Add’l Contact: Henry R. Kranzler, M.D.
University of Connecticut Health Center
Add’l Contact: David Overstreet, Ph.D.
University of North Carolina at Chapel Hill
Alcoholism: Clinical & Experimental Research
It’s no secret that smokers often drink, and drinkers often smoke. Addiction scientists believe that alcohol consumption may contribute to increased cigarette smoking; certainly alcohol is considered a major risk factor for relapse during smoking cessation. Similarly, smoking is believed to increase the pleasurable effects of alcohol, and may be a risk factor for alcoholism relapse. Two studies in the March issue of Alcoholism: Clinical & Experimental Research examine the mechanisms underlying the two addictive behaviors. One study uses rodents to investigate the impact that alcohol and nicotine have on dopamine (DA) release in the brain; the other study looks at the impact a drug used to block nicotinic effects called mecamylamine has on alcohol’s effects for humans. The results collectively suggest that nicotinic mechanisms are involved in alcohol consumption.
‘We believe that the mesolimbic circuit, which originates in the ventral tegmental area of the brain and projects to the nucleus accumbens, is intimately involved in the ‘reward’ or reinforcing effects of alcohol and nicotine as well as many other drugs of abuse,” said Yousef Tizabi, associate professor and researcher at Howard University College of Medicine and lead author of one of the studies. “This circuit mainly utilizes the neurotransmitter dopamine. The release of dopamine in the terminal region of this circuit, the nucleus accumbens, appears to be important for the reinforcing process.”
For the Tizabi study, researchers simultaneously administered alcohol and nicotine to rodents in order to examine their effects on DA release in the nucleus accumbens. They found that both substances resulted in a dose-dependent increase in DA release. Simultaneous administration of lower doses of nicotine and alcohol resulted in an additive effect on the release of DA, which was not observed with higher doses of nicotine and alcohol. When mecamylamine was administered into the ventral tegmental area, it completely blocked alcohol-induced DA release.
“The findings suggest that part of the reason why people drink and smoke at the same time is to increase their pleasure,” noted Tizabi. “Increased pleasure is reflected by the increased dopamine in the nucleus accumbens. That lower doses have additive effects implies that the pleasurable effects, in terms of dopamine release, are additive. However, with higher doses, the dopamine release might have maxed out, so that an additive effect might not be observed. Although one might still get a larger increase in dopamine with the combination of drugs than with each drug alone, the reason for combining the two at higher doses might be different. That is, a heavy drinker who also smokes heavily does so not so much for the additive pleasure, but perhaps to counteract some of the sedative effects of alcohol with the stimulant effects of nicotine. However, it should be emphasized that we are extrapolating from rats to humans.”
Nonetheless, said David Overstreet, associate professor of psychiatry with the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill, “if this outcome were applied to the human condition, we would predict that smokers should be able to attain the reinforcing effects of alcohol with fewer drinks. Likewise, drinkers should be able to get a nicotine ‘high’ without smoking as much. However, there is a problem with this prediction or viewpoint. It is made on the basis of an acute study, where the drugs are given only once. Would we see this nicotine/alcohol interaction observed by Tizabi in rats that have been chronically treated with nicotine and/or alcohol?” Overstreet proposed that individuals who abuse nicotine, alcohol or both tend to develop some degree of tolerance to one or both drugs “Therefore,” he said, “they may need to smoke more and drink more to achieve the same ‘high’ as casual [users].”
The second study examined the impact of mecamylamine on the pharmacokinetic, stimulating, and pleasurable effects of alcohol among casual drinkers. Mecamylamine is approved for the treatment of hypertension by the U.S. Food and Drug Administration (it is no longer used for that purpose, however, as more effective antihypertensives are available). It is also used experimentally in conjunction with transdermal nicotine (“the patch”) for smoking cessation. Mecamylamine blocks the binding of the neurotransmitter acetylcholine at specific connections on brain cells called nicotinic cholinergic synapses. Blockade of these synapses appears to reduce the release of the neurotransmitter dopamine.
Volunteers (10 male, 10 female) with no history of alcohol or substance-use disorders participated in two laboratory sessions, receiving either mecamylamine or a placebo before consuming a standard dose of alcohol. Participants then had their breath alcohol levels (BALs), blood pressure and heart rates measured, and were administered three different self-report questionnaires to measure alcohol’s effects. Compared to the placebo, mecamylamine reduced their BALs. It also appeared to reduce scores on all three questionnaires, indicating reduced pleasurable or rewarding effects of alcohol. The reduced BAL, however, was not the sole reason for the reduced rewarding effects.
“Alcohol is both absorbed and metabolized in the stomach and gut,” explained Henry R. Kranzler, professor of psychiatry, Associate Scientific Director of the Alcohol Research Center at the University of Connecticut School of Medicine, and corresponding author for the study. “This occurs prior to alcohol’s reaching the general circulation, including the brain, where it exerts its psychoactive effects. Because cholinergic blockade by mecamylamine would be expected to slow the normal movements of alcohol and other ingested substances through the stomach and gut, there is a greater opportunity for alcohol to be metabolized before ever reaching the blood. We believe that this explains the reduced BAL that we observed following mecamylamine treatment. However, it is important to recognize that the effects of mecamylamine occurred not only in the gut, but [also] in the brain, since the drug reduced alcohol’s stimulating and rewarding effects even after the effects on BALs was controlled for statistically.”
Kranzler added that reduced stimulation as well as pleasurable responses to alcohol are consistent with the behavioral effects observed in rodents. “Alcohol causes stimulation and other pleasurable effects through the release of specific brain chemicals,” he said. “Dopamine has been most consistently implicated in these effects. Mecamylamine blocks acetylcholine-induced increases in dopamine release that occur as part of the cascade of effects of alcohol. In short, nicotinic cholinergic synapses appear to be important in the positive effects of alcohol, which suggests that modification of this neurochemical system could be useful in the treatment of alcoholism.”
“Both of these studies support the growing body of evidence suggesting an involvement of nicotinic mechanisms in alcohol drinking,” said Overstreet. “On one hand, the Tizabi study shows that nicotine and alcohol additively stimulate dopamine release in rats. The Kranzler study shows that the nicotine blocker mecamylamine can reduce the activating effects of alcohol in humans. These results raise the possibility that treatments that are effective in smoking cessation may also be beneficial for alcoholics. Bupropion (Zyban™), for example, which is approved by the Food and Drug Administration as an antismoking medication, has not been adequately tested in human alcoholics. It would be particularly exciting if a single therapeutic agent could be beneficial for both smokers and drinkers.”
Co-authors of the Kranzler paper, “Mecamylamine Modifies the Pharmacokinetics and Reinforcing Effects of Alcohol,” included: Ola Blomqvist, Carlos A. Hernandez-Avila, and Jeffrey Van Kirk of the Alcohol Research Center in the Department of Psychiatry at the University of Connecticut School of Medicine; and Jed E. Rose of the Department of Psychiatry at the Duke University Medical Center and Health System. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, and the University of Connecticut General Clinical Research Center. (Dr. Blomqvist, whose research with rodents provided the rationale for the study in humans, was visiting the University of Connecticut as a postdoctoral fellow from the University of Gothenberg in Sweden.)
Co-authors of the Tizabi paper, “Effects of Combined Systemic Alcohol and Central Nicotine Administration into VTA on Dopamine Release in the Nucleus Accumbens,” included: Robert L. Copeland, Jr., Vely A. Louis, and Robert E. Taylor of the Department of Pharmacology in the College of Medicine at Howard University. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, and the Office of Research on Minority Health.
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