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Thls article was a distinguished lecture of the fifth annual John W. Umstead Series of Distinguished Lectures held In Raleigh in February of 1968. Dr. Witt ts director of the Division on Research of the N. C. Department of Mental Health.

BIOLOGIC AND ADDICTIVE ASPECTS OF ALCOHOLISM

Biological roots of addiction are seen in the phenomenon of adapta­ tion in nature and in genetic coding. ONE way of improving our under­ standing of alcoholism is to look at its place in a wider framework. I propose to look at alcoholism as a specific case of drug addiction. Alcohol is a drug like morphine or cocaine, peculiar in some ways, simi­lar in others. Alcoholism shows all the characteristic properties of drug addiction. One can learn about it by reviewing the strange phenomenon that a human being can become de­pendent on the intake of a chemical substance, can commit an anti-social, criminal act to obtain the substance, can regard the drug as the most im­portant part of his life, both an angel and a devil, to be praised and curse hut hardly able to exist without. Man and his reaction to drugs can be regarded from many different angles. For the purpose of under­standing, one has to look at these angles separately-look at man as a biochemical machine, a physiological organism, an individual who behaves in reaction to surroundings according to inherited and acquired guidelines, a social and a religious one. In stres­sing the biological angle of man’s addiction, it is assumed that every­body realizes that this is only one of many viewpoints. One of the puzzling aspects of ad­diction is its compulsive nature: the addict has to take the drug again and again, increasingly threatened by the appearance of frightening with· drawal symptoms as soon as he is without drugs. Addicts frequently compare the way they feel in the ab­sence of the drug with hunger; it feels “as if something were missing.” “I feel normal after my injection, sick only without it,” can be heard frequently. Sudden withholding of the drug can cause severe circulatory and autonomic nervous symptons, f;,U of blood pressure, change of heart rate, shallow respiration, goose pimples, diarrhea, etc. The with· _drawn addict lies for several days moaning under his blanket, unhappy, depressed, weak. On the other hand, the achieve· ment of “normality” under drugs fre­quently requires the taking of in­creasing doses. De Quincy in “Con­fession of an Opium Eater” tells us that he finally had to take 133 drachms (about 300 times the ther­apeutic close). In order to feel “nor­mal” and comfortable an addict has to take an amount of the substance that would kill the unaccustomed. Do we know something more about this? Can we understand It better as a gen­eral biological phenomenon, or is this only the manifestation of an individ­ual’s mad search for pleasure?

A look at the phenomenon of a­daptation in nature appears to be helpful. Adaptation is built into all living beings. It can be studied at any level of organization and is eas­iest to study at the level of animals with one cell. Dr. Phillip B. Dunham, a biochem­ically oriented zoologist at Syra􀀃use University, New York, observed such mono-cellular organisms in their nor­mal surroundings, namely in tap water. The animals swam around, ate, propagated, and showed all the signs of healthy behavior. He then added some sodium chloride to the water in increasing amounts every day. As long as he kept the daily increase small, these animals lived “happily” in a 200 mm sodium chlo· ride solution, the same solution which would have killed them if they had been put into it at the be· ginning. Another experiment show· ed that the little animals were no longer the same; when he transfer­red some individuals back into clear

water they burst Immediately and died. Only a gradual, slow reversion to original living conditions permit· ted the animals to survive. Dr. Dunham, in trying to find out what the difference between the adapted and unadapted animals was, went a step further in his investiga­tion. The normal animal of this kind tries to preserve a steady concentra­tion of 12 mg per cent sodium on the inside. It achieves this with the help of a pumping mechanism with which It eliminates excess sodium or lets sodium in from the environment. The cells brought into the high sodium concentration at first accumulated much more sodium insicle-105 mg per cent instead of 12 mg per cent. But soon their pump began to work faster, and the sodium concentration was brought back near control levels (to 21 mg per cent). This new level of pump activity could no longer be reduced on short notice, and the cell brought into the original medium riled from lack of sodium inside. Only gradual reduction of sodium concentration outside permitted the pump to reduce Its speed. The cell had adjusted to cope with the high sodium outside in the course of sever­al weeks, and was unable to stand sudden reduction. I leave it to you to draw a parallel between these ob­servations and the phenomena of tol· erance and withdrawal symptoms in the addict who Is, after all, another biological system in a chemically changed environment.

From the first model, the compul­siveness of the process becomes un­derstandable. Whether there ls much pleasure involved in obtaining the effect of the drug seems, at least at the later stage of addiction and after the development of tolerance, quite irrevelant. The fact that some drugs which cause a most interesting and frequently enjoyable experience like mescaline (from cacti) or psllocy· bin (from mushrooms) are not liable to produce addiction while others show a high addiction liability should have already made us cautious toward the conclusion that the in· dividual seeks pleasure through re­peated drug administration. It can be experimentally established that some drugs possess a priori a high addiction liability and others do not. What makes a drug this way is not known. Could it be that addicting drugs stimulate a certain area in the central nervous system, and that this area has to be stimulated again and again to obtain satisfaction, estab· lishing a vicious circle, once the process has started? Experiments of James and Marianne Olds in Mich· igan seem to pinpoint such a center. Experiments Conducted

These experiments managed to implant in a number of rats two elec­trodes in different areas of the brain. Each pair of electrodes was connect· ed by means of wires to an electronic stimulation device above the cage, the wires being designed in a way which did not restrain the animals in their movements. The Olds’ built a lever into the circuit which could be pressed by the rat; each pressing would release a series of small elec· tric stimuli of one half second dura· lion. If the lever was held down, or if it was released and not pressed again, no stimulation would occur. The experimenters wanted to find out whether such stimuli would be perceived and manipulated by rats in a way that would reduce stimulus frequency to a low level. A recording device indicated the amount of stimu­lation that the rat had produced over a certain period of time. The surprising discovery, which has since been confirmed by many investigators, was that when the electrodes were placed in such a way that certain areas in the forebrain system were stimulated, the animal quickly learned to press the lever very frequently. Rates (in eight minutes) ranged from 600 up to 1200 responses and higher. All other areas showed the rats either carefully avoiding restimulation after one ef· fort, or the animals were indifferent. To clarify further the nature of this effect, Olds and Olds compared the rewarding nature of the stimuli with those of eating in hungry ani· mals. Instead of food as reward, self· stimulation was used to cause or· ganization of a complicated response pattern like learning to run through a maze. When two groups of rats were compared, one receiving food as reward for crossing the maze and the other receiving self-stimulation, both learned equally fast to- reduce mistakes. However, the stimulation group ran faster for the reward than the hunger group. When, after four days of training, the stimulatition re­ward was withdrawn, extinction of the acquired response appeared with the same speed for both groups in about four days. These observations appear particularly interesting in the light of the frequently quoted remark hy addicts that drug withdrawal is like getting hungry, and the drug makes them feel satiated. But notice that in these experiments no drugs were involved. Let us return to drugs, but stay with our animal models for the pur· pose of obtaining further insight into the self medication and regulation of dosage. The experiments to be de· scribed in the following were car­ried out by J. R. Weeks in rats and monkeys. They chose settings in which rats could take the drug at will, regarding this as a model re· latively close to the human addict.

For the purpose of their investiga­tion a tube was positioned in the rat’s heart and connected to a sy­ringe. The syringe, outside the cage, was pushed forward by a motor to Inject a measured standard amount of fluid as soon as the rat pressed the lever. In the beginning of the experiment, the rat received a shot of morphine every hour for two days, starting with 2 mg and building up to 40 mg per kg. At the end of the second day the mechanism was ad­justed so that the rat could inject itself with a 10 mg dose of morphine each time it pressed the switch. Most rats stabilized thereafter at one in­jection every two hours-some a little more frequently, some less. They were apparently able to gauge the desired dose. The next step in the experiment was taken to find out how well the rat would be able to adjust the dose if conditions were changed. Instead of 10 mg/kg morphine per Injection, the solution was diluted to deliver 3.2 mg/kg each time the lever was pressed. In a few trials the rats established a new rhythm, Injecting themselves now about twice as fre­quently as before. If morphine was further reduced, Injections grew even more frequent. And leaving out mor­phine from the Bolution altogether, a high frequency injection pattern was followed by slowing down to al­most cessation of lever pressing. All abstinence symptoms could be ob­served In the rats, and the symptoms could be promptly relieved by a single Injection of morphine. The mechanism could be program· med to· inject a single dose of mor­phine only after ten lever pressings. The rats reacted with keeping quies­cent in the intervals and pressing 10

times in a row at the end of two hours, so that the original dose per time was received-indicating again the ability to titrate the optimal amount. Replacement of morphine with other addicting drugs showed the same pattern of response. A last set of animal experiments should be discussed now because they shed light on the role of dif­ferences In different individuals. On closer observation It becomes ap­parent that some persons do not be­come addicted to drugs in spite of extensive exposure, while others seem to seek out the places and sur­roundings where drugs can be ob· tained and are used. It Is very dif­ficult to separate the role of the early experience of a person from that of his inherited traits. Though it seems likely that addiction In parents makes children more suscep­ tible to similar behavior, we hardly know how much of this Is due to early Influences and how much Is inescapably anchored In the genes. Another question that the following experiments try to answer Is that of the choice of drugs. Can a certain person or personality become addict­ed only to a certain drug, or Is drug selection a question of more or less accidental exposure?

Just last year two investigators, Nichols and Hsiao, published the re­sults of a series of experiments in Science which, I believe, shed some light on these questions. They caged rats individually and offered two calibrated 100 ml drinking tubes­one with tap water and one with 0.5 mg morphine per ml water. Rats au­tomatically preferred the water and never touched the morphine solu· tion, even after they had been in· jected with morphine once per day in the amount of 10 mg/kg for 17 successive days. However, If the rats were deprived of water for 24 hours, then received only morphine solution to drink for 24 hours, then they got tap water for another 24 hours, and If this was repeated 5 times for al­together 15 days, they preferred the morphine solution to water. When the morphine solution was with­drawn, three days of severe with· drawal symptoms appeared; 12 days later animals were close to normal and no longer showed signs of phy­sical dependence. At this time rats were brought into the original situa­tion in single cages with tubes of 100 ml drinking water and 100 ml morphine solution to choose from. Soon some animals now drank reg­ularly large amounts of morphine sclution, while others drank little and preferred water. After morphine preference had been established as a stable trait In certain individuals, the rats were sep­arated into two groups-thosP. that would prefer morphine over water and those that would rather drink large amounts of water. Animals in the middle range-which drank equally from both solutions-were eliminated. The morphine-drinking rats were now bred to each other and the water drinkers were also bred to each other. The morphine preference of the offspring was then tested. This procedure was followed through four generations. It could be estab· lished that the morphine preference increased from generation to genera­tion in the one group and decreased In the other. The difference from gen­eration to generation was increasing significantly below the 0.005 prob­a blll ty level. After having established this pre­ference pattern In the animals, the authors asked the question whether the preference of morphine over water was specific for morphine In each strain or whether it was a rather general drug preference.

Again two strains or rats were used which had now been bred for four generations and they were tested for their preference for alcohol in water or clear water. It was again neces­sary to proceed through five periods of alcohol exposure in the way de­scribed above; one day of complete withdrawal of drink, one day of ex­clusive exposure to alcohol water, and one day exposure to tap water. At the end of this period the rats were again given a choice between the alcohol + water 􀀫nd clear water. It may be useful to remember at this point that previously rats would not have drunk water with alcohol at all; they apparently found this quite dis­tc>.steful. It became quite clear that the morphine rats now became ad­dicted to alcohol. After successful withdrawal, the morphine susceptible strain of rats drank twice as much alcohol as the other strain (24 vs 12 ml), and this difference was signi­ficant at the 0.005 probability level. Non-addictive drugs were not found to be preferred over water by any of the animals. It is time to summarize what we have learned from the animal experi­ments. Let me repeat that we have only touched on a small sector of the problems which are related to drug addiction. No mention has been made of the preference for cer­tain drugs in certain parts of the world: alcohol in the West and opium In the East. Little has been said about personality traits of the addict, his early experience, the ex­posure and opportunity to obtain the drug, his mental and physical health. We have also taken the liberty of lumping drug addiction together in­to one big category in spite of the fact that we know very well that one drug may stimulate the addict, an­other may make him sleepy, another -like alcohol-acts first one way

and then the other. This was done to draw a more general picture of the biological roots of addiction, cer· tainly a simplified one, but one which is important and impressive. All experiments have clearly in· dicated the compulsive nature of drug addiction at the cellular level, in brain stimulation, or in self medi· cation. Once started, the deviation, or ‘adaptation, grows according to its own laws. The development of toler­ance, or adaptation, and the causally related withdrawal symptoms force the addict to continue drug self medi· cation with increasing doses. For some unknown reason tolerance to the undesirable effects of the drug frequently develops not at the same rate as tolerance to its desired effect, and the addict gets increasingly un­comfortable. Once “hooked,” he looks no longer for a pleasurable experi­ence or “the shortest way to paradise on earth,” he just wants to feel-in his own words-“normal.” Indepen­dent of whether we attribute freedom of will and moral responsibility to man, the observation that an animal can be bred to high or low drug pre­ference is a biological argument in favor of regarding the addict as a person severely afflicted, rather than as somebody with evil designs. But in reading newspaper articles and even some of the professional journals, one cannot help getting the impression that addicts are some­times considered as people who have cnly to be severely reprimanded or even threatened with punishment and they will pull themselves to· gether and break the habit. The deep roots of addiction in biological pro· perties of adaptation and in genetic coding contradicts the reasonableness of such an attitude.

The results of the experiments just quoted together with much other evidence seem to me to teach us another lesson: to put all the blame on the drug appears to be too easy a way out. Remember the rats which became “addicted” to an elec· trical stimulus in the brain and pre· ferred this as a reward over food? Remember the animals which show­ed high morphine preference but then manifested a similar preference for alcohol? I propose that we regard the drug as only an instrument; it can be used in many ways, skillful or clumsy, for good .or bad, depending on the hands of the􀀥 user. The instru­ment can easily be exchanged, but it is the guiding hand that makes it useful or damaging. Biological think· ing warns us not to get too satisfied with pointing to alcohol, morphine, or LSD as the source of trouble. We should rather treat sick individuals and a sick society if they are found to misuse a drug.