Mecamylamine is a central nicotinic receptor antagonist that is believed to reduce the rewarding effects of cigarette smoking. Scientists have suspected for some time that common mechanisms may be involved in both nicotine and alcohol reward. Furthermore, prior research has suggested that mecamylamine blocks the reinforcing effects of alcohol in animals. A new study, published in the May issue of Alcoholism: Clinical & Experimental Research, has found that mecamylamine reduces the self-reported stimulant and euphoric effects of alcohol in humans, and also decreases their desire to drink more.
"Of all the drugs that act in the brain to produce their rewarding effects," said Harriet de Wit, associate professor in the department of psychiatry at the University of Chicago and corresponding author for the study, "alcohol has some of the most complex and varied effects on neurotransmitter receptor systems. One of the receptor systems where alcohol may act is the nicotinic acetylcholine (NACh) receptor system, the same system where nicotine acts. By acting at these NACh receptors, alcohol also increases the activity of another neurotransmitter system, the dopamine system, which is where most drugs are thought to produce their rewarding effects. We hypothesized that mecamylamine would block the effects of alcohol on the NACh receptors which would, in turn, reduce the activity of the dopamine system, resulting in a dampening of the rewarding effects of the alcohol."
Researchers recruited 27 (14 males, 13 females) non-smoking social drinkers to participate in six laboratory sessions lasting roughly four hours each. At the beginning of each session, study subjects received either a placebo or one of two doses of mecamylamine (7.5 or 15 mg), followed two hours later by either an alcohol (0.8 g/kg) or a placebo beverage. For two hours following beverage consumption, physiological and subjective-effect measures were taken at 30-minute intervals. The physiological measures included heart rate and blood pressure; subjective effects included stimulation and euphoria.
"Our findings extend previous observations made in animals," said de Wit, "that alcohol produces its mood-altering effects, in part, through actions on the nicotinic receptor system. These findings also fit nicely with observations that alcohol users are often also smokers, and smokers tend to drink more than non-smokers. This suggests that these associations may have a biological basis, that is, they reflect shared actions on some of the same receptor systems."
Only one other published human study, by authors Ola Blomqvist and Henry Kranzler, has previously examined the effects of mecamylamine on subjective responses to alcohol. The present study expanded on their findings by testing another dose of mecamylamine, and by including a placebo beverage as a control condition.
"Clearly this study extends our findings," said Kranzler, a professor in the department of psychiatry at the University of Connecticut Health Center, "and provides another step in linking pre-clinical, animal findings with the effects of alcohol in humans. The study sample is also larger, which helps to validate our initial findings. It should be noted, however, that as with our study, the humans were healthy subjects, so additional work is needed to evaluate the clinical significance of these findings in heavy drinkers. It is likely, based on other research, that these effects can be extended to heavy drinkers."
Researchers also found some unexpected gender differences in the results.
"First, we found that male subjects reported more of a stimulant effect from the alcohol then the females," said de Wit, "regardless of whether they were pretreated with mecamylamine. Second, mecamylamine reduced the stimulant effects of alcohol more in men. Third, women reported more effects from the mecamylamine alone, specifically, self-reported feelings of sedation." Both de Wit and Kranzler cautioned, however, that these differences may be due to gender differences in pharmacokinetics.
"We gave the women the same amount of alcohol as we gave to the men," said de Wit, "and there is evidence that women attain a higher concentration of alcohol because of differences in body composition. This could have accounted for some of the sex differences we saw in responses to alcohol. We also gave the same dose of mecamylamine to men and women. Although doses of most drugs – except alcohol – are usually not adjusted for sex or body weight, it is possible that the greater response to mecamylamine in the women could be related to their smaller size." Notwithstanding possible gender differences in response to mecamylamine, Kranzler is optimistic about the clinical applications of this study’s findings.
"Developments in the pharmacotherapy of alcoholism have been limited by the paucity of agents with demonstrated effects on alcohol reinforcement," said Kranzler. "This study, in conjunction with other research findings, shows that the nicotinic cholinergic system is a promising one for evaluation as a pharmacotherapeutic target in alcoholism." Kranzler cautioned that "mecamylamine is not particularly well tolerated in high doses … however, other, possibly more selective drugs that are active at the nicotinic receptor are becoming available, and may provide better tolerability."
Next, de Wit and her colleagues plan to examine the effects of nicotine on subjective responses to alcohol. "If our ideas are correct," she said, "nicotine should increase the stimulant-like effects of alcohol. In addition, we are studying whether either mecamylamine or nicotine changes the amount of alcohol subjects consume. In the completed study, we asked subjects how they felt when we administered alcohol with or without mecamylamine. In the planned study, we will instead allow subjects to consume alcohol in the laboratory, and measure the amount consumed, with or without mecamylamine or nicotine."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Chi, H., de Wit, H. (May 2003). Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcoholism: Clinical & Experimental Research, 27(5), 780-787.
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