sign in sign up
<<
Home , Euphoria, Nicotine

Behavioral Mechanisms Underlying the Link Between and Drinking

Hilary J. Little, Ph.D.

Many people use both and (i.e., and other products). The behavioral effects of these two differ, and they do not act on the same target sites in the , although they may share, or partly share, certain properties. The initiation of alcohol or nicotine use may be precipitated by similar personality characteristics in the user, such as impulsivity and sensation seeking. Moreover, the mechanisms underlying the development of dependence may be similar for alcohol and nicotine. Thus, certain factors, such as reinforcing effects, conditioning processes, automatic behavior, and stress, may influence the development of dependence on both drugs. Other factors, such as tolerance and sensitization to the drugs’ actions and the development of withdrawal symptoms, may also contribute to dependence. This review discusses the actions of the two drugs on certain brain chemical (i.e., ) systems and the extent to which the effects of the two drugs may interact. KEY WORDS: nicotine; neurobehavioral theory of AODU (alcohol or other drug [AOD] use, abuse, and dependence); synergistic ; impulsive behavior; sensation- seeking behavior; beneficial vs. adverse drug effect; AOD tolerance; AOD sensitivity; stress as an AODC (cause of AOD use, abuse, and dependence); tension reduction theory of AODU

he use of drugs1 outside clinical and . Whenever the drugs’ acute pharmacological effects, medicine is motivated by many possible, these discussions highlight the such as relief of or stress and Tfactors, including experimenta- mechanisms that may account for alco- induction of (see figure 1). tion, peer pressure, self- for hol and nicotine co-dependence. These effects result from the drugs’ actions psychological problems (e.g., anxiety and on various brain chemical (i.e., neuro- ), and dependence. Therefore, transmitter) systems in the central ner- the strong association between alcohol Behavioral Mechanisms vous system (CNS). These initial target consumption and smoking is Involved in the Initiation sites in the CNS for alcohol and nico- also likely to be attributable to multiple of Drinking and Smoking tine differ in many respects. Nicotine factors, including pharmacological actions interacts with specific “docking molecules” common to both alcohol and nicotine. (i.e., protein receptors) on the surface This article first explores the reasons Acute Behavioral Effects of certain nerve cells (i.e., ). In underlying initiation of drug use, such as of Nicotine and Alcohol the pharmacological effects of alcohol HILARY J. LITTLE, PH.D., is a professor of and nicotine, then reviews the behav- The reasons why most people initially2 and heads the Drug ioral mechanisms involved in alcohol experiment with drugs are related to Dependence Unit, Psychology Department,

1The term “drug” refers to both alcohol and other licit and 2In this article, the term “initial use” refers to the first few Durham University, Durham, United illicit drugs, including tobacco (i.e., nicotine). times a person or animal uses a drug, not just the first time. Kingdom.

Vol. 24, No. 4, 2000 215 contrast, alcohol produces selective actions • At higher doses, nicotine has been • Higher alcohol doses have effects on several neurotransmitter systems. reported to have a effect ranging from intoxication and seda- (For more information on these actions, on mood and , although this tion to general anesthesia. see the section “Neuronal Mechanisms effect is not as pronounced as that Involved in Dependence” on p. 221 of of alcohol. The increased ability to concentrate this article). after nicotine ingestion is thought to be The acute behavioral effects of alco- • Low alcohol doses cause such effects one reason underlying its use by . hol and nicotine and the interactions as a decrease in the normal social Studies in humans have also shown that between these effects have been described of behavior, loss nicotine decreases the proper- in detail (Perkins 1997). As with all of motor control, incoordination, ties of alcohol (Perkins 1997), an effect drugs that act on the CNS, these effects and increased reaction times. These that may promote the combined intake are crucially determined by the behavioral effects of alcohol gener- of the two drugs. that is taken,3 as follows: ally are not shared by nicotine, with The possible presence of a with- the possible exception of a decrease drawal state and the influence of such a • At lower doses, nicotine has an in inhibitory control of behavior that state on measurements must be consid- alerting effect, resulting in increased has been suggested by some experi- ered when assessing the acute effects of and improved concentration. mental results (Olausson et al. 1999). alcohol and nicotine. This influence may

A. Reasons for and consequences of initial alcohol use

Self-medicationSelf-medication (e.g.,(e.g., forfor anxietyanxiety andand depression)depression) EuphoricEuphoric (i.e.,(i.e., rewarding)rewarding) effectseffects ofof alcoholalcohol ImpulsivityImpulsivity SensationSensation seekingseeking PeerPeer pressurepressure

Initial alcohol use

Social use of on alcohol

B. Reasons for and consequences of tobacco (i.e., nicotine) use

Self-medicationSelf-medication (e.g.,(e.g., forfor anxietyanxiety andand depression)depression) ImpulsivityImpulsivity SensationSensation seekingseeking PeerPeer pressurepressure

Initial tobacco use

Social use of tobacco Dependence on nicotine

Figure 1 Reasons for and consequences of initial use of alcohol (A) and tobacco (i.e., nicotine) (B). Several factors can motivate a person to drink or smoke during the initial phase (i.e., the first few times) of alcohol or tobacco use. Among drinkers, the majority of people develop a pattern of social drinking; only a minority of drinkers becomes dependent on alcohol. Conversely, the vast majority of smokers become nicotine dependent; only a few smokers maintain a pattern of social use. The thickness of the arrows reflects the proportion of people that develop the drinking and smoking patterns indicated.

216 Alcohol Research & Health Behavioral Mechanisms differ for alcohol and nicotine, because In animal experiments, researchers experiments, where one cannot directly the rate with which people develop have assessed the effects of measure such as euphoria, dependence on these drugs differs. Thus, both alcohol and nicotine using the rewarding effects are defined as those dependence on nicotine appears to elevated plus maze test. In that test, drug actions that promote approach develop rapidly (i.e., possibly within rodents are placed in a plus-shaped behavior. months). Moreover, high proportions maze that is elevated above the ground. People commonly report euphoria of people who try nicotine become Of the four arms of the maze, two are after drinking alcohol, although the extent dependent on it. In contrast, alcohol open and two are enclosed. The inves- depends on the social setting. This dependence develops more slowly (i.e., tigators then measure the amount of effect is frequently given as an impor- normally over several years) and is seen in time the animals spend in the enclosed tant reason for the social use of alcohol. only a small proportion of people who or open arms of the maze. Because open Smokers also have described euphoria regularly drink alcohol. Consequently, spaces are a potentially threatening from cigarettes. This effect, however, is in studies evaluating the effects of these environment for rodents, an increase in not necessarily produced in people who drugs (e.g., in volunteer populations), the time spent in the open arms after do not use nicotine regularly and may investigators must consider the extent drug administration is thought to reflect be attributable to removal of the unpleas- to which the subjects are dependent an anxiolytic drug action, although this ant experience of on the drugs. For example, people who assumption is not entirely uncontrover- rather than an intrinsic euphoric action regularly smoke cigarettes are likely sial (Olausson et al. 1999). Both alco- of nicotine. to be dependent on nicotine, and this hol and nicotine have positive effects In animal experiments, rewarding dependence may influence the effects in this test. Furthermore, these effects properties of drugs are tested using an of nicotine when the volunteers have may be additive—that is, when alcohol experimental design called conditioned been asked to stop smoking, even for and nicotine are used together, the anx- place preference, which measures the a couple of days. This finding is partic- iolytic effect is greater than when either extent to which a rodent chooses to be ularly relevant to the estimation of the drug is used alone (Onaivi et al. 1989). in a location where it has previously anxiety-reducing and euphoric effects Other studies, however, have suggested experienced the effects of a drug. This of nicotine. Conversely, many people that nicotine has an anxiogenic effect. experimental design has the advantage who use alcohol regularly do not show The occurrence of both clinical that the test measurements are made in symptoms of dependence, and thus depression and dependence on drugs in the absence of the drug; therefore, such abstinence from alcohol for a few days the same person (i.e., comorbidity) is drug effects as motor impairment or will have a lesser influence on the acute common, and depression may be a sedation do not confound the results. actions of alcohol in volunteers. contributing factor in the development However, the procedure normally of both nicotine dependence and exces- requires repeated drug administration sive alcohol use. In many cases, how- to produce the association between the Anxiety-Reducing and ever, it is difficult to determine whether place in which the animal is located Effects pre-existing depression leads to excessive and the effects of the drug (i.e., condi- of Alcohol and Nicotine drug use and dependence or whether tioning). Consequently, adaptive changes Many people use drugs for self-medica- depression is the result of drug use in brain function may occur during tion of psychological problems, and both (Markou et al. 1998). Animal experi- this procedure, and the test results may alcohol and nicotine have been sug- ments that are thought to predict not reflect initial drug effects. gested to have anxiety-reducing (i.e., antidepressant properties of drugs have Both alcohol and nicotine have been anxiolytic) and antidepressant effects. suggested that both alcohol and nico- shown to cause approach behavior to The use of alcohol for the relief of anxi- tine may have such an effect (Ciccocioppo the paired environment in the condi- ety, particularly in social situations, was et al. 1999; Semba et al. 1998). The tioned place preference test. For nicotine, described many years ago in the “tension- mechanisms underlying these effects, a complex relationship exists in these reduction” hypothesis. Nicotine has also and whether the combination of alco- studies between the nicotine dose admin- been said to have anxiolytic properties; hol and nicotine has a greater effect istered and the effects in the test. For however, these properties have been than either drug alone, however, have alcohol, conditioned place preference observed primarily in nicotine-dependent not been thoroughly investigated. has been reported to occur only after people, in whom the drug may act by longer periods of conditioning than are preventing or relieving the anxiety- required for other psychostimulant Production of Euphoria drugs (e.g., ), and differ- producing (i.e., anxiogenic) effects caused and the Rewarding Effects ences among species have been found. by nicotine withdrawal. of Alcohol and Nicotine Thus, it can be difficult to produce such The term “euphoria” describes the an effect in rats, whereas an effect can 3Because most of these effects were observed in animal pleasant , or “high,” produced be seen in mice after relatively short studies, one cannot convert measures, such as “high” or “low” alcohol or nicotine doses, into easily quantifiable by many drugs and is considered a conditioning periods. There has been units, such as drinks or cigarettes smoked. rewarding effect in humans. In animal limited investigation of the extent to

Vol. 24, No. 4, 2000 217 which the combination of alcohol and Aversive Effects of The association between impulsivity nicotine shows additive effects in this test. Alcohol and Nicotine and alcohol and nicotine use has two important aspects. The first aspect is the Relatively strong evidence indicates Both alcohol and nicotine frequently extent to which an individual’s innate that the acute euphoric actions of alco- have unpleasant effects that are aversive hol contribute to its use in humans, impulsive behavior results in increased (e.g., ) and which depend on the alcohol or nicotine use, often despite although evidence of this same effect dose of and previous experience with from nicotine is weaker. It will be impor- knowledge of the adverse consequences. the drug. For both drugs, the aversive Dependence on both alcohol and on tant for researchers to establish whether properties, at least in part, result from using alcohol and nicotine in combina- nicotine has been found to be associated irritation of the stomach. Some of alco- with high levels of impulsivity (Poulos tion increases the euphoric, and there- hol’s unpleasant effects are caused by fore rewarding, actions of these drugs et al. 1998; Mitchell 1999). This impul- , the first breakdown product sivity is thought to contribute to the or whether concomitant alcohol drink- (i.e., metabolite) of alcohol. However, ing may perhaps result in a euphoric person’s initial use of the drugs and these two factors may not explain all possibly to the development of depen- effect of nicotine in humans that is not the aversive effects of nicotine and alco- dence. The second aspect is the propen- seen when nicotine is used alone. hol. The development of tolerance to sity of the drugs themselves to increase There has, however, been little exper- these aversive effects may be a con- impulsivity. There is little direct evidence imental investigation of such interactions tributing factor in the continued use of that nicotine affects impulsivity. Alcohol in humans. In one study, participants both alcohol and nicotine. Laboratory consumption has resulted in increases reported greater subjective enjoyment evidence suggests that administration in measurements of impulsivity (Poulos of cigarettes during alcohol consumption, of either alcohol or nicotine and devel- et al. 1995). An increase in impulsive although this finding was not reflected opment of tolerance to its aversive effects behavior caused by alcohol consump- in their subsequent preferences for can also decrease the conditioned tion would be expected to increase cigarettes that were similar (i.e., of the aversion to the other drug (Kunin et al. cigarette smoking during drinking. same color) to those they had smoked 1999). If confirmed in humans, this Sensation seeking is defined as an while under the influence of alcohol phenomenon, which is called cross- individual’s for novel or arousing (Glautier et al. 1996). Experimental inves- tolerance, may have important implica- experiences. Studies in humans have tigation of nicotine’s euphoric effects in tions for the combined use of nicotine found strong correlations between high humans is complicated both by the need and alcohol in humans. ratings of sensation seeking and experi- to remove the potentially confounding mental use of drugs, including alcohol effects of nicotine withdrawal if tests are Impulsivity and Sensation Seeking and nicotine (Zuckerman 1994). It is conducted on smokers and by the ethical as yet unclear whether sensation seek- considerations (i.e., the strong potential Two additional factors involved in the ing also promotes the concurrent use for inducing dependence) of examining initiation of drug use are impulsivity of alcohol and nicotine, although this the behavioral effects of nicotine in and sensation seeking. The term appears likely. Similarly, researchers have nonsmokers. “impulsivity” describes an individual’s not yet identified the neurochemical tendency to make rapid behavioral Another experimental design thought basis of the association between sensa- changes regardless of detrimental con- to be related to rewarding properties tion seeking and drug use. It has been sequences or the loss of a later reward of drugs is intracranial self-. suggested that brain signaling pathways of greater magnitude (e.g., taking a drug involving the Animals will voluntarily press a lever despite knowing the potential adverse to receive an electrical stimulation from and serotonin may a role. In addi- effects on health or wealth). In labora- tion, the effects of alcohol and nicotine electrodes implanted in certain brain tory animals, researchers can measure on stress (which are discussed areas, particularly the hypothalamus and the degree of impulsivity by comparing in the section “The Influence of Stress” the . Conversely, whether rodents preferentially press a lever on p. 222 of this article) may be involved the animals show no apparent to receive a larger, delayed food reward both in the initial use of these drugs in or even actively avoid stimulation of or a smaller, rapidly available reward. an experimental way—for example, by many other areas of the CNS. Drugs, Another strategy to assess impulsivity adolescents—and in the continued including both alcohol and nicotine, (called differential of low drug use during dependence. lower the thresholds for such self- rate responding [DLR]) involves tests stimulation (i.e., the threshold at which in which low rates of responding are such responding is initiated). Schaefer selectively rewarded. Researchers have Mechanisms of Dependence and Michael (1992) found additive identified several different forms of effects of alcohol and nicotine on self- impulsivity, at least some of which involve The American Psychiatric Association stimulation of the lateral hypothalamus, reduced transmission of nerve signals (1994) has defined specific criteria for a but only with one dose combination of involving the neurotransmitter 5-HT diagnosis of dependence in its Diagnostic the two drugs. (also known as serotonin). and Statistical Manual of Mental Disorders,

218 Alcohol Research & Health Behavioral Mechanisms

Fourth Edition (DSM–IV). These crite- anisms of dependence, or whether the when these drugs are taken repeatedly ria include the development of toler- difficulties of giving up smoking in addi- or over long periods (see figure 2). As ance and the appearance of withdrawal tion to alcohol may make life harder previously described, the rate of devel- symptoms when drug consumption is and create a more stressful situation opment of dependence on nicotine is discontinued after prolonged heavy for the alcoholic. No extensive evidence faster than that on alcohol, and the use. Other criteria describe the pattern regarding these issues exists to date; neuroadaptive changes need to be eval- of compulsive use that is the predomi- however, several studies have indicated uated in this context. To what extent nant characteristic of dependence on that giving up smoking as well as drink- tolerance contributes to the develop- drugs, together with its long-term nature. ing does not reduce abstinence rates ment of dependence on alcohol and Thus, addicts can revert to drug taking from alcohol and that it may actually nicotine is a matter of debate. Tolerance and frequently experience all the symp- be beneficial to abstain from both alco- to the unpleasant effects of a drug, toms of dependence after weeks, months, hol and nicotine simultaneously which is thought to develop with both or even years of abstinence. Such relapse (Breslau et al. 1996). alcohol and nicotine, is likely to increase occurs with both alcohol and nicotine, Researchers must learn more about drug use, as described earlier in this and it is important from a clinical per- the mechanisms underlying the depen- article. Tolerance to the pleasant effects spective to know whether the contin- dence on alcohol and nicotine to maxi- of a drug, which develops at least with ued use of one drug affects the patient’s mize the success of treatment for both alcohol, also may result in the drug success in abstaining from the other . Some of those mechanisms being taken in larger doses in order to drug. For example, alcoholics attempt- are described in the following sections. achieve the same effect. Furthermore, ing to abstain from alcohol most com- cross-tolerance between the behavioral monly continue smoking. Accordingly, Tolerance and Sensitization effects of alcohol and nicotine has been clinicians need to know whether this After Prolonged Use seen in experimental studies—that is, continued smoking has adverse effects animals that develop tolerance to the on abstinence from alcohol, as might The effects of alcohol and nicotine on effects of one drug may also become be the case if there are common mech- brain neurons and on behavior change tolerant to the effects of the other drug (e.g., Collins et al. 1993)—but the sit- uation is complex and depends on the measurement and the strain of rodent. Initial use of alcohol and/or tobacco (i.e., nicotine) In recent years much attention has been paid to sensitization, which is an increase in the effects of drugs of depen- Neuroadaptive changes dence, including alcohol and nicotine, Reinforcement seen after repeated intake. This sensiti- Habit formation zation is a long-lasting effect and there- fore is a prime candidate for the pro- longed nature of dependence. There is Repeated social use considerable uncertainty, however, as to whether sensitization occurs in humans. The “incentive-sensitization” theory of Robinson and Berridge (1993) sug- Dependence gested that the “incentive salience” (i.e., the importance to an individual) of Withdrawal drugs of dependence and of stimuli associated with the drugs increases as Relapse these drugs are taken repeatedly and therefore acquire strong motivating Abstinence properties and control over behavior. Animal studies have focused primarily on sensitization to the effects of drugs Figure 2 Consequences of continued alcohol and tobacco (i.e., nicotine) use. on locomotor activity. Sensitization to During the initial use of alcohol and tobacco, changes in the activity of nerve cells (i.e., neuroadaptive changes) occur, resulting in reinforce- the locomotor actions of both ment and habit formation. These changes lead to repeated social use, nicotine and alcohol occurs in experi- which may result in dependence in some people. In those people, mental animals, although with consid- sudden abstinence from alcohol or nicotine leads to withdrawal symp- erable strain differences in the case of toms, which cease during prolonged abstinence. However, even after alcohol. Researchers also have reported prolonged abstinence, relapse may occur. cross-sensitization between drugs, includ- ing those from different pharmacological

Vol. 24, No. 4, 2000 219 classifications, such as psychostimulants tigation of behavioral and neurochemi- an intravenous injection of nicotine and opiates. Chronic alcohol consump- cal changes that occur or persist at or presentation of a dipper containing tion was found to increase the locomotor longer times into the abstinence period. alcohol). The experiments measure the activity following repeated injections of Conditioned withdrawal (which is dis- number of times the animal will perform nicotine (Watson and Little 1999). If a cussed in the section “Conditioning the motor task to obtain small amounts similar situation existed in humans (i.e., and Automatic Behavior” on p. 222 of of the drug. These motor tasks frequently if prior alcohol consumption could this article) can also occur after consid- involve complex schedules of task per- enhance the effects of nicotine), this erable duration of abstinence. formance and drug presentation. The would have important implications for important aspect is that the lever press- the combined use of the two drugs. The Reinforcing Effects ing provides a measure of the motiva- of Alcohol and Nicotine tion to obtain the drug. For example, Withdrawal Symptoms an animal will perform large numbers Reinforcing effects are those actions of of lever presses for one drug dose only The appearance of a withdrawal syn- drugs that increase the relationship if the animal is strongly motivated to drome after cessation of long-term drug between a stimulus (e.g., presentation obtain the drug. Both alcohol and consumption is an important criterion of an alcoholic beverage) and a response nicotine are voluntarily self-adminis- in the diagnosis of dependence and in (e.g., drinking). In behavioral terms, a tered by laboratory animals. For studies the definition of a drug’s dependence reinforcing effect of a drug will promote assessing alcohol self-administration, liability. The importance of the with- the behavior that preceded the stimu- however, the situation is complicated drawal syndrome in the genesis of depen- lus. These reinforcing properties of drugs by the fact that many animals find the dence, however, is now uncertain. The are often confused with, and equated taste of alcohol aversive. Consequently, acute manifestations of withdrawal dif- with, the rewarding effects of drugs, operant self-administration is normally fer for nicotine and alcohol. , which have been discussed earlier. How- induced by training the animals to convulsion, and hallucinations are evi- ever, the two properties are not identi- respond for sweet solutions containing dent following cessation of long-term cal, and the distinction has been elegantly alcohol, analogous to the situation in alcohol consumption, whereas nicotine discussed by White (1989). “Reward” many humans who are introduced to withdrawal is associated predominantly involves of and there- alcohol in the form of sweetened and with , sleep disturbances, and fore describes the hedonic or euphoric flavored drinks. hunger. There is some similarity, how- effects of drugs, whereas “reinforcement” Operant self-administration studies ever, in the occurrence of anxiety and refers to the relationship between the on the interactions between alcohol unhappiness (i.e., ) in both behavior and the stimulus (in this and nicotine have not given consistent syndromes. It is still unknown whether instance, the drug). Many drugs that results. Thus, nicotine injections decreased simultaneous withdrawal from alcohol cause dependence have both reinforc- self-administration of alcohol (Nadal and nicotine results in a more severe ing and rewarding effects, but the rein- and Samson 1999; Nadal et al. 1998). syndrome than withdrawal from each forcing actions need not involve pleas- However, an agent that counteracted drug separately. Some laboratory evidence ant or euphoric effects, and some rein- nicotine’s effects (i.e., a nicotine antag- suggests, however, that this may indeed forcing stimuli are actually aversive. onist) called had a sim- be the case (e.g., Onaivi et al. 1989). Negative reinforcement occurs when ilar effect on alcohol self-administra- The symptoms described above are the response involves avoidance of the tion (Nadal et al. 1998). Chronic infu- the subjective feelings seen immediately stimulus and is used to describe the sion of certain doses of nicotine, how- after withdrawal from chronic intake of situation when a drug is taken to remove ever, increased operant self-administra- the drugs and last a relatively short time the unpleasant effects of drug with- tion of alcohol (Clark et al. 1998). after cessation of drug use. The com- drawal. Reinforcement has been equated One aspect that should be taken pulsive drug taking, however, lasts far with memory and learning; however, into consideration here is that a large longer, which has led many researchers whereas nicotine can improve memory proportion of such research has con- to discount withdrawal as an important and learning, alcohol, over the dose centrated on psychostimulant drugs, factor in dependence, although addicts range normally consumed by humans, amphetamine, and . Animals often report taking drugs to remove the does not have this action and at high will press levers at high rates to obtain subjectively unpleasant experience of doses is amnesic (i.e., causes memory intravenous injections of these drugs, withdrawal as a major reason to continue impairment). and this is reflected in the experimental drug taking. In addition, treatment of In animal experiments, reinforcing designs. Alcohol and nicotine have the acute withdrawal symptoms does effects are measured primarily through been said to possess weaker reinforcing not prevent dependence on drugs. The a test design called operant self- properties, because they do not support importance of withdrawal signs, how- administration. Laboratory animals learn such high rates of responding. The ever, depends on the duration of with- that performance of a motor task (e.g., evidence indicates clearly the drawal that is considered, and recently pressing a lever) results in the adminis- high-dependence liability of both nico- attention has been turning to the inves- tration of a small dose of a drug (e.g., tine and alcohol, however, and it is

220 Alcohol Research & Health Behavioral Mechanisms

possible that the apparently weaker test (see figure 3). Substantial evidence alcohol is therefore somewhat uncer- effects of alcohol and nicotine reflect indicates that this system plays an tain. In addition, the dopamine antag- the fact that the experimental designs important role in the motivation of onist haloperidol did not prevent the are not optimal for these drugs. Stolerman animals (including humans) to obtain effect of alcohol in conditioned place and Jarvis (1995) have pointed out that natural rewards, such as food or sex, preference (Cunningham et al. 1992). research on the reinforcing actions of although not in the consummatory Recent studies have suggested that the nicotine was many years behind that on behavior subsequent to gaining such mesolimbic dopamine system is more other drugs, and it appears that despite rewards. Although the initial target sites concerned with the importance of improvements, this is still the case. for alcohol and nicotine differ, these drugs environmental stimuli and the choice both increase the activity of mesolimbic of behavioral responses to these stimuli. Neuronal Mechanisms neurons, albeit through Dopaminergic neurons respond more Involved in Dependence different mechanisms. Neurochemical strongly to novel stimuli than to pre- dopamine depletion in the nucleus dictable stimuli (Schultz 1997). In the To what extent do we understand the accumbens decreases operant self- case of drug dependence, the drugs may underlying neuronal changes responsible administration of nicotine by rodents produce similar effects on dopamine as for the reinforcing and rewarding effects (Stolerman and Shoaib 1991) and the does an important stimulus, and thus of alcohol and nicotine and their capac- acquisition of self-administration of alco- the drugs themselves become the focus ity to produce dependence? One brain hol. However, both dopamine antago- of attention. Researchers do not yet system frequently implicated in the nists and dopamine (i.e., agents understand, however, how those changes reinforcing effects of drugs is the mesolim- that act like dopamine) have been reported in dopamine transmission take place bic dopamine system, which includes to decrease responding for alcohol. The during the development of drug depen- the ventral tegmental area, the nucleus role of mesolimbic dopaminergic trans- dence. It is also worth considering accumbens, and the prefrontal cortex mission in the reinforcing effects of 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 Prefrontal cortex is not available, although they may respond to cues that they have previ- (terminals of dopamine- ously associated with the drug. releasing cells) Some studies have investigated the role of the mesolimbic dopamine sys- tem in the interaction between alcohol and nicotine. Blomqvist and colleagues (1997) found that the nicotine antago- (terminals of dopamine- nist mecamylamine, when injected releasing cells) either into peripheral parts of the body or directly into the ventral tegmental area, could prevent alcohol’s effects Nicotine increases Ventral tegmental area on the mesolimbic dopamine system. dopamine release. (cell bodies of dopamine- Prior nicotine administration increased releasing cells) the effects of alcohol on that system (Blomqvist et al. 1993). These findings ¥ Alcohol activates neurons directly and suggest that alcohol’s actions on the indirectly. mesolimbic dopamine system involve ¥ Nicotine acts on certain molecules located the activation of nicotine receptors. How on neurons (i.e., nicotinic receptors). these effects relate to alcohol consump- tion is uncertain, however; as described previously, the effects of nicotine and Figure 3 Effects of alcohol and nicotine on the mesolimbic dopamine system. nicotinic antagonists on operant self- Dopamine is a brain chemical believed to play an important role in . The mesolimbic dopamine system includes three brain regions: the ventral administration of alcohol by rodents tegmental area, nucleus accumbens, and prefrontal cortex. The ventral are complex. tegmental area contains dopamine-releasing nerve cells (i.e., neurons). The Another group of brain chemicals extensions of those neurons lead into the nucleus accumbens and prefrontal thought to be intimately involved in cortex, where they release dopamine to activate other neurons. The mechanisms of reward and possibly of actions of alcohol and nicotine in these brain areas are shown in italic. reinforcement are the endogenous opi- ates (e.g., enkephalins). Alcohol con-

Vol. 24, No. 4, 2000 221 sumption in both laboratory rodents physiological responses to alcohol and rapidly, without conscious awareness and alcoholics is decreased by adminis- nicotine), and conditioned responses are or involvement of cognitive processes. tration of an opiate antagonist, such as then seen in the absence of the drug. Such processes form a stereotypic series the medication , which has Such responses can be either in the of actions that is difficult to halt. It some efficacy in the treatment of alco- opposite direction to the drug’s effects, has been suggested that automatic pro- holics (Volpicelli et al. 1995). There causing tolerance, or in the same direc- cesses contribute to the dependence appears to be some interaction between process (Tiffany 1990). According to endogenous opiates and the mesolim- this theory, repeated association of drug bic dopaminergic system, because the effects with drug-taking behavior alcohol-induced release of dopamine causes incremental strengthening of the in the nucleus accumbens is blocked by Traumatic life stimulus-response relationship, resulting opiate antagonists (Benjamin et al. 1993). in drug taking becoming an automatic The use of opiate antagonists in nico- events and chronic process. Such processes may contribute tine dependence has not yet proved stressful experiences particularly to nicotine dependence, beneficial, although experimental inter- because cigarette smoking involves actions have been reported and this line are associated with stereotyped, ritualistic behavioral pat- of approach is being pursued (Pomer- terns (e.g., taking the cigarette out of leau 1998). the development of the package and lighting it). It is diffi- Withdrawal from chronic intake of both alcohol and cult, however, to reconcile this theory alcohol or nicotine decreases the release with the occurrence of relapse drinking of dopamine in the nucleus accumbens. nicotine dependence. and smoking that continues despite It has been suggested that such decreased the knowledge of serious health conse- mesolimbic activity causes a lack of abil- quences and the adverse reactions on ity to experience pleasure (i.e., anhedo- the part of family and friends, or in sit- nia) and that this effect is involved in uations in which the drug is not easily drug dependence. However, a simple tion, mimicking drug action. Drug- available. In such scenarios, a person decrease in mesolimbic activity would associated cues therefore acquire the abil- would become much more conscious be expected to lower the ability of drugs ity to control behavior, and this effect of his or her behavior (e.g., to obtain a to produce rewarding effects. In contrast, has been suggested to be involved in drug), and thus the behavior would no recent evidence indicates that changes relapse drug taking. longer be automatic. by in the mesolimbic system continue Conditioning factors that contribute alcoholics also does not fit a pattern of beyond the acute phase of withdrawal, to dependence on one drug may increase automatic behavior. The theory also at least in the case of alcohol (Diana et dependence on another drug, and it is posits that during co-dependence of al. 1996; Bailey et al. 1998). It is possi- possible that conditioning factors are alcohol and nicotine, alcohol may act ble that a decrease in baseline activity involved in the cross-tolerance reported as a triggering cue for the automatic of this system could occur in conjunction between some actions of alcohol and behavior leading to nicotine use as well with increased activation in response nicotine. Thus, an increase in locomo- as interfere with nonautomatic process- to drugs; such an alteration could be tor activity in an environment in which ing aimed at the avoidance of smoking involved in relapse to drug taking. mice had previously experienced nicotine (Tiffany 1990). was seen only in animals that had pre- Conditioning and Automatic viously consumed alcohol chronically, The Influence of Stress Behavior suggesting that prior chronic alcohol intake may increase conditioned responses One factor common to the use of nico- Conditioning occurs when a stimulus to nicotine (Watson and Little 1999). tine and alcohol is the influence of or cue (e.g., food) that results in a spe- Conditioned withdrawal—that is, stress. Traumatic life events and chronic cific effect (e.g., salivation) is repeatedly the precipitation of withdrawal symp- stressful experiences are associated with paired with a previously unrelated stim- toms by environmental cues previously the development of both alcohol and ulus (e.g., a certain sound). After a associated with the drug—has been nicotine dependence. Stress has also while, the unrelated stimulus becomes reported for alcohol and for nicotine. been reported to precipitate relapse a conditioned stimulus that can evoke This response can be produced at long drug taking (Piazza and Le Moal 1998) the same effect, even in the absence of intervals after cessation of drug use and may conditioning. Stressful the original stimulus. Conditioning is and therefore is likely to contribute experiences result in the release of stress involved in several ways in dependence to relapse drug use during abstinence. hormones called from on both alcohol and nicotine. Environ- With repeated practice, many every- the adrenal glands, which are located mental cues present during drug taking day processes (e.g., getting dressed or on top of the kidneys. The primary (e.g., the sight or smell of a ) become driving a car) become so automatic in humans is cortisol; associated with the drug effect (e.g., that a person can carry them out the corresponding in rodents

222 Alcohol Research & Health Behavioral Mechanisms

is . Laboratory studies ing and reinforcing effects—before co- GLAUTIER, S.; CLEMENTS, K.; WHITE, J.A.W.; AND have shown that corticosterone increases dependence can be fully understood. STOLERMAN, I.P. Alcohol and the reward value of smoking. Behavioural 7:144−154, 1996. alcohol consumption by rodents. Further- more, stress has been shown to reinstate KUNIN, D.; SMITH, B.R.; AND AMIT, Z. Nicotine References and ethanol interaction on conditioned taste aver- operant responding for alcohol and sions induced by both drugs. Pharmacology, Bio- − nicotine after such behavior had been American Psychiatric Association (APA). Diagnostic chemistry and Behavior 62:215 221, 1999. extinguished by cessation of the drug and Statistical Manual of Mental Disorders, Fourth LE, A.D.; QUAN, B.; JUZYSTCH, W.; FLETCHER, presentation (Le et al. 1998; Buczek Edition. Washington, DC: APA, 1994. P.J.; JOHARCHI, N.; AND SHAHAM, Y. Reinstatement of alcohol seeking by priming injections of alcohol et al. 1999). Both alcohol and nicotine BAILEY, C.P.; MANLEY, S.J.; WATSON, W.P.; and exposure to stress in rats. Psychopharmacology increase release of glucocorticoid hor- WONNACOTT, S.; MOLLEMAN, A.; AND LITTLE, − mones, and this effect may contribute H.J. Chronic ethanol administration alters activity 135:169 174, 1998. to their use. Corticosterone has been in ventral tegmental area neurons after cessation of MARKOU, A.; KOSTEN, T.R.; AND KOOB, G.F. shown to be self-administered by rodents withdrawal hyperexcitability. Brain Research 803: Neurobiological similarities in depression and drug 144–152, 1998. dependence: A self-medication hypothesis. Neuro- and therefore may itself have reinforc- psychopharmacology 18:135−174, 1998. ing properties (Piazza et al. 1993). The BENJAMIN, D.; GRANT, E.R.; AND POHORECKY, L.A. Naltrexone reverses ethanol-induced dopamine MITCHELL, S.H. Measures of impulsivity in cigarette effects of glucocorticoid hormones on release in the nucleus accumbens in awake, freely smokers and non-smokers. Psychopharmacology the CNS also may be involved in sensa- moving, rats. Brain Research 621:137–140, 1993. 146:455–464, 1999. tion seeking, a currently speculative but BLOMQVIST, O.; NISSBRANDT, H.; ENGEL, J.A.; NADAL, R., AND SAMSON, H.H. Operant ethanol interesting line of investigation. AND SODERPALM, B. The mesolimbic dopamine- self-administration after nicotine treatment and Long-term changes in the control of activating effects of ethanol are antagonized by withdrawal. Alcohol 17:139−147, 1999. stress hormone release have been demon- mecamylamine. European Journal of Pharmacology 249:207–213, 1993. NADAL, R.; CHAPPELL, A.M.; AND SAMSON, H.H. strated after stressful experiences, and Effects of nicotine and mecamylamine microinjec- these changes may also influence drug- BLOMQVIST, O.; ERICSON, M.; ENGEL, J.A.; AND tions into the nucleus accumbens on ethanol and taking behavior and the development SODERPALM, B. Accumbal dopamine overflow after self-administration. : Clinical and ethanol: Localization of the antagonizing effect of Experimental Research 22:1190–1198, 1998. of dependence. Stress has been found mecamylamine. European Journal of Pharmacology experimentally to cause sensitization to 249:207–213, 1997. OLAUSSON, P.; ENGEL, J.A.; AND SODERPALM, B. drugs and may thus increase their reward- Behavioral sensitization to nicotine is associated with BRESLAU, N.; PETERSON, E.; SHULTZ, L.; ANDRESKI, behavioral : Counteraction by citalo- − ing and/or reinforcing actions and incen- P.; AND CHILCOAT, H. Are smokers with alcohol pram. Psychopharmacology 142:111 119, 1999. tive salience. It is conceivable that changes disorders less likely to quit? American Journal of Public ONAIVI, E.S.; TODD, S.; AND MARTIN, B.R. Health 86:985–990, 1996. in the control of stress hormone release Behavioral effects in the mouse during and follow- caused by alcohol or nicotine may be BUCZEK, Y.; LE, A.D.; WANG, A.; STEWART, J.; AND ing withdrawal from ethanol ingestion and/or nico- involved in co-dependence on both SHAHAM, Y. Stress reinstates nicotine seeking but tine administration. Drug and Alcohol Dependence − drugs, but more information is needed not sucrose solution seeking in rats. Psychopharmacology 24:205 211, 1989. 144:183−188, 1999. before such a link can be validated. PERKINS, K.A. Combined effects of nicotine and alco- Prolonged excess alcohol consumption CICCOCIOPPO, R.; PANOCKA, I.; FROLDI, R.; hol on subjective, behavioral and physiological responses − has been reported to affect hormonal COLOMBO, G.; AND GESSA, G.L. Antidepressant-like in humans. Addiction Biology 2:255 167, 1997. effects of ethanol revealed in the forced swimming responses to stress and to nicotine. PIAZZA, P.V., AND LE MOAL, M. The role of stress test in Sardinian alcohol-preferring rats. Psycho- in drug self-administration. Trends in Pharmacological pharmacology 144:151–157, 1999. Sciences 19:67−74, 1998. CLARK, A.; WATSON, W.P.; AND LITTLE, H.J. Effects Conclusions PIAZZA, P.V.; DEROCHE, V.; DEMINIERE, J-M.; of nicotine infusion on operant self-administration MACCARI, S.; LE MOAL, N.; AND SIMON, H. of ethanol. British Journal of Pharmacology 125:1P, Corticosterone in the range of stress-induced levels Many factors that contribute to the initial 1998. possesses reinforcing properties: Implications for use of both alcohol and nicotine differ sensation-seeking behaviors. Proceedings of the National COLLINS, A.C.; ROMM, E.; SELVAAG, S.; TURNER, Academy of Sciences USA 90:11738−11742, 1993. for the two drugs, but some factors may S.; AND MARKS, M.J. A comparison of the effects of be synergistic. The prolonged nature of chronic nicotine infusion on tolerance to nicotine POMERLEAU, O.F. Endogenous and smok- dependence on both drugs suggests that and cross-tolerance to ethanol in long- and short- ing: A review of progress and problems. Psychoneuro- long-term changes occur in neuronal sleep mice. Journal of Pharmacology and Experimental endocrinology 23:115−130, 1998. Therapeutics 266:1390−1397, 1993. activity and that these may be common POULOS, C.X.; LE, D.A.; AND PARKER, J.L. Impulsivity to both drugs. Considerably more infor- CUNNINGHAM, C.L.; MALOTT, D.H.; DICKINSON, predicts individual susceptibility to high levels of mation is needed, however, about the S.D.; AND RISINGER, F.O. Haloperidol does not alter alcohol self-administration. Behavioural Pharmacology expression of ethanol-induced conditioned place 6:810−814, 1995. behavioral and neurochemical interactions preference. Behavioral Brain Research 50:1−5, 1992. between the two drugs—in particular, POULOS, C.X; PARKER, J.L.; AND LE, D.A. Increased DIANA, M.; PISTIS, M.; MUNTONI, A.; AND GESSA impulsivity after injected alcohol predicts later alco- their effects on impulsivity and sensa- G.L. Mesolimbic dopaminergic reduction outlasts hol consumption in rats: Evidence for “loss of con- tion seeking and in relieving anxiety ethanol withdrawal syndrome: Evidence of pro- trol drinking” and marked individual differences. and depression, as well as their reward- tracted abstinence. Neuroscience 71:411−415, 1996. Behavioral Neuroscience 112:1247−1257, 1998.

Vol. 24, No. 4, 2000 223 ROBINSON, T.E., AND BERRIDGE, K.C. The neural chronic nicotine on learned helplessness paradigm. holism: Predicting responses to naltrexone. Journal basis of drug craving: An incentive-sensitization Biological Psychiatry 43:389−391, 1998. of Clinical Psychiatry 56(Suppl. 7):39−44, 1995. theory of addiction. Brain Research and Brain Research STOLERMAN, I.P., AND JARVIS, M.J. The scientific WATSON, W.P., AND LITTLE, H.J. Effects of chronic Reviews 18:247−291, 1993. case that nicotine is addictive. Psychopharmacology ethanol consumption on responses to nicotine: 117:2−10, 1995. SCHAEFER, G.J., AND MICHAEL, R.P. Interactions Interaction with environmental cues. Neuropharm- between alcohol and nicotine on intracranial self- STOLERMAN, I.P., AND SHOAIB, M. The neurobiol- acology 38:587−595, 1999. stimulation and locomotor activity in rats. Drug ogy of tobacco addiction. Trends in Pharmacological − WHITE, N.H. Reward or reinforcement. What’s the and Alcohol Dependence 30:37−47, 1992. Science 12:467 473, 1991. difference? Neuroscience and Behavioral Reviews TIFFANY, S.T. A cognitive model of drug urges and SCHULTZ, W. Dopamine neurons and their role in 13:181−186, 1989. drug-use behavior: Role of automatic and non- reward mechanisms. Current Opinion in Neurobiology − automatic processes. Psychological Review 97:147 ZUCKERMAN, M. Smoking, drinking, drugs and 7:191−197, 1997. 168, 1990. eating. In: Behavioral Expressions and Biosocial Basis SEMBA, J.; MATAKI, C.; YAMADA, S.; NANKAI, M.; VOLPICELLI, J.R.; CLAY, K.L.; WATSON, N.T.; AND of Sensation Seeking. Cambridge, United Kingdom: AND TORU, M. Antidepressant-like effects of O’BRIAN, C.P. Naltrexone in the treatment of alco- Cambridge University Press, 1994. pp. 225−257.

Are the latest NIAAA Research Monographs in your collection? Each monograph presents research by noted scientists, reviews research progress, and offers a glimpse of future research in key areas. Scientists, clinicians, and others with an interest in alcohol research will find these volumes a welcome addition to their library.

Alcohol and Intracellular Signaling (No. 35) presents research on alcohol’s effects on intracellular signaling pathways and their impli- cations for alcohol-induced organ injury and the development of alcoholism. Topics include: • Biochemical mechanisms of alcoholic disease • The role of genetics in alcoholism vulnerability • The use of animal models to study alcohol’s effects on cellular protein synthesis • Alcohol’s effects on the inflammatory process • Intracellular effects that contribute to fetal alcohol syndrome

Alcohol Epidemiology of Small Geographic Areas (No. 36) reviews progress made over the past decade in the study of alcohol con- sumption and problems in small geographic areas. Topics include: • Estimating rates of alcohol problems within demographic and geographic subgroups • Measuring the severity of psychiatric and addictive disorders • Determining the effectiveness of local prevention programs • Evaluating the relative need for alcoholism treatment services in different communities • Predicting alcohol-related risks on a geographic basis

Supplies are limited. To order your free copies, contact National Institute on and Alcoholism Publications Distribution Center, P.O. Box 10686 Rockville, MD 20849–0686 You may fax your order to (202) 842–0418 or order through NIAAA’s World Wide Web site (www.niaaa.nih.gov).

224 Alcohol Research & Health