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involving a number of genes, and while it is possible that one or several of those genes might also influence abuse of other drugs," there are not sufficient data to indicate that the same constellation of genetic and/or biological factors underlie the abuse of alcohol and other substances.
ln summary, there is good evidence from divergent methodologies in different countries which points to the probable importance of genetics as a contributory factor in alcoholism. Similar data on other drugs of abuse are not available, and the existing information is preliminary and open to interpretation either as being consistent with an environmental or social model, or as indicating an influence of genetics.
POSSlBLE GENETlC MECHANlSMS
For a genetic model to have credence, the population being studied must be carefully defined so that one does not confuse transient alcoholrelated difficulties, which may be seen in the majority of people age 18 to 25 (Cahalan 1970), with persistent alcohol- and drug-related difficulties—i.e., alcoholism or drug abuse (Schuckit 1973). lt is essential that those persons with major preexisting psychiatric disorders in which alcohol or drug abuse might be symptomatic (secondary alcoholics or drug abusers) be excluded from the generalizations about the genetics of alcoholism or drug abuse, as they may be carrying genetic loading for other problems. lt is also important to note at this juncture that even with carefully defined alcoholism or drug abuse there will probably be intense and unusual environmental situations which can copy the clinical picture. ln this case a good example might be the drug use and abuse patterns noted in soldiers sent to Vietnam, who might otherwise never have used drugs and who, according to some fine followup studies, cease their drug misuse once they return to their home communities (Robins et al. 1975).
With these caveats in mind, in the genetic hypothesis an individual would enter life with a certain level of a genetically influenced biological predisposition toward alcoholism or drug abuse. lt is probable that multiple genes are involved or that other factors affect the strength of the actions of a particular gene (i.e., incomplete penetrance of the gene). lf the disorder is polygenic (i.e., involving more than one gene) there is probably a combination of genes which might predispose an individual to alcoholism (e.g., the possibility of getting a different level of intoxication when drinking or an unusual effect of alcohol on anxiety, etc.) and some which might help to protect a person from demonstrating alcoholism (e.g., becoming very ill at even low alcohol doses). The person, then, could go through a variety of life events and stresses, some of which would predispose him or her to alcoholism (e.g., working in a heavy-drinking environment, such as the armed services) and others which would protect the person from demonstrating the predisposition (e.g., being a woman in a society with heavy proscriptions against drinking for women). The final alcoholic picture . would depend upon the balance between the positive and negative N
genetic effects interacting with the positive and negative environmental factors.
ln this model, a genetic predisposition toward alcoholism might have nothing to do with why people begin drinking in a heavy-drinking society such as ours. Genetic factors might make a modest contribution to the development of relatively minor and evanescent alcohol-related
problems, such as those seen in late adolescence and early adulthood. The greatest impact might be on factors which determine why some individuals continue to increase their alcohol intake during their third decade while others gradually but significantly decrease their drinking and, thus, decrease the risk of associated problems.
lt is probable that no one genetic factor explains the entire predisposition toward alcoholism. There may be a variety of things involved, including those which might affect the metabolism of alcohol, differences in reactions to acute doses of alcohol, differential responses to more subacute exposure to the drug, differential vulnerabilities to adverse consequences from continued use, different personality types, etc. (Omenn 1975). At the present time, there are some preliminary data to support the theory that the offspring of alcoholics metabolize alcohol differently, showing higher levels of the toxic substance acetaldehyde. At the same time they show a decreased sensitivity of the nervous system to the acute effects of alcohol (perhaps equivalent to innate tolerance) (Schuckit and Rayses 1979; Schuckit 1979c).
The degree of "genetic loading" could combine with the intensity of environmental events to determine the characteristics of the drug-related problems as well. For example, the level of genetic factors could determine which alcoholics begin to have problems in the third decade (heavier genetic load) and which do not demonstrate difficulties until reaching the mid-fifties. Biological factors might also be involved in spontaneous remission from alcoholism through alterations in either the reaction to or metabolism of alcohol which may parallel aging and which might negate the original biological factors responsible for the predisposition. Environmental events could have a large impact in determining age of onset and may help to explain some of the "spontaneous remission" seen with all drugs of abuse, as the decision to continue misuse of the substance may represent a cost/benefit ratio, with the chances of continued abuse decreasing with increasing costs of life problems.
ln summary, l feel that alcoholism is probably a multifactorial, polygenically influenced disorder. The relative balance between the degree of genetic loading toward alcoholism and the detrimental as well as protective environmental influences could determine the age of onset of alcohol abuse and the characteristic course for primary alcoholics. Comparable data are not available on drug misuse, but for heuristic purposes, l would picture a similar situation. At the present time, data are not strong enough to support a theory wherein the same genetic mechanisms would be responsible for a general propensity toward all types of drugs, and thus l favor a theory in which the biological mechanisms for alcoholism are different from those for other substances of abuse.
A short methodological note is needed. To optimize the chances of discovering any relevant genetic factor, it is important that the group of alcoholics studied be as homogeneous as possible. This requires using a definition stated in relatively objective terms (so that similar studies can be done in different settings) which has been applied to other populations which were followed up over time and shown to run a relatively homogeneous course (Schuckit 1973; Haglund and Schuckit 1977; Woodruff et al. 1974). While there is a great deal of crossover
in the populations outlined by definitions utilizing physical dependence, psychological dependence (which is quite difficult to define), a quantityfrequency approach to alcoholism, and the life-problem definition, most of the studies on the genetics of alcoholism have utilized the life-problem definition. Simply stated, persons would be considered alcoholics who demonstrate any one of a number of end-stage life problems related to alcohol (e.g., a marital separation or divorce because of alcohol or physical evidence that alcohol has harmed health or a job loss or layoff related to alcohol or multiple arrests related to drinking) (Schuckit 1979b).
Of course, alcohol or other drug problems can be primary or can develop in the midst of another (possibly genetically influenced) psychiatric disorder (i.e., secondary). lt would not make much sense, however, to include in studies of the genetics of alcoholism people who fulfill the research criteria for schizophrenia and who then go on to develop alcohol or other drug problems. lt would be equally selfdefeating to include in such studies those individuals with unipolar affective disorder, manic depressive disease, or the antisocial personality (Schuckit 1973; Woodruff et al. 1974; Schuckit 1979b). While secondary alcoholics (i.e., individuals demonstrating alcoholism only after the onset of another major psychiatric problem) might be genetically predisposed toward both alcoholism and the primary disease, this would be very difficult to pick up by our present methods.
The pattern of use and abuse of a substance within any population subgroup is, of course, the result of a combination of social, psychological, and biological factors. ln this section, l will discuss a number of possible genetically influenced biological factors and environmental events. These will be applied to a variety of subgroups including Native Americans, other ethnic groups including the lrish and Jews, the elderly, women, and youth, and substance-related difficulties in health-care deliverers such as physicians.
Native American groups have exceptionally high rates of alcoholism. This might result in part from high levels of any of the proposed genetically influenced biological mechanisms, although data to date on differences between Native Americans and Caucasians in the metabolism of alcohol have been inconclusive (Bennion and Li 1976). Because members of this group tend to marry other members, any genetically influenced factor raising the propensity toward alcoholism would be likely to be perpetuated. No matter what the level of biological predisposition, the high rate of alcoholism is probably also a response to the heavy-drinking lifestyle on the reservation, the extreme level of social stress that comes from the disintegration of the Native American culture, historical differences in the meanings of alcohol use and intoxication between Native American cultures and Caucasian groups, etc. The final prevalence of alcoholism in this group probably reflects an increased level of genetic predisposition within Native Americans and an environment which maximizes the chance that any such predisposition would become manifest.
The purported high rates of alcoholism in lreland and among Americans of lrish descent (persisting even when one controls for the level of available income after bare necessities are met) compared with the low
rate of alcoholism in Jews in both the United States and lsrael is also of interest (Haglund and Schuckit 1977). As is true for Native Americans, individuals in these groups tend to marry other people within the same subgroup, thus perpetuating any genetic propensity that exists, no matter which of the hypothesized mechanisms might be involved. At the same time, environmental factors might alter the expression of any biological propensities. Thus any genetic predisposition toward alcoholism existing in Jews might be dampened by the heavy proscriptions against intoxication and the emphasis on learning how to drink in moderation seen within closely knit Jewish families. Even low to modest rates of biological predisposition in the lrish might be clinically expressed through such factors as the tendency toward late marriage, the ethic of needing to "learn to drink like a man," the social life centering on the pub, etc. (Schuckit and Haglund 1977).
Three other subgroups present interesting questions regarding a genetic hypothesis in alcoholism. The actively drinking elderly alcoholic is likely to have begun alcohol abuse in his or her forties or fifties, after many years of "normal" drinking (Schuckit 1977). This is probably the result of a combination of a lowered level of genetic propensity and earlier life experiences of drinking in a relatively structured environment. The problem may be more likely to become manifest when protective factors disappear as one's children grow up and leave the home, romance leaves the marriage, one recognizes the probability of no further advancements at work, approaching retirement, etc.
The lowered risk for alcoholism in women (Haglund and Schuckit 1977) might reflect some modest differences in metabolism of alcohol or acute reactions to alcohol at various phases of the menstrual cycle (Greenblatt and Schuckit 1976). The alcoholism rate is also consistent with a strong differential effect of environment on men and women, perhaps reflecting the (historically) heavier proscriptions against heavy alcohol intake for women (Cloninger et al. 1978).
The purported increase in alcohol problems in youths is mentioned here only in passing, as a reliable definition for primary alcoholism in adolescents has not yet been developed. Most young people demonstrating alcohol-related difficulties have been shown either to have a primary antisocial personality or to demonstrate polydrug misuse and rarely fit even tentative criteria for primary alcoholism (Greenblatt and Schuckit 1976).
While not many data are available, similar generalizations can probably be made for other drugs of abuse. One notable example is the reported high rate of substance abuse in physicians and nurses when compared to other individuals of the same socioeconomic class (Jones 1977). ln this instance, the increased level of problems might not reflect a heightened genetic loading but rather an increased chance that any biological propensity will be expressed. This would reflect the ready availability of drugs and the long hours and life stresses inherent in the health-care professions. However, it is possible that there is some connection between the type of individual likely to go into the healthcare professions and an altered acute reaction to drugs, metabolism of drugs, or personality traits predisposing one toward drug misuse.
Opiate Receptors and Their
Eric J. Simon, Ph.D.
The implication of the opiate receptor in human disease has not been fully established (Simon and Hiller 1978; Terenius 1978), but it promises to hold exciting implications for the future. The hypothesis held by some investigators for several decades and discussed here is that narcotic analgesics bind to highly specific sites or receptors in the central nervous system to produce their many well-known responses.
Why the human and animal brain should contain sites that can bind with high specificity and affinity substances derived from plants was an important question that led to the discovery of the endogenous opioid peptides. The evidence for receptor sites is compelling, and consists primarily of the remarkable stereospecific action displayed by the narcotic analgesic drugs. This stereospecific characteristic refers to the structural specificity opiate molecules exhibit in interacting with particular substances in the central nervous system.
THE DISCOVERY OF OPIATE RECEPTORS
The search for opiate receptors began in the 1950s and bore fruit in the early 1970s. lt was easy to show binding of opiates to cell constituents (Simon and van Praag 1966) but to distinguish specific from nonspecific binding proved difficult.
lt was the measurement of stereospecific binding that led to success. lngoglia and Dole (1970) were the first to apply stereospecificity to the search for receptors. Goldstein et al. (1971) devised a method for measuring stereospecific binding in mouse brain tissue. ln 1973, the laboratories of Simon (Simon et al. 1973), Snyder (Pert and Snyder 1973), and Terenius (1973), using modifications of the Goldstein procedure, independently and simultaneously reported the observation in animal brains of stereospecific binding of opiates. Since that time stereospecific binding studies have been done in many laboratories and much evidence has been accumulated suggesting that these stereospecific sites are indeed receptors which are responsible for many of the pharmacological actions of the opiates. They have been found in