alcohol research. Most of the physiologic and psychologic data on the effects of alcohol have derived from male

106 Annals New York Academy of Sciences

subjects. Given the fact that women experience a lesser risk to alcoholism than men, it is important to elucidate the factors that account for this difference. This knowledge could have applications in the prevention and control of alcoholism. To meet the need for this information, a program of research with women has been initiated at the Center. Jones has found that men and women reach different peak blood alcohol concentrations on equivalent doses of alcohol given on the basis of body weight. Men require almost twice as much alcohol as women to obtain identical blood alcohol concentrations. Another interesting phenomenon is the great variabil- ity of response to the effects of alcohol observed a t different points of the menstrual cycle. This variability might account for certain unpredictability of the effects of alcohol in women. The variability of response might offer some protection from habituation. It is also interesting that the highest blood alcohol concentrations, with equivalent doses of alcohol given on the basis of body weight, are obtained at the premenstrual time. On the other hand, the first day of the cycle usually shows the lowest blood alcohol concentration. Other sex differences have been identified in the same laboratory. For example, memory and other cognitive tasks performed by women are more severely affected by alcohol than are the same tasks performed by men.21

The genetic hypothesis of alcoholism has interested some of our researchers. For example, Sassoon in his search for genetic markers observed an association between alcoholism and blue-yellow color vision deficits diagnosed by the Farnsworth- Munsell D-15 test. Sassoon has speculated that there might be a risk factor transmitted through females. Families with blue-yellow errors had a high incidence of the disorder.22

Our concern with the predicament of the native American population who suffer a high prevalence of alcoholism led us to investigate reports in the literature that suggested that there are differences in biologic sensitivity to alcohol among Mongo- lians, American Indians, and Cauca~ians.~3-27 We had access to the Tarahumara Indians, an ethnic group who, in addition to having a great genetic homogeneity, still live under the same social system and maintain the life styles that existed before the white man arrived in America. Studies conducted by Zeiner and the present author on these Indians have failed to support the differential sensitivity hypothesis. For example, we could not document the flushing phenomenon supposedly induced by alcohol and reported by other investigators.**

Investigations performed by the author a t affiliated clinical facilities have challenged simplistic formulations of the “loss of control” hypothesis in alcoholism. We have demonstrated that the exposure of alcoholics to alcohol does not necessarily lead to alcohol-seeking behavior.29 A sequel of this investigation was a follow-up study of patients to determine if the exposure to a schedule of alcohol drinking within the residential treatment setting had adverse effects on the behavior of the same patients when they returned to the community.3(’ Our findings demonstrated the feasibility of implementing drinking training exercises that could be used to teach alcoholics to drink more safely. For example, related research in progress at the Center has shown that it is possible to train alcoholics to make accurate subjective estimates of their blood alcohol concentrations and to have these subjects maintain prescribed levels for given periods of time.3’

Data from studies on the ecology of alcoholism conducted by Paredes el at. have been used to postulate that alcoholism is to a great extent a n active process. Considerable demands must be met to maintain this type of behavior, which is repeated for long periods of time, affects the person’s physical well-being, is objected to by others, and involves considerable expense. Such behavior can only be maintained if it is supported by an array of physiologic and psychologic mechanisms

Paredes: Research Plans & Goals 107

and social conditions, all of which require considerable organization and work

Commonly, a sharp distinction is made between service and research activities. In my opinion, these areas have much to share. The researcher formulates a hypothesis or makes a prediction, designs an experiment to test his assumptions, collects data, and conducts statistical analyses to prove or disprove the hypothesis. Providers of rehabilitative services for alcoholics are placed in an analogous position. They assume that the therapeutic manipulations or rehabilitative procedures incorporated in their programs will benefit their patients along certain behavioral dimensions. Providers of services are under increasing pressure to demonstrate that these expectations are realized. The providers also are expected to document the relation- ships that exist among the amount of expertise, manpower, and fiscal resources applied to treat alcoholics and the magnitude of the benefits obtained by those who receive the services. It cannot be assumed that therapeutic maneuvers that in clinical trials have shown measurable effects will exhibit the same in the complex setting of clinical practice. The evidence from research that used a few dozen subjects cannot necessarily carry a greater weight than reliable information collected from clinical settings that process hundreds and perhaps thousands of subjects. However, this clinical experience cannot be utilized unless we develop and implement information systems and organize clinical services in ways that permit the collection of reliable data. Evaluative activities, which in the past have received a low priority from most clinical programs, now require urgent attention. Documentation of the impact of programs is needed if we wish to persuade the public decision makers to allocate significant amounts of financial resources for rehabilitative activities. The tools needed to evaluate programs are similar to those utilized by research. In congruence with this point of view, we thought it would be desirable to develop a close liasion between the Center and service delivery systems for alcoholics in our state. One of our purposes was to facilitate the channeling of research expertise into evaluative processes and to other issues raised in the service area. The liaison was accomplished when the Director of the Center also became Director of the Division on Alcoholism of the State Department of Mental Health. The Division is responsible for monitor- ing indices of alcohol problems in the state and for the development and implementa- tion of programs for alcoholics. This association has contributed to familiarize researchers with the characteristics of alcoholism problems as they occur in the community. Such experience is likely to exert considerable influence on the concep- tual models of alcoholism utilized by researchers in their studies. A concrete contribution that emerged from this association was the design and implementation of an information system for health care data. The system retrieves data on patients who receive services. The same information measures the performance of alcoholism programs and is used as a vehicle for the dispersal of Formula Grant funds for alcoholism programs in the state. This information system follows a fee-for-service format. The instruments used to document the services provided generate computer- ized displays easy to read by clinicians. The displays give monthly summaries of the demographic and clinical characteristics of patients treated, the types of services provided, data on the rate of utilization and costs of services provided, and outcome measures. These data will be used to make reliable predictions on the demands for resources and manpower required to meet alcohol problems in the state. With the assistance of the system, we are planning to examine the relationships that exist between the amount of resources applied to the control and rehabilitation of alcoholics and the benefits experienced by the clients and the community.33 It has been observed in studies conducted elsewhere that in the health delivery area, there is a lack of direct relationship between the amount of financial resources and expertise

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applied in the treatment of health problems and the improvement of health indices measured in the community. In fact, inverse relationships have been noted.34 This has led to political decisions to withdraw or to attempt to withdraw financial support from many health care activities. This consideration highlights the importance of developing an information system such as ours, which is helping to make a rational application of resources t o combat alcoholism.

The success to be achieved in the prevention and control of alcoholism will be based on the quality and magnitude of research efforts. Vigorous research activity a t the basic and applied levels and the rapid channeling of this information to the service area are fundamental. Information generated by daily service activity is also fundamental to orient the questions and concepts that guide research. The soundness of this position is currently being tested in Oklahoma.

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