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Alcohol Alert

National Institute on Alcohol Abuse and Alcoholism No. 24 PH 350 April 1994


Animal Models in Alcohol Research

Animals are used in alcoholism research for the same reasons that they are used in all medical research: to understand the causes of disease and to develop new treatments. Animals are used in three principal ways in research on alcoholism: to model the drinking behavior of human alcoholics, to learn from the brain and other organs of drinking animals how brain chemistry leads to a drinking behavior, and to study how alcohol damages organs. No animal model completely reproduces all the features of the human disease. On the other hand, individual features of alcoholism can be studied in animals in great detail. Moreover, the researcher has full control over experimental conditions such as nutrition, environment, species, and ancestry. This Alcohol Alert reviews animal research designed to answer questions pertaining to human alcohol use and abuse.

Why do people drink alcohol?

One reason people drink is that alcohol is reinforcing. People experience effects from drinking alcohol that can cause them to drink again to repeat the experience. Through its effects, alcohol can be a positive reinforcer, producing positive sensations in the brain, or a negative reinforcer, alleviating negative sensations such as anxiety (1).

Animal research has proved that alcohol is reinforcing. Demonstrating that alcohol is positively reinforcing, studies have shown that some of alcohol's actions in the brain and bloodstream can cause an animal to seek alcohol and even to work for it (e.g., press a lever) to repeat the experience it elicits (1). Demonstrating that alcohol is negatively reinforcing, studies have shown that alcohol reduces anxiety in mice placed in an open maze. If mice are given alcohol before being placed in sections of the maze that they would otherwise avoid, they then spend more time in those sections (2). With animal models of reinforcement, scientists are learning which networks of nerve cells are responsible for it and how reinforcement may be modified.

If alcohol alleviates anxiety, then does higher anxiety lead to increased drinking? A study that compared drinking in adolescent rhesus monkeys raised by their mothers with drinking in monkeys raised only with their peers noted that peer-reared monkeys displayed more anxiety-related behaviors and drank more alcohol than mother-reared animals. However, when the mother-reared monkeys were isolated from one another, an event that caused stress, their levels of drinking increased until they almost matched those of peer-reared animals. Within each group, the animals that displayed more anxiety also drank more alcohol (3). The study suggests that anxiety or situations that produce high degrees of stress may trigger excessive alcohol consumption. Such research allows scientists to study how the brain produces this response to stress (3).

Although humans and animals may drink because the effects of alcohol are reinforcing, they often find the initial taste of alcohol aversive. Animals may be induced to begin drinking when the taste of alcohol is disguised in a sweet solution. Researchers gradually reduce the amount of sweetened solution in the beverage as the animals acquire a taste for alcohol (4). Many people may begin drinking alcohol by mixing it with a sweet substance, but research has not determined whether this is a factor in initiating drinking in humans (5).

Is there a genetic, or inherited, component of responses to alcohol?

Twin and adoption studies in humans have demonstrated a genetic component of vulnerability to alcoholism (6). To study such genetic components, research ers have bred animals with differing responses to alcohol. For example, lines of rats called alcohol preferring (P) and nonpreferring (NP) have been bred to differ in their voluntary preference for consuming alcohol (7). Animals that are bred for differences in responses to alcohol allow researchers to study the variations in brain chemistry underlying these genetic differences.

Finding specific genes associated with drinking in animals may aid in the study of genetic differences in reactions to alcohol. One study connected a high preference for alcohol in mice with one form of a gene found in the brain and other tissues. The study found the same form of the gene in 19 separate lines of mice, all of which had high alcohol preference (8). This gene may play a role in animals' voluntary consumption of alcohol. This type of research allows scientists to correlate animal genes with the human genes that may be associated with alcohol consumption.

To find genes that influence responses to alcohol, researchers use animals to look for areas on chromosomes called quantitative trait loci (QTL). Each QTL is a cluster of genes that accounts for part of a whole behavior. Once identified, QTL in animals can be used as a guide to examine probable locations for the genes in humans (9).

How do genes influence preference for alcohol?

Genes controlling levels of certain chemicals in the brain may contribute to a person's preference for alcohol. Levels of serotonin, a brain chemical important in transmitting nerve impulses, are associated with differences in alcohol preference between P and NP rats. P rats have been found to have lower serotonin levels than NP rats (10). Such variations suggest that genes that control serotonin activity may influence alcohol preference.

Building on this research, one study used the experimental drug fluoxetine to increase the level of serotonin in the brains of P rats. When more serotonin was pres- ent in the brain, the rats reduced their alcohol intake. When fluoxetine was withdrawn and less serotonin was present in the brain, the rats increased their drinking (11). Because the change in serotonin levels led to changes in the P rats' drinking, the study provides further evidence of an association between serotonin and drinking behavior (11).

Why are some people more sensitive than others to alcohol's effects?

Genes may alter the way individual brain cells are affected by alcohol, thereby influencing sensitivity. Lines of mice called long sleep (LS) and short sleep (SS) have been bred for differing sensitivities to the depressant effects of alcohol. Individual brain cells from each mouse line also exhibit differing sensitivities to alcohol. Less alcohol is needed to suppress activity in LS mouse brain cells than is needed to suppress activity in SS mouse brain cells (12).

Researchers are working to identify basic variations in genetic products, or proteins such as receptors, that will explain differences in sensitivity and many other responses to alcohol. In one technique, scientists remove genetic material from mouse brains and transplant it to frog eggs. The frog eggs follow instructions in the mouse genetic material and make mouse brain cell receptors, allowing researchers to examine the way these receptors interact with alcohol in a clearly defined system separate from the whole animal.

Using frog eggs to study sensitivity differences, scientists have determined that alcohol may interact with a receptor that plays a role in suppressing nerve impulses. Alcohol's sedative effects could be caused by suppression of these impulses. This research suggests that genetically determined variations in the function of this receptor could account for differences in sensitivity to alcohol (13).

Why do some alcoholics develop liver disease while others do not?

Nutrition may play a role in the development of alcoholic liver disease. Animals have been instrumental in investigating this possibility. Some studies have found that baboons consuming a nutritionally adequate diet while deriving half of their total calories from alcohol can develop liver fibrosis and even cirrhosis after several years. These findings suggest that alcohol causes liver damage regardless of nutritional status (14). Other studies have found that rats develop liver scarring, a symptom also seen in humans and baboons, only when fed a high-fat diet in conjunction with alcohol (15). In addition to the role of alcohol and nutrition, there may be a genetic predisposition to liver disease. It is clear that a variety of approaches are still needed to determine the roles of alcohol, nutrition, and genetics in the development of liver disease.

Is alcohol equally damaging to the fetus at all stages of pregnancy?

Animal research has shown that physical and cognitive damage to the fetus results from alcohol exposure during pregnancy, depending on the period during which alcohol is consumed. For example, researchers who gave high doses of alcohol to mice on one day, early in gestation, found that forelimbs in the offspring were malformed. This suggests that alcohol's effects on limb formation can be correlated with consumption of alcohol during a distinct period early in pregnancy (16).

Some research suggests that cognitive function in the fetus may be more affected by alcohol in early rather than late pregnancy. A study of the effects of alcohol on mental development examined offspring of macaque monkeys who were fed alcohol once each week during their pregnancies beginning at either week 1 or week 5. Infants of mothers whose drinking began in week 1 of pregnancy were the most developmentally delayed. Even infants whose mothers had been given higher doses of alcohol beginning at week 5 had fewer developmental deficiencies than infants exposed to lower doses of alcohol throughout gestation (17).

What new pharmacologic treatments for alcoholism are being developed and tested?

The opioid-blocking drug naltrexone has had promising results in preliminary human clinical trials as an adjunct therapy in the treatment of alcoholism (18). Researchers are using animal studies in conjunction with human clinical trials to determine naltrexone's mechanism of action as well as its effectiveness. They have concluded that alcohol consumption may be related to the naturally occurring opioid system in the brain (19). Naltrexone has been administered to rhesus monkeys who voluntarily consume alcohol. The monkeys decrease their alcohol intake when naltrexone is administered before drinking occurs (20).


Animal Models in Alcohol Research--A Commentary by
NIAAA Director Enoch Gordis, M.D.

Clearly, human use of animals in research derives from the premise that our first priority must be the relief of human suffering. Without research on animals, progress in understanding the process of alcoholism itself or of damage to body systems caused by alcohol use would come to a halt and the prevalence of alcohol-related illness and disease would remain unchanged.

In some areas, such as genetics, the alcohol field is ahead of many others in the use of animals to explore and resolve questions of human illness and disease. Results of studies with animals are advancing our knowledge of vulnerability to alcoholism and of alcohol's effects on brain chemistry, information necessary for the development of new treatments.

Although animal research is critical to reducing the tremendous social and personal
burden of alcohol abuse and alcoholism, researchers in the alcohol field, like those in all fields of research, are committed to the appropriate use of animals in research and their h umane treatment.


References

(1) Grant, K.A. Behavioral animal models in alcohol abuse research. Alcohol Health & Research World 14(3):187-192, 1990. (2) Lister, R.G. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180-185, 1987. (3) Higley, J.D.; Hasert, M.F.; Suomi, S.J.; & Linnoila, M. Nonhuman primate model of alcohol abuse: Effects of early experience, personality, and stress on alcohol consumption. Proceedings of the National Academy of Sciences 88(16):7261-7265, 1991. (4) Schwarz-Stevens, K.; Samson, H.H.; Tolliver, G.A.; Lumeng, L.; & Li, T.-K. The effects of ethanol initiation procedures on ethanol reinforced behavior in the alcohol-preferring rat. Alcoholism: Clinical and Experimental Research 15(2):277-285, 1991. (5) Samson, H.H. Initiation of ethanol-maintained behavior: A comparison of animal models and their implication to human drinking. In: Thompson, T.; Dews, P.B.; and Barrett, J.E., eds. Neurobehavioral Pharmacology: Volume 6. Advances in Behavioral Pharmacology. Hillsdale, NJ: Lawrence Erlbaum Associates, 1987. pp. 221-248. (6) National Institute on Alcohol Abuse and Alcoholism. In: Eighth Special Report to the U.S. Congress on Alcohol and Health. NIH Pub. No. 94-3699. Bethesda, MD: National Institutes of Health, 1993. pp. 62-65. (7) Li, T.-K.; Lumeng, L.; McBride, W.J.; & Waller, M.B. Indiana selection studies on alcohol-related behaviors. In: Development of Animal Models as Pharmacogenetic Tools. National Institute on Alcohol Abuse and Alcoholism Research Monograph No. 6. DHHS Pub. No. (ADM)81-1133. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1981. pp. 171-191. (8) Goldman, D.; Lister, R.G.; & Crabbe, J.C. Mapping of a putative genetic locus determining ethanol intake in the mouse. Brain Research 420:220-226, 1987. (9) Plomin, R., & McClearn, G.E. Quantitative trait loci (QTL) analyses and alcohol-related behaviors. Behavior Genetics 23(2):197-211, 1993. (10) Murphy, J.M.; McBride, W.J.; Lumeng, L.; & Li, T.-K. Regional brain levels of monoamines in alcohol-preferring and -nonpreferring lines of rats. Pharmacology Biochemistry and Behavior 16(1):145-149, 1982. (11) Murphy, J.M.; Waller, M.B.; Gatto, G.J.; McBride, W.J.; Lumeng, L.; & Li, T.-K. Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats. Alcohol 5(4):283-286, 1988. (12) Sorenson, S.; Palmer, M.; Dunwiddie, T.; & Hoffer, B. Electrophysiological correlates of ethanol-induced sedation in differentially sensitive lines of mice. Science 210(4474):1143-1145, 1980. (13) Wafford, K.A.; Burnett, D.M.; Dunwiddie, T.V.; & Harris, R.A. Genetic differences in the ethanol sensitivity of GABAA receptors expressed in Xenopus oocytes. Science 249:291-293, 1990. (14) Lieber, C.S., & DeCarli, L.M. An experimental model of alcohol feeding and liver injury in the baboon. Journal of Medical Primatology 3(3):153-163, 1974. (15) French, S.W.; Miyamoto, K.; & Tsukamoto, H. Ethanol-induced hepatic fibrosis in the rat: Role of the amount of dietary fat. Alcoholism: Clinical and Experimental Research 10(6):13S-19S, 1986. (16) Kotch, L.E.; Dehart, D.B.; Alles, A.J.; Chernoff, N.; & Sulik, K.K. Pathogenesis of ethanol-induced limb reduction defects in mice. Teratology 46(4):323-332, 1992. (17) Clarren, S.K.; Astley, S.J.; & Bowden, D.M. Physical anomalies and developmental delays in nonhuman primate infants exposed to weekly doses of ethanol during gestation. Teratology 37(6):561-569, 1988. (18) O'Malley, S.S.; Jaffe, A.; Chang, G.; Witte, G.; Schottenfeld, R.S.; & Rounsaville, B.J. Naltrexone in the treatment of alcohol dependence: Preliminary findings. In: Naranjo, C.A., and Sellers, E.M. , eds. Novel Pharmacological Interventions for Alcoholism. New York: Springer-Verlag, 1992. pp. 148-157. (19) Czirr, S.A.; Hubbell, C.L.; Milano, W.C.; Frank, J.M.; & Reid, L.D. Selected opioids modify intake of sweetened ethanol solution among female rats. Alcohol 4(3):157-160, 1987. (20) Altshuler, H.L.; Phillips, P.E.; & Feinhandler, D.A. Alteration of ethanol self-administration by
naltrexone. Life Sciences 26:679-688, 1980.


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Updated: October 2000