The Reinforcing Effects of Alcohol and Nicotine

by National Institute of Health

(Page 5 of 6)

In animal experiments, reinforcing effects are measured primarily through a test design called operant selfadministration. Laboratory animals learn that performance of a motor task (pressing a lever) results in the administration of a small dose of a drug (an intravenous injection of nicotine or presentation of a dipper containing alcohol). The experiments measure the number of times the animal will perform the motor task to obtain small amounts of the drug. These motor tasks frequently involve complex schedules of task performance and drug presentation. The important aspect is that the lever pressing provides a measure of the motivation to obtain the drug. For example, an animal will perform large numbers of lever presses for one drug dose only if the animal is strongly motivated to obtain the drug. Both alcohol and nicotine are voluntarily self-administered by laboratory animals. For studies assessing alcohol self-administration, however, the situation is complicated by the fact that many animals find the taste of alcohol aversive. Consequently, operant self-administration is normally induced by training the animals to respond for sweet solutions containing alcohol, analogous to the situation in many humans who are introduced to alcohol in the form of sweetened and flavored drinks.

Operant self-administration studies on the interactions between alcohol and nicotine have not given consistent results. Thus, nicotine injections decreased self-administration of alcohol. However, an agent that counteracted nicotine's effects (a nicotine antagonist) called mecamylamine had a similar effect on alcohol self-administration. Chronic infusion of certain doses of nicotine, however, increased operant self-administration of alcohol.

One aspect that should be taken into consideration here is that a large proportion of such research has concentrated on psychostimulant drugs, amphetamine, and cocaine. Animals will press levers at high rates to obtain intravenous injections of these drugs, and this is reflected in the experimental designs. Alcohol and nicotine have been said to possess weaker reinforcing properties, because they do not support such high rates of responding. The human evidence indicates clearly the high-dependence liability of both nicotine and alcohol, however, and it is possible that the apparently weaker test effects of alcohol and nicotine reflect the fact that the experimental designs are not optimal for these drugs. Stolerman and Jarvis have pointed out that research on the reinforcing actions of nicotine was many years behind that on other drugs, and it appears that despite improvements, this is still the case.

Neuronal Mechanisms Involved in Dependence

To what extent do we understand the underlying neuronal changes responsible for the reinforcing and rewarding effects of alcohol and nicotine and their capacity to produce dependence? One brain system frequently implicated in the reinforcing effects of drugs is the mesolimbic dopamine system, which includes the ventral tegmental area, the nucleus accumbens, and the prefrontal cortex. Substantial evidence indicates that this system plays an important role in the motivation of animals (including humans) to obtain natural rewards, such as food or sex, although not in the consummatory behavior subsequent to gaining such rewards. Although the initial target sites for alcohol and nicotine differ, these drugs both increase the activity of mesolimbic dopaminergic neurons, albeit through different mechanisms. Neurochemical dopamine depletion in the nucleus accumbens decreases operant selfadministration of nicotine by rodents and the acquisition of self-administration of alcohol. However, both dopamine antagonists and dopamine agonists (agents that act like dopamine) have been reported to decrease responding for alcohol. The role of mesolimbic dopaminergic transmission in the reinforcing effects of alcohol is therefore somewhat uncertain. In addition, the dopamine antagonist haloperidol did not prevent the effect of alcohol in conditioned place preference.

Recent studies have suggested that the mesolimbic dopamine system is more concerned with the importance of environmental stimuli and the choice of behavioral responses to these stimuli. Dopaminergic neurons respond more strongly to novel stimuli than to predictable stimuli. In the case of drug dependence, the drugs may produce similar effects on dopamine as does an important stimulus, and thus the drugs themselves become the focus of attention. Researchers do not yet understand, however, how those changes in dopamine transmission take place during the development of drug dependence. It is also worth considering whether rodents that self-administer alcohol are actually dependent on the drug. For example, the animals do not usually show overt signs of behavioral changes or drug seeking when the drug is not available, although they may respond to cues that they have previously associated with the drug.

Some studies have investigated the role of the mesolimbic dopamine system in the interaction between alcohol and nicotine. Blomqvist and colleagues found that the nicotine antagonist mecamylamine, when injected either into peripheral parts of the body or directly into the ventral tegmental area, could prevent alcohol's effects on the mesolimbic dopamine system. Prior nicotine administration increased the effects of alcohol on that system. These findings suggest that alcohol's actions on the mesolimbic dopamine system involve the activation of nicotine receptors. How these effects relate to alcohol consumption is uncertain, however; as described previously, the effects of nicotine and nicotinic antagonists on operant selfadministration of alcohol by rodents are complex.

Another group of brain chemicals thought to be intimately involved in mechanisms of reward and possibly of reinforcement are the endogenous opiates (enkephalins). Alcohol consumption in both laboratory rodents and alcoholics is decreased by administration of an opiate antagonist, such as the medication naltrexone, which has some efficacy in the treatment of alcoholics. There appears to be some interaction between endogenous opiates and the mesolimbic dopaminergic system, because the alcohol-induced release of dopamine in the nucleus accumbens is blocked by opiate antagonists. The use of opiate antagonists in nicotine dependence has not yet proved beneficial, although experimental interactions have been reported and this line of approach is being pursued.

Withdrawal from chronic intake of alcohol or nicotine decreases the release of dopamine in the nucleus accumbens. It has been suggested that such decreased mesolimbic activity causes a lack of ability to experience pleasure (anhedonia) and that this effect is involved in drug dependence. However, a simple decrease in mesolimbic activity would be expected to lower the ability of drugs to produce rewarding effects. In contrast, recent evidence indicates that changes in the mesolimbic system continue beyond the acute phase of withdrawal, at least in the case of alcohol. It is possible that a decrease in baseline activity of this system could occur in conjunction with increased activation in response to drugs; such an alteration could be involved in relapse to drug taking.

About the Author

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