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Oral Self-Administration of Alcohol: A Valid
to the Study of Drug Self-Administration and Human Alcoholism
Z. Amit, B. R. Smith, and E. A. Sutherland
Center for Studies in Behavioral Neurobiology
Department of Psychology
Montreal, Quebec, Canada H3G 1M8
|The purpose of the present paper is to examine the use of animal models in psychopharmacology with particular emphasis on oral self-administration of drugs. As most of the studies in this area involve alcohol, the bulk of this paper will deal with questions related to this abused drug. Various techniques of oral self-administration are reviewed and their utility as methods of investigation in the area of psychopharmacology are examined. It is concluded that the question under investigation is critical in determining the validity of any animal model and that the use of oral paradigms may be the most appropriate method to examine the question of alcohol self-administration.|
Many methods of drug administration can be used in the study of drug action, and the choice of one technique over another should be determined exclusively by the specific question under examination. This is particularly the case in the area of drug self-administration. Numerous procedures have been used in humans to elucidate the mechanisms mediating the self-administration of various substances; however, obvious ethical, methodological and practical considerations place limits on the kinds of information that can be gained from these studies. in general, these studies utilize clinical populations with long histories of drug intake and use relatively non-invasive procedures of drug administration.
In order to investigate more basic internal, biobehavioral mechanisms underlying drug intake, it became necessary to develop appropriate animal models. While many criteria have been suggested in order for an animal model to qualify as adequate, one criterion seems to be immutable—the data gathered in animal studies must have predictive validity to human voluntary drug intake.
As with other areas of psychopharmacology, many animal models of drug self-administration exist, and the suitability of each should be (but has not always been) determined by the question and the drug under study. One important consideration in the selection of a particular methodology is the route of administration employed for the drug. Many drugs are taken by humans via the oral route: In fact, the oral route of drug intake is by far the most common. This is evidenced by the exclusive utilization of this route for alcohol intake, cannabis intake and the ingestion of minor tranquilizers, barbiturates and hallucinogens. In addition, opium, cocaine and some psychomotor stimulants are frequently taken through the oropharyngeal route. Nevertheless, the validity of the oral route in animal studies of drug self-administration does not enjoy a broad consensus. For example, animal studies using oral self-administration of ethanol as a model of human alcohol intake have been the subject of an ongoing controversy (Amit & Sutherland, 1976; Amit, Sutherland & White, 1976; Cicero, 1980; Lester & Freed, 1973; Mello, 1973). Many criticisms have been leveled against the appropriateness of animal models of human alcohol use and this whole issue has produced its fair share of extreme antagonists and protagonists.
The purpose of the present review is to examine this technique with regard to its suitability as a model of human drug administration. Since the choice of this route has been particularly prevalent in animal studies of ethanol intake, this paper will focus on work in this area as an example to illustrate issues relating to the oral route in the field of drug self-administration in general.
It has been shown that animals will preferentially consume large quantities of ethanol when it is presented in a free choice with water (Kahn & Steller, 1960; Richter & Campbell, 1940; Wilson, 1972). This observation, however, is most commonly seen when the ethanol concentrations are below 6% since rats display a natural aversion to solutions of higher concentrations (Eriksson, 1968; Meisch, 1977; Myers, 1968). However it is important to note that preferences for ethanol solutions in concentrations exceeding 20% have also been reported (Mendelson & Mello, 1964). A related problem is the fact that animals under conditions of voluntary consumption do not seem to consume sufficient amounts of ethanol to result in intoxication. Furthermore, signs of physical dependence are not normally observed in this paradigm. These two factors (i.e., the inability to produce drinking to intoxication and the absence of the development of physical dependence) which were linked to the reluctance of animals to drink sufficient amounts of ethanol have been suggested as necessary conditions in any animal model of alcohol intake (Lester & Freed, 1973).
As a result of this suggestion and despite the fact that the importance of these factors in determining the adequacy of animal models of alcoholism has been seriously challenged (e.g., Amit et al., 1976; Eriksson, 1968), many investigators have focused on the development of techniques to induce animals to consume larger amounts of ethanol. One such method has been to restrict all drinking liquids to ethanol solutions. It was shown that animals drank more ethanol during forced-choice periods than when they had the option of a free choice with water (Carey, 1972; Eimer & Senter, 1968; Ratcliffe, 1972; Rick & Wilson, 1966; Wise, 1973). This method has produced equivocal results when animals are subsequently given a free-choice test, as this procedure has been reported to lead to increased ethanol intake (Campbell, Taylor, & Haslett, 1967; Mirone, 1952, 1957; Myers, 1961; Parisella & Pritham, 1964; Powell, Kamano & Martin, 1966; Wallgren & Forsander, 1963) as well as decreased or no change in intake (Eimer & Senter, 1968; Rodgers & McClearn, 1962; Rodgers, Ward, Thiessen, & Whitworth, 1967). Ethanol has also been offered in a liquid diet as the only source of nutrients and while intake increased sufficiently to produce dependence, a free-choice test revealed that the animals maintained an aversion to ethanol despite the presence of withdrawal symptoms (Hunter, Walker, & Riley, 1974).
A number of studies have attempted to provide response contingent reinforcement in an attempt to induce increased ethanol drinking. Lick-contingent hypothalamic stimulation (Martin & Myers, 1972) and reinforcement with milk (Mello & Mendelson, 1965a) or food (Black & Martin, 1972; Coulson, Koffer, & Coulson, 1971; Keehn, 1969; Keehn & Coulson, 1970; Perensky, Senter, & Jones, 1968; Senter, Smith, & Lewin, 1967) have been used to induce consumption of intoxicating amounts of ethanol. While this criterion was achieved, discontinuation of the response contingencies resulted in decreased ethanol intake (Black & Martin, 1972; Martin & Myers, 1972; Mello & Mendelson, 1965a). The use of electric shock and escape contingencies has also failed to produce continued elevated ethanol intake since termination of the shock caused ethanol consumption to return to baseline levels (Kamback, 1973; Ramsey & Van Dis, 1967; Senter et al., 1967).
One procedure which has been relatively successful in achieving ethanol intake leading to dependence has been the use of schedule-induced polydipsia. It was demonstrated that food-deprived rats receiving small pellets of food spaced over time would consume larger quantities of fluid (Falk, 1961). When ethanol was substituted for water, rats consumed intoxicating quantities of ethanol (Everett & King, 1970; Falk, Samson, & Winger, 1972; Freed, 1972; Lester, 1961; Meisch & Thompson, 1972; Ogata, Ogata, Mendelson, & Mello, 1972; Samson & Falk, 1974; Senter & Sinclair, 1967) and physical dependence was observed following several ethanol polydipsia sessions per day (Falk et al., 1972). The termination of the concurrent food reinforcement does not result in a decrease in ethanol intake as a preference for ethanol over water remains (Falk et al., 1972; Freed, Carpenter, & Hymowitz, 1970; Freed & Lester, 1970; Meisch & Thompson, 1971, 1974). However, it is important to note that the concentration of ethanol solutions in Falk’s studies was low (5.6%) and, therefore, in the range that animals prefer normally. When the concentration of ethanol solutions was increased to 20%, preference was not maintained after polydipsia sessions were discontinued (Meisch & Thompson, 1972).
Electrical brain stimulation has also been used to elevate ethanol drinking and has been reported to produce a voluntary preference for relatively concentrated solutions of ethanol (Amir & Stern, 1978; Amit, Stern, & Wise, 1970; Corcoran & Amit, 1974). This preference persisted long after the stimulation was discontinued (Amit & Stern, 1971; Amit et al., 1970; Wayner, Gawronski, Roubie, & Greenberg, 1971; Wayner & Greenberg, 1972). Signs of physical dependence, however, were not reported.
Each of the techniques described above produces an increased intake of alcohol; however, in most cases a prolonged voluntary preference for ethanol is not established and intake during each manipulation can hardly be described as "voluntary." With this in mind investigators developed a procedure which relied on voluntary consumption with a specific schedule of presentation to induce animals to obtain a preference for high concentrations of ethanol. This technique utilizes a phenomenon known as the "alcohol deprivation effect," first described by Sinclair and Senter (1968). It was shown that periodic availability of ethanol, presented in a free choice with water, resulted in increased ethanol consumption of solutions which would otherwise be avoided. This method was first described by Amit and Stern (1971) and later confirmed by others (Pinel, Mucha, & Rovner, 1976; Sinclair & Senter, 1968; Wayner & Greenberg, 1972; Wise, 1973). As a result of this technique, a prolonged preference for the ethanol solutions was maintained.
The examination of the procedures to increase voluntary consumption of ethanol in animals as described above, which attempted to meet Lester and Freed’s postulated criteria for an animal model of human alcoholism (Lester & Freed, 1973), may have combined two unrelated issues. The present authors (Amit et al., 1976) and others (Meisch, 1980; Sinclair, 1980) have argued that the phenomena of alcohol intoxication and physical dependence, on the one hand, and voluntary consumption of ethanol, on the other hand, may be unrelated. (For a detailed discussion of this issue, see Amit et al., 1976.)
If this is in fact the case, as the bulk of animal data as well as some of the human data seem to suggest, then the inclusion of both requirements in the same model produces an unnecessary confusion. Thus, as mentioned earlier, the adequacy of an experimental procedure must be determined by the question it attempts to study. In other words, if the research is attempting to focus on mechanisms underlying intoxication and physical dependence, then techniques to produce these states are relevant and necessary. If, on the other hand, the focus of the research is ethanol self-administration, then a well-controlled preference paradigm is the necessary and sufficient condition.
There has recently been growing acceptance for the notion that alcohol self-administration in humans is a distinct set of responses governed primarily by its reinforcing properties (Amit & Sutherland, 1976; Bigelow & Liebson, 1972; Mello & Mendelson, 1965b, 1972; Sanders, Nathan, & O’Brien, 1976). In a similar fashion it has been demonstrated that ethanol drinking in animals is also an operant response which can be modified by the same manipulations as any other operant response (Amit & Stern, 1969; Meisch, 1977, 1980; Sinclair, 1974). Lester and Freed (1972) challenged that view and suggested that animals consume ethanol for its caloric value and not for its reinforcing, psychopharmacological effects. While this is a relevant argument, it does not seem to be defensible since it has been demonstrated that food-satiated animals will drink ethanol solutions greater than 8% concentration in preference to water (Beardsley, Lemaire, & Meisch, 1978; Meisch & Thompson, 1973; 1974). In addition, animals have been shown to work for ethanol despite free access to food and water (Penn, McBride, Lumeng, Gaff, & Li, 1978; Sinclair, 1974). Also, merely depriving animals of food did not result in increased ethanol intake (Amit & Stern, 1969). Animals drinking more ethanol than water in situations where food and competing fluids are continuously available seem likely to be doing so for reasons other than thirst and hunger. Furthermore, the fact that hungry animals will not increase their ethanol consumption relative to satiated controls argues quite strongly against the "drinking for calories" hypothesis.
Even among those who adhere to the notion that drug self-administration is governed primarily by its reinforcing properties, there has been some doubt as to the appropriateness of the oral route of intake for studying the reinforcing properties of ethanol (Wise & Bozarth, 1982). Wise’s main argument is that under conditions of free choice one cannot observe the willingness of animals to work for alcohol. Since the ability of animals to work or to perform a distinct operant is purported to be a prerequisite for demonstrating reinforcement bound behavior, the clarification of this issue becomes critical. This position, once again, is not defensible since it has been shown that animals will learn to perform a task in order to drink ethanol (Anderson & Thompson, 1974; Meisch, 1980, this volume; Meisch & Beardsley, 1975; Penn et al., 1978) and will learn a new response to obtain drops of ethanol through the oral route (Sinclair, 1974). It would appear then that animals will orally consume ethanol for its pharmacologically reinforcing effects. In this context it is interesting to note that the behavioral responses of the animals to ethanol consumed through this route are strikingly similar to those displayed with other reinforcing drugs or substances (e.g., food and water). Furthermore, humans can also be observed to perform similar behaviors in a laboratory setting in order to obtain alcohol (Ludwig, Wikler, & Stark, 1974; Mello & Mendelson, 1972; Sanders et al., 1976).
Finally, it has been shown that the same neurochemical manipulation that will block oral self-administration of ethanol (Amit, Brown, Levitan, & Ogren, 1977) will also block intragastric self-administration of ethanol (Davis, Werner, & Smith, 1979). Davis et al. (1979) have also demonstrated that this neurochemical manipulation will also block second order conditioning of a stimulus previously paired with ethanol. This set of observations argues strongly for the fact that alcohol is a substance endowed with primary reinforcing properties which seem to underlie alcohol self-administration through any route of administration.
As mentioned in the opening section of this paper, the ultimate test of the viability of an animal model must be its ability to generate inferences to the human condition it was set up to model. The question remains: Does the oral self-administration of ethanol in animals allow us to draw inferences to human voluntary consumption of alcohol? As we have argued in preceding sections of this review, until fairly recently such data was generally unavailable. The attempts to validate such an animal model were therefore often based on tenets which were derived from more or less relevant theoretical considerations. As new data emerged, many of the earlier theoretical assumptions proved to be less critical or even irrelevant.
More recently, several lines of alcohol research have provided empirical evidence suggesting that an oral preference model of ethanol intake in animals may be predictive of alcohol self-administration in humans. One area of alcohol research which has shown concordance between animal and human data is the investigation of a genetic component of alcohol intake which has been studied exclusively through the oral self-administration paradigm.
An increasing body of evidence suggests than an inherited predisposition towards alcoholism may exist in humans (for a review, see Goodwin, 1979). In this context it is interesting to note that Schuckit and Rayses (1979) reported that human populations with high risk for alcoholism have high levels of acetaldehyde. In animals it has been demonstrated (Brown, Amit, & Smith, 1980) that self-administration of acetaldehyde is correlated with oral self-administration of ethanol. Recent data seem to point to an alteration in the alcohol metabolizing enzymes, specifically those enzymes responsible for the metabolism of ethanol’s primary metabolite acetaldehyde as the critical factor in this predisposition (Ewing, Rouse, & Pellizzari, 1974; Haranda, Agarwal, Goedde, & Ishikawa, 1983; Mizoi, Ijiri, Tatsumo, Kijima, Fujiwara, Adachi, & Hishida, 1979; Mizoi, Tatsumo, Adachi, Kogame, Fukunasa, Fujiwara, Hishida, & Ijiri, 1983; Reed, Kalant, Gibbons, Kapur, & Rankin, 1976; Zeiner, Paredes, & Christianson, 1979).
Research has also demonstrated that alcohol consumption can be selectively bred in rats (e.g., Eriksson, 1968; Li & Lumeng, 1977; Lumeng, Hawkins, & Li, 1977) and in mice (e.g., Rodgers & McClearn, 1962) suggesting that ethanol consumption in both humans and animals may be genetically determined. Furthermore, it has been shown that the activity of aldehyde dehydrogenase, the primary enzyme responsible for acetaldehyde metabolism, is highly correlated with voluntary ethanol consumption in several strains of rats and mice (Amir, 1977, 1978; Schlesinger, Kakihana, & Bennett, 1966; Sheppard, Albersheim, & McClearn, 1968; Socaransky, Aragon, Amit, & Blander, 1984). These reports are indicative of a concordance in the results of studies using an oral route of administration between human and animal experiments examining the genetic determinants of alcohol consumption.
While these results are an example of indirect evidence supporting the predictive value of animal consumption studies, a direct comparison involving identical manipulations in animals and man is necessary in order to properly evaluate the utility of this experimental procedure. Recently, this approach was used in an attempt to compare the mediators of alcohol self-administration in rats and man. It was observed that the administration of zimelidine, a serotonin re-uptake inhibitor, attenuated voluntary ethanol consumption in rats as measured in an oral preference paradigm (Lawrin, Naranjo, & Sellers, 1983; Rockman, Amit, Carr, Brown, & Ogren, 1979). This finding led two independent laboratories to test zimelidine’s effect on alcohol consumption in humans. Both groups reported similar findings with zimelidine treatment resulting in a decreased alcohol intake (Sutherland, Amit, Sossanpour, & Selvaggi, 1983) and an increased number of abstinent days (Narnajo, Lawrin, Addison, Roach, Harrison, Sanchez-Craig, & Sellers, 1983; Narnajo, Sellers, Roach, Woodley, Sanchez-Craig, & Sykora, 1983). While additional studies are necessary in order to elucidate the mechanisms of this observation and also to determine the significance of the drug effect, it is nevertheless the case that these results suggest, independent of the specific mechanism involved, that animal oral consumption studies may serve as a predictor of human self-administration of alcohol.
The purpose of the present review was to evaluate the oral self-administration model of ethanol intake in animals as a viable procedure to study human voluntary consumption of alcohol in particular and also to assess the model’s usefulness for the study of oral self-administration of psychoactive drugs in general. We presented evidence demonstrating that the oral self-administration paradigm is endowed with all the properties required of other "valid" self-administration paradigms—animals will work and will perform an operant to obtain ethanol through the oral route, they will also respond to a second order conditioned stimulus previously paired with alcohol and, finally, the same neuropharmacological manipulations will block both oral and intragastric self-administration of ethanol. We also argued that the objections raised against the animal model as a tool for studying human alcohol consumption have become either noncritical or irrelevant in that the reluctance of animals to drink to intoxication and the absence of withdrawal signs were shown to be either incorrect or unimportant in the context of a paradigm which perceives reinforcement to be the primary factor mediating voluntary consumption of alcohol.
Finally, we presented evidence, unique in the field of drug self-administration, that the predictive validity of the animal model of oral alcohol intake was tested directly in human populations and found to be defensible. We therefore conclude that oral self-administration of ethanol in animals is a valid procedure to study mechanisms of drug self-administration and a uniquely suitable approach to investigate human consumption of alcohol.
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