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Study tests drugs to alter drinking behavior by Dick Peterson Public Relations If there's a point at which a heavy drinker cannot refuse another drink, Institute of Psychiatry Alcohol Research Center investigator Ray Anton, M.D., wants to find it and eliminate it. His research, funded by the Charleston Alcohol Research Center under a grant from the National Institutes of Health, is about choice. It's about giving people who need it the power to choose not to take another drink, and to reduce their alcohol consumption to a level that neither impairs their judgement nor compromises their health.  The power to say no may lie in a combination treatment of two drugs—naltrexone and ondansetron. But for now, Anton's double-blind, randomized, placebo-controlled study will test the effectiveness of naltrexone alone to alter alcohol consumption in heavy drinkers who really have no desire to change their drinking habits. He expects the already clinically effective drug to give heavy drinkers more control over the cues that lead to drinking and over the inclination to drink excessively. “These are not severe alcoholics, as we would define the term,” Anton said. He explained that they are people who may have some alcohol-related problems, and consume 20 or more drinks in a week. “Some may drink as much as seven or eight in a day—more than they intend to—and not have complete control of their drinking.” To recruit for the study, Anton advertises and offers compensation according to the restrictions spelled out in the grant. “We don't have a long line of applicants outside the door,” he said, “but we do have an adequate flow of subjects,” despite their lack of motivation to reduce their alcohol consumption, he said. Some of the people entering the randomized study are given the drug and others a look-alike placebo. No one, not the study subjects nor the researchers, know which group is which. That data is reserved for the time when the study ends and the results are compiled. For six days and having received no information about alcohol consumption, the study subjects go about their normal lives as before. When they return to the center, they receive a measured amount of alcohol served in a bar-like setting— enough to create a low, but significant, blood alcohol level.  The aim is to measure the craving and other effects that may lead to more alcohol consumption. Other drinks are offered, albeit containing smaller amounts of alcohol than the first. “We try to mimic what would happen in the real world,” Anton said. “The question is, when individuals in treatment ‘slip’ and have one drink, will that one drink lead to more? Will a lapse lead to a relapse? Or will the medication stop them? That is what we are trying to model in the clinical laboratory.” Once Anton's study protocol is established and naltrexone's effectiveness is measured, he plans to test ondansetrone and other medications, possibly leading to drug combinations for more effective treatments. An effective opiate blocker, naltrexone works by binding to opiate receptors in brain cells, thereby blocking the effects that alcohol molecules have on them. “But the trouble with alcohol,” Anton said, “it's a messy drug from a pharmacological point of view.” By ‘messy,’ he means that alcohol can bind to more than just the opiate receptors. It can bind to other receptors in the brain, as well, affecting people in different ways and affecting some people more than others.  Ondansetrone, for instance, would add another dimension to the treatment—a medication that works on the brain's serotonin system. Considered safe and effective in treating nausea following chemotherapy, ondan-setrone in lower doses than used for nausea has been shown to reduce the consumption of alcohol in mice and in some early human studies. Anton expects to test each medication separately and together to measure the added effect. “It may be we will be hitting both systems (opiate and serotonin) at the same time, gaining more effect from the therapy,” Anton said. It's like treating resistant hypertension with two drugs. They may work synergistically. The studies conducted in the clinical lab setting are a prelude to full-scale clinical trials that are more costly both in dollars and in patient burden. This work may provide the leads that could make the whole process more efficient.   Alcoholic mice mimic human addiction Mice don't like alcohol. But don’t tell that to C57Black6, a genetically inbred mouse strain with a special fondness for the old watering hole. The mouse serves as a model for alcohol-related problems. “We set up conditions for the mouse which model some of the conditions which initiate or maintain drinking by alcoholics. Our measures assess how rewarding alcohol and alcohol-related cues are for the mouse,” said Lawrence Middaugh, Ph.D.  “We can measure how much alcohol he will drink, how much work he'll perform for the alcohol reward, what degree of impairment the alcohol has on him and the effect of alcohol conditioned cues on his behavior. More important, we can determine the effects of potential therapeutic agents on these alcohol-related behaviors.” Middaugh describes his research with the mice as utilizing principles of operant and classical conditioning, not just to determine the extent the mice will go to get the alcohol, but to learn if certain medications dampen the rodent's enthusiasm for booze. People drink alcohol not only for its positive reward effects but also to avoid negative consequences associated with not drinking, Middaugh explained. In either case, they drink to create a shift toward a positive state, he said. His mice behave in much the same way. In fact, C57Black6 will drink alcohol in preference to water and if prevented access for a period of time will increase the amount they drink much like what is observed during alcohol relapse for alcoholics, he said. In one of Middaugh's research protocols, mice are conditioned to press a lever for access to alcohol. The lever response produces delivery of a measured amount of ethanol to a fountain from which the mouse can drink. Computer programs control the number of responses required to obtain each drink. By determining the maximum number of responses the animal will make for each drink, we have a measure of its reward value.  “Our experiments have shown that preventing access to alcohol will increase its reward value for mice just as frequently noted for humans,” Middaugh said. More importantly, drugs that show promise for treatment of alcoholism (e.g., naltrexone and ondansetron) reduce the rewarding value of ethanol for these mice. Future studies will investigate other potential therapeutic agents, he said. Under another research protocol, Pavlovian classical conditioning is used to pair environmental stimuli with alcohol.  The environmental stimuli will then elicit approach responses suggesting their reward value.  A testing chamber is divided with a small hole for passage between a black compartment and a second, white compartment.  Middaugh explained that mice, being nocturnal animals, spend little time in the lighted, white area. Pairing this non-preferred environment with alcohol however increases the amount of time the mouse spends in the environment suggesting that the environmental cues have increased positive valence.  Interestingly, this increase in positive valence of the environment produced by being paired with alcohol is attenuated by naltrexone. With the behavioral-addiction data in hand, Middaugh, in collaboration with Peter W. Kalivas, Ph.D., assesses  neurochemical activity in a brain area important for mediating reward. In these experiments, the amounts of dopamine neurotransmitter released in response to ethanol consumption or to the presentation of alcohol conditioned cues is measured.  Current experiments indicate that mice consume sufficient ethanol to increase the amounts of dopamine in brain areas which mediate reward. Preliminary experiments indicate that when a mouse is medicated with naltrexone, an effective opiate blocker,  an attenuation of the alcohol-induced increase in dopamine is observed.  Such a reduction may reflect an attenuation of the mouse’s “desire” for alcohol.