John was beginning to feel that perhaps he would be able to get his life back together. It looked as though his drug habit was going to be licked. He had started taking drugs several years ago. At first, he had used them only on special occasions—mostly on weekends with his friends—but heroin proved to be his undoing. One of his acquaintances had introduced him to the needle, and John had found the rush so blissful that he couldn’t wait a whole week for his next fix. Soon he was shooting up daily. Shortly after that, he lost his job and, to support his habit, began earning money through car theft and small-time drug dealing. As time went on, he needed more and more heroin at shorter and shorter intervals, which necessitated even more money. Eventually, he was arrested and convicted of selling heroin to an undercover agent.

The judge gave John the choice of prison or a drug rehabilitation program, and he chose the latter. Soon after starting the program, he realized that he was relieved to have been caught. Now that he was clean and could reflect on his life, he realized what would have become of him had he continued to take drugs. Withdrawal from heroin was not an experience he would want to live through again, but it turned out not to be as bad as he had feared. The counselors in his program told him to avoid his old neighborhood and to break contact with his old acquaintances, and he followed their advice. He had been clean for eight weeks, he had a job, and he had met a woman who really seemed sympathetic. He knew that he hadn’t completely kicked his habit, because every now and then, despite his best intentions, he found himself thinking about the wonderful glow that heroin provided him. But things were definitely looking up.

Then one day, while walking home from work, he turned a corner and saw a new poster plastered on the wall of a building. The poster, produced by an antidrug agency, showed all sorts of drug paraphernalia in full color: glassine envelopes with white powder spilling out of them, syringes, needles, a spoon and candle used to heat and dissolve the drug. John was seized with a sudden, intense compulsion to take some heroin. He closed his eyes, trying to will the feeling away, but all he could feel were his churning stomach and his trembling limbs, and all he could think about was getting a fix. He hopped on a bus and went back to his old neighborhood.

Drug addiction poses a serious problem to our species. Consider the disastrous effects caused by the abuse of one of our oldest drugs, alcohol: automobile accidents, fetal alcohol syndrome, cirrhosis of the liver, Korsakoff’s syndrome, increased rate of heart disease, and increased rate of intracerebral hemorrhage. Smoking (addiction to nicotine) greatly increases the chances of dying of lung cancer, heart attack, and stroke; and women who smoke give birth to smaller, less healthy babies. Cocaine addiction can cause psychotic behavior, brain damage, and death from overdose; and competition for lucrative and illegal markets terrorizes neighborhoods, subverts political and judicial systems, and causes many violent deaths. The use of “designer drugs” exposes users to unknown dangers of untested and often contaminated products, as several people discovered when they acquired Parkinson’s disease after taking a synthetic opiate that was tainted with a neurotoxin. (This unfortunate event was described in the opening case of Chapter 5 .) Addicts who take their drugs intravenously run a serious risk of contracting AIDS, hepatitis, or other infectious diseases. What makes these drugs so attractive to so many people?

The answer, as you might have predicted from what you have learned about the physiology of reinforcement in Chapter 13 , is that all of these substances stimulate brain mechanisms responsible for positive reinforcement. In addition, most of them also reduce or eliminate unpleasant feelings, some of which are produced by the drugs themselves. The immediate effects of these drugs are more powerful than the realization that in the long term, bad things will happen.

Common Features of Addiction

The term addiction derives from the Latin word addicere, “to sentence.” Someone who is addicted to a drug is, in a way, sentenced to a term of involuntary servitude, being obliged to fulfill the demands of his or her drug dependency.

A Little Background

Long ago, people discovered that many substances found in nature—primarily leaves, seeds, and roots of plants but also some animal products—had medicinal qualities. They discovered herbs that helped to prevent infections, that promoted healing, that calmed an upset stomach, that reduced pain, or that helped to provide a night’s sleep. They also discovered “recreational drugs”—drugs that produced pleasurable effects when eaten, drunk, or smoked. The most universal recreational drug, and perhaps the first one that our ancestors discovered, is ethyl alcohol. Yeast spores are present everywhere, and these microorganisms can feed on sugar solutions and produce alcohol as a by-product. Undoubtedly, people in many different parts of the world discovered the pleasurable effects of drinking liquids that had been left alone for a while, such as the juice that had accumulated in the bottom of a container of fruit. The juice may have become sour and bad-tasting because of the action of bacteria, but the effects of the alcohol encouraged people to experiment, which led to the development of a wide variety of fermented beverages.

Our ancestors also discovered other recreational drugs. Some of them were consumed only locally; others became so popular that their cultivation as commercial crops spread throughout the world. For example, Asians discovered the effects of the sap of the opium poppy and the beverage made from the leaves of the tea plant, Indians discovered the effects of the smoke of cannabis, South Americans discovered the effects of chewing coca leaves and making a drink from coffee beans, and North Americans discovered the effects of the smoke of the tobacco plant. Many of the drugs they discovered were actually poisons that served to protect the plants from animals (primarily insects) that ate them. Although the drugs were toxic in sufficient quantities, our ancestors learned how to take these drugs in amounts that would not make them ill—at least, not right away. The effects of these drugs on their brains kept them coming back for more. Table 18.1 lists the most important addictive drugs and indicates their sites of action.

Positive Reinforcement

Drugs that lead to dependency must first reinforce people’s behavior. As we saw in Chapter 13 , positive reinforcement refers to the effect that certain stimuli have on the behaviors that preceded them. If, in a particular situation, a behavior is regularly followed by an appetitive stimulus (one that the organism will tend to approach), then that behavior will become more frequent in that situation. For example, if a hungry rat accidentally bumps into a lever and receives some food, the rat will eventually learn to press the lever. What actually seems to happen is that the occurrence of an appetitive stimulus activates a reinforcement mechanism in the brain that increases the likelihood of the most recent response (the lever press) in the present situation (the chamber that contains the lever).

Addictive drugs have reinforcing effects. That is, their effects include activation of the reinforcement mechanism. This activation strengthens the response that was just made. If the drug was taken by a fast-acting route such as injection or inhalation, the last response will be the act of taking the drug, so that response will be reinforced. This form of reinforcement is powerful and immediate and works with a wide variety of species. For example, a rat or a monkey will quickly learn to press a lever that controls a device that injects cocaine through a plastic tube inserted into a vein.

TABLE 18.1 Addictive Drugs

Drug	Sites of Action
Ethyl alcohol	NMDA receptor (indirect antagonist), GABAAreceptor (indirect agonist)
Barbiturates	GABAA receptor (indirect agonist)
Benzodiazepines (tranquilizers)	GABAA receptor (indirect agonist)
Cannabis (marijuana)	CB1 cannabinoid receptor (agonist)
Nicotine	Nicotinic ACh receptor (agonist)
Opiates (heroin, morphine, etc.)	μ and δ opiate receptor (agonist)
Phencyclidine (PCP) and ketamine	NMDA receptor (indirect antagonist)
Cocaine	Blocks reuptake of dopamine (and serotonin and norepinephrine)
Amphetamine and methamphetamine	Causes release of dopamine (by running dopamine transporters in reverse)

Source: Adapted from Hyman, S. E., and Malenka, R. C. Nature Reviews: Neuroscience, 2001, 2, 695–703.

ROLE IN DRUG ABUSE

When appetitive stimuli occur, they usually do so because we just did something to make them happen—and not because an experimenter was controlling the situation. The effectiveness of a reinforcing stimulus is greatest if it occurs immediately after a response occurs. If the reinforcing stimulus is delayed, it becomes considerably less effective. The reason for this fact is found by examining the function of instrumental conditioning: learning about the consequences of our own behavior. Normally, causes and effects are closely related in time; we do something, and something happens, good or bad. The consequences of the actions teach us whether to repeat that action, and events that follow a response by more than a few seconds were probably not caused by that response.

As we saw in Chapter 4 , drug users prefer heroin to morphine not because heroin has a different effect, but because it has a more rapid effect. In fact, heroin is converted to morphine as soon as it reaches the brain. But because heroin is more lipid soluble, it passes through the blood–brain barrier more rapidly, and its effects on the brain are felt sooner than those of morphine. The most potent reinforcement occurs when drugs produce sudden changes in the activity of the reinforcement mechanism; slow changes are much less reinforcing. A person taking an addictive drug seeks a sudden “rush” produced by a fast-acting drug. (As we will see later, the use of methadone to treat opiate addiction and nicotine patches to treat tobacco addiction are based on this phenomenon.)

Earlier, I posed the question of why people would ever expose themselves to the risks associated with dangerous addictive drugs. Who would rationally chose to become addicted to a drug that produced pleasurable effects in the short term but also produced even more powerful aversive effects in the long term: loss of employment and social status, legal problems and possible imprisonment, damage to health, and even premature death? The answer is that, as we saw, our reinforcement mechanism evolved to deal with the immediate effects of our behavior. The immediate reinforcing effects of an addictive drug can, for some individuals, overpower the recognition of the long-term aversive effects. Fortunately, most people are able to resist the short-term effects; only a minority of people who try addictive drugs go on to become dependent on them. Although cocaine is one of the most addictive drugs currently available, only about 15 percent of people who use it become addicted to it (Wagner and Anthony, 2002 ). As we will see later, particular brain mechanisms are responsible for inhibiting behavior that has unfavorable long-term consequences.

If an addictive drug is taken by a slow-acting route, reinforcement can also occur, but the process is somewhat more complicated. If a person takes a pill and several minutes later experiences a feeling of euphoria, he or she will certainly remember swallowing the pill. The recollection of this behavior will activate some of the same neural circuits involved in actually swallowing the pill, and the reinforcement mechanism, now active because of the effects of the drug, will reinforce the behavior. In other words, people’s ability to remember having performed a behavior make it possible to reinforce their behavior vicariously. The immediacy is between an imagined act and a reinforcing stimulus—the euphoria produced by the drug. Other cognitive processes contribute to the reinforcement, too, such as the expectation that euphoric effects will occur. Perhaps someone said, “Take one of these pills; you’ll get a great high!” But if a nonhuman animal is fed one of these pills, its behavior is unlikely to be reinforced. By the time the euphoric effect occurs, the animal will be doing something other than ingesting the drug. Without the ability to recall an earlier behavior and thus activate circuits involved in the performance of that behavior, the delay between the behavior and the reinforcing effect of the drug prevents the animal from learning to take the drug.

NEURAL MECHANISMS

As we saw in Chapter 13 , all natural reinforcers that have been studied so far (such as food for a hungry animal, water for a thirsty one, or sexual contact) have one physiological effect in common: They cause the release of dopamine in the nucleus accumbens (White, 1996 ). This effect is not the only effect of reinforcing stimuli, and even aversive stimuli can trigger the release of dopamine (Salamone, 1992 ). But although there is much that we do not yet understand about the neural basis of reinforcement, the release of dopamine appears to be a necessary (but not sufficient) condition for positive reinforcement to take place.

Addictive drugs—including amphetamine, cocaine, opiates, nicotine, alcohol, PCP, and cannabis—trigger the release of dopamine in the nucleus accumbens (NAC), as measured by microdialysis (Di Chiara, 1995 ). Different drugs stimulate the release of dopamine in different ways. The details of the ways in which particular drugs interact with the mesolimbic dopaminergic system are described later, in sections devoted to particular categories of drugs.

The fact that the reinforcing properties of addictive drugs involve the same brain mechanisms as natural reinforcers indicated that these drugs “hijack” brain mechanisms that normally help us adapt to our environment. It appears that the process of addiction begins in the mesolimbic dopaminergic system and then produces long-term changes in other brain regions that receive input from these neurons (Kauer and Malenka, 2007 ). The first changes appear to take place in the ventral tegmental area (VTA). Saal et al. ( 2003 ) found that a single administration of a variety of addictive drugs (including cocaine, amphetamine, morphine, alcohol, and nicotine) increased the strength of excitatory synapses on dopaminergic neurons in the VTA in mice. This change appears to result from insertion of additional AMPA receptors into the postsynaptic membrane of the DA neurons (Mameli et al., 2009 ). As we saw in Chapter 13 , this process, normally mediated by glutamatergic NMDA receptors, is the neural basis of many forms of learning. A single injection of an addictive drug produces synaptic strengthening in the VTA that lasts for about five days. If an animal receives cocaine for about two weeks, the changes in the VTA persist.

As a result of the changes in the VTA, increased activation is seen in a variety of regions that receive dopaminergic input from the VTA, including the ventral striatum, which includes the NAC, and the dorsal striatum, which includes the caudate nucleus and putamen. Synaptic changes that are responsible for the compulsive behaviors that characterize addiction occur only after continued use of an addictive drug. The most important of these changes appears to occur in the dorsal striatum. We saw in Chapter 13 that the basal ganglia (which includes the dorsal striatum) play a critical role in instrumental conditioning, and the process of addiction involves just that.

At first, the potential addict experiences the pleasurable effects of the drug, reinforcing the behaviors that cause the drug to be delivered to the brain (procuring the drug, taking necessary steps to prepare it, then swallowing, smoking, sniffing, or injecting it). Eventually, these behaviors become habitual, and the impulse to perform them becomes difficult to resist. The early reinforcing effects that take place in the ventral striatum (namely, in the NAC) encourage drug-taking behavior, but the changes that make the behaviors become habitual involve the dorsal striatum. As we saw in Chapter 8 , an important role of the dorsal striatum is establishment of automatic behaviors—the type of behaviors that are impaired in people with Parkinson’s disease, which is caused by disruption of dopaminergic input to this region. Studies with monkeys performing a response reinforced by infusion of cocaine over a long period of time show a progression of neural changes, beginning in the ventral striatum (in the NAC) and continuing upward to the dorsal striatum (Letchworth et al., 2001 ; Porrino et al., 2004 , 2007 ). A study with rats found that infusion of a dopamine antagonist into the dorsal striatum suppressed lever presses that had been reinforced by the illumination of a light that had been paired with intravenous injections of cocaine Vanderschuren et al. ( 2005 ).

An experiment by Belin and Everitt ( 2008 ) suggests that the neural changes responsible for addiction follow a dorsally cascading set of reciprocal connections between the striatum and the ventral tegmental area. Anatomical studies show that neurons in the ventral NAC project to the VTA, which sends dopaminergic projections back to a more dorsal region of the NAC, and so on. This back-and-forth communication continues, connecting increasingly dorsal regions of the striatum, all the way up to the caudate nucleus and putamen. Belin and Everitt found that bilateral infusions of a dopamine antagonist into the dorsal striatum of rats suppressed responding to a light that had been associated with infusions of cocaine but that unilateral infusions had no effect. They also found that a unilateral lesion of the NAC had no effect on responding. However, they found that a lesion of the NAC on one side of the brain combined with infusion of a dopamine antagonist into the dorsal striatum on the other side of the brain suppressed responding to the light. (See Figure 18.1 . ) These results suggest that the control of compulsive addictive behavior is established by interactions between the ventral and dorsal striatum that are mediated by dopaminergic connections between these regions and the VTA.

FIGURE 18.1 Establishment of Neural Changes in the Dorsal Striatum

The graph shows the effects of infusing various amounts of a drug that blocks dopamine receptors into the dorsal striatum contralateral to a lesion of the nucleus accumbens.

(Based on data from Belin and Everitt, 2008 .)

The alterations that occur in the NAC and later in the dorsal striatum include changes in dopamine receptors on the medium spiny neurons, which are the source of axons that project from both of these regions to other parts of the brain. Increases are seen in dopamine D1 receptors, which cause excitation and facilitate behavior, and decreases are seen in dopamine D2 receptors, which cause inhibition and suppress behavior. A study by Witten et al. ( 2010 ) found that one of the neural changes in the NAC caused by cocaine intake involves acetylcholinergic interneurons. ACh neurons comprise less than one percent of the neurons in the NAC, but these neurons have a powerful effect on the activity of the medium spiny neurons located there. Witten and her colleagues found that cocaine increased the firing of the interneurons, and that inhibiting the firing of these neurons by optogenetic methods blocked the reinforcing effect of cocaine.

Functional-imaging studies by Volkow and her colleagues (reviewed by Volkow et al., 2011 ) provide evidence that addiction involves the dorsal striatum in humans, as well as in other animals. The investigators found that when cocaine addicts are given an injection of methylphenidate (a drug with effects like those of cocaine or amphetamine), they show a much smaller release of dopamine in the NAC or dorsal striatum than do non-addicted people. However, when addicted people are shown a video of people smoking cocaine, they showed an increased release of dopamine in the dorsal striatum. Thus, the response to the drug itself is diminished in addicts, but the response to cues associated with the drug is augmented—in the dorsal striatum. (See Figure 18.2 . )

These results are consistent with those of studies with animals cited above: The release of dopamine in the NAC leads to acquisition of a drug addiction, but changes in the dorsal striatum are responsible for the establishment of the drug-taking habit. In addition, in addicted individuals dopamine is released in the dorsal striatum not by the drug itself but by stimuli associated with procuring and taking the drug, including places where the drug was taken and people with whom it was taken. So when people first take an addictive drug, they experience pleasurable effects. If they continue to take the drug and become addicted, their compulsion to take the drug is not motivated by the pleasurable effects, but by drug-related cues that give rise to the urge to perform drug-seeking behaviors. As Volkow and her colleagues note, drug addicts are aroused and motivated when they are seeking a drug but are withdrawn and apathetic when they are in a drug-free environment, engaged in activities not related to drug taking.

FIGURE 18.2 Dopamine Release Stimulated by Methylphenidate

The scatter plot shows that increases in the release of dopamine in the putamen (part of the dorsal striatum) are associated with increased craving in cocaine addicts.

(Based on data from Volkow et al., 2011 .)

Most people who are exposed to addictive drugs do not become addicted (Volkow and Li, 2005 ). The likelihood of becoming addicted is a function of heredity, age (adolescents are most vulnerable), and environment (such as access to drugs and stressful life events). The role of heredity is discussed in a later section of this chapter. The role of the prefrontal cortex in judgment, risk taking, and control of inappropriate behaviors may explain why adolescents are much more vulnerable to drug addiction than are adults. Adolescence is a time of rapid and profound maturational change in the brain—particularly in the prefrontal cortex. Before these circuits reach their adult form, adolescents are more likely to display increased levels of impulsive, novelty-driven, risky behavior, including experimentation with alcohol, nicotine, and illicit drugs. Addiction in adults most often begins in adolescence or young adulthood. Approximately 50 percent of cases of addiction begin between the ages of fifteen and eighteen, and very few begin after age twenty. In addition, early onset of drug-taking is associated with more severe addiction and a greater likelihood of multiple substance abuse (Chambers, Taylor, and Potenza, 2003 ). In fact, Tarter et al. ( 2003 ) found that ten- to twelve-year-old boys who scored the lowest on tests of behavioral inhibition had an increased risk of developing substance use disorder by age nineteen. Some regions of the prefrontal cortex have inhibitory connections with the striatum, and increased activity of these regions is correlated with resistance to addiction. Presumably, the increased vulnerability of adolescents to drug addiction is related to the relative immaturity of inhibitory mechanisms of their prefrontal cortex. The final development of neural circuits involved in behavioral control and judgment, along with the maturity that comes from increased experience, apparently helps people emerging from adolescence to resist the temptation to abuse drugs.

Two peptides, orexin and MCH, play a crucial role in the reinforcing effects of drugs. As we saw in Chapters 9 and 12 , orexin (also called hypocretin) plays an important role in control of sleep stages and food-seeking behavior. Orexin is synthesized in neurons in the lateral hypothalamus and released in many parts of the brain, including those that play a role in addiction, such as the VTA, NAC, and dorsal striatum. Administration of addictive drugs or presentation of stimuli associated with them activate orexinergic neurons, and infusion of orexin into the VTA reinstate drug seeking that was previously extinguished. (Relapse—resumption of drug-seeking—is discussed later in this chapter.) In addition, infusion into the VTA of a drug that blocks orexin receptors also blocks cocaine seeking elicited by drug-related cues and prevents the learning of a conditioned place preference—preference for a place where morphine was previously administered (Aston-Jones et al., 2009 ; Sharf, Sarhan, and DiLeone, 2010 ; Kenney, 2011 ).

The second peptide, MCH (melanin-concentrating hormone), is also synthesized in the lateral hypothalamus, and as we saw in Chapter 12 , stimulates hunger and reduces metabolic rate. MCH receptors are found in several places in the brain, including the NAC, where it is found on neurons that also contain DA receptors. Chung et al. ( 2009 ) found that stimulating both DA receptors and MCH receptors increased firing of NAC neurons, and that administering a drug that blocks MCH receptors decreased the effectiveness of cocaine or cocaine-related cues on the animals’ behavior. A targeted mutation against the MCH receptor gene had the same effect. Cippitelli et al. ( 2010 ) found that MCH played a similar role in alcohol intake.

Negative Reinforcement

You have probably heard the old joke in which someone says that the reason he bangs his head against the wall is that “it feels so good when I stop.” Of course, that joke is funny (well, mildly amusing) because we know that although no one would act that way, ceasing to bang our head against the wall certainly does feel better than continuing to do so. If someone started hitting us on the head and we were able to do something to get the person to stop, whatever it was that we did would certainly be reinforced.

A behavior that turns off (or reduces) an aversive stimulus will be reinforced. This phenomenon is known as negative reinforcement , and its usefulness is obvious. For example, consider the following scenario: A woman staying in a rented house cannot get to sleep because of the unpleasant screeching noise that the furnace makes. She goes to the basement to discover the source of the noise and finally kicks the side of the oil burner. The noise ceases. The next time the furnace screeches, she immediately goes to the basement and kicks the side of the oil burner. The unpleasant noise (the aversive stimulus) is terminated when the woman kicks the side of the oil burner (the response), so the response is reinforced.

negative reinforcement The removal or reduction of an aversive stimulus that is contingent on a particular response, with an attendant increase in the frequency of that response.

It is worth pointing out that negative reinforcement should not be confused with punishment. Both phenomena involve aversive stimuli, but one makes a response more likely, while the other makes it less likely. For negative reinforcement to occur, the response must make the unpleasant stimulus end (or at least decrease). For punishment to occur, the response must make the unpleasant stimulus occur. For example, if a little boy touches a mousetrap and hurts his finger, he is unlikely to touch a mousetrap again. The painful stimulus punishes the behavior of touching the mousetrap.

People who abuse some drugs become physically dependent on the drug; that is, they show tolerance and withdrawal symptoms. As we saw in Chapter 4 , tolerance is the decreased sensitivity to a drug that comes from its continued use; the user must take larger and larger amounts of the drug for it to be effective. Once a person has taken an opiate regularly enough to develop tolerance, that person will exhibit withdrawal symptoms if he or she stops taking the drug. Withdrawal symptoms are primarily the opposite of the effects of the drug itself. The effects of heroin—euphoria, constipation, and relaxation—lead to the withdrawal effects of dysphoria, cramping and diarrhea, and agitation.

Most investigators believe that tolerance is produced by the body’s attempt to compensate for the unusual condition of heroin intoxication. The drug disturbs normal homeostatic mechanisms in the brain, and in reaction these mechanisms begin to produce effects opposite to those of the drug, partially compensating for the disturbance. Because of these compensatory mechanisms, the user must take increasing amounts of heroin to achieve the effects that were produced when he or she first started taking the drug. These mechanisms also account for the symptoms of withdrawal: When the person stops taking the drug, the compensatory mechanisms make themselves felt, unopposed by the action of the drug.

Although positive reinforcement seems to be what provokes drug taking in the first place, reduction of withdrawal effects could certainly play a role in maintaining someone’s drug addiction. The withdrawal effects are unpleasant, but as soon as the person takes some of the drug, these effects go away, producing negative reinforcement.

Negative reinforcement could also explain the acquisition of drug addictions under some conditions. If a stressed person is suffering from some unpleasant feelings and then takes a drug that eliminates these feelings, the person’s drug-taking behavior is likely to be reinforced. For example, alcohol can relieve feelings of anxiety. A person who finds him- or herself in a situation that arouses anxiety might find that having a drink or two makes him or her feel much better. In fact, people often anticipate this effect and begin drinking before the situation actually occurs.

Craving and Relapse

Why do drug addicts crave drugs? Why does this craving occur even after a long period of abstinence? Even after going for months or years without taking an addictive drug, a former drug addict might sometimes experience intense craving that leads to relapse. Clearly, taking a drug over an extended period of time must produce some long-lasting changes in the brain that increase a person’s likelihood of relapsing. Understanding this process might help clinicians to devise therapies that will assist people in breaking their drug dependence once and for all.

As everyone knows, a taste of food can provoke hunger, which is why we refer to tidbits we eat before a meal as “appetizers.” For a person with a history of drug abuse, a small dose of the drug has similar effects: It increases craving, or “appetite,” for the drug. In addition, through the process of classical conditioning, stimuli that have been associated with drugs in the past can also elicit craving. For example, an alcoholic who sees a liquor bottle is likely to feel the urge to take a drink. In the past, agencies that sponsored antiaddiction programs sometimes prepared posters illustrating the dangers of drug abuse that featured drug paraphernalia: syringes, needles, spoons, piles of white powder, and so on. Possibly, these posters did succeed in reminding people who did not use drugs that they should avoid them. But we do know that their effect on people who were trying to break a drug habit was exactly the opposite of what was intended. As we saw in the case at the beginning of this chapter, John, a former drug addict, saw a poster that pictured drug paraphernalia, and this sight provoked an urge to take the drug again. For this reason, such posters are no longer used in campaigns against drug addiction.

One of the ways in which craving has been investigated in laboratory animals is through the reinstatement model of drug seeking. Animals are first trained to make a response (for example, pressing a lever) that is reinforced by intravenous injections of a drug such as cocaine. Next, the response is extinguished by providing injections of a saline solution rather than the drug. Once the animal has stopped responding, the experimenter administers a “free” injection of the drug (drug reinstatement procedure) or presents a stimulus that has been associated with the drug (cue reinstatement procedure). In response to these stimuli, the animals begin responding at the lever once more (Kalivas, Peters, and Knackstedt, 2006 ). Presumably, this kind of relapse (reinstatement of a previously extinguished response) is a good model for the craving that motivates drug-seeking behavior in a former addict. (See Figure 18.3 . )

FIGURE 18.3 The Reinstatement Procedure, a Measure of Craving

The graph shows the acquisition of lever pressing for injections of an addictive drug during the self-administration phase and the extinction of lever pressing when the drug was no longer administered. A “free” shot of the drug or presentation of a cue associated with the drug during acquisition will reinstate responding.

(Based on data from Kalivas et al., 2006 .)

To understand the process of reinstatement (and the craving the underlies it), let’s first consider what happens during extinction. As we saw in Chapter 11 , extinction is a form of learning. An animal does not forget to make a particular response; it learns not to make it. The ventromedial prefrontal cortex (vmPFC) plays a critical role in this process. For example, we saw in Chapter 11 that lesions of the vmPFC impair the extinction of a conditioned emotional response, that stimulation of this region inhibits conditioned emotional responses, and that extinction training activates neurons located there.

Studies with rats indicate that different regions of the prefrontal cortex exert facilitatory and inhibitory effects on drug-related responding by means of excitatory and inhibitory connections with the brain’s reinforcement system. These effects appear to be responsible for extinction and reinstatement. Peters, LaLumiere, and Kalivas ( 2008 ) found that stimulation of the vmPFC with an infusion of AMPA, a glutamate agonist, blocked reinstatement of responding normally produced by a free shot of cocaine or the presentation of a stimulus associated with cocaine reinforcement. That is, activation of the vmPFC inhibited responding. McFarland, Lapish, and Kalivas ( 2003 ) found that reinstatement of lever pressing for infusions of cocaine was abolished by injecting a GABA agonist into the dorsal anterior cingulate cortex (dACC), a region or the dorsal PFC that has excitatory connections with the NAC. That is, inhibition of the dACC prevented the reinstatement of the response. These results indicate that the dACC plays a role in craving and the vmPFC plays a role in its suppression.

Volkow et al. ( 1992 ) found that the activity of the medial prefrontal cortex of cocaine abusers was lower than that of normal subjects during abstinence. In addition, when addicts are performing tasks that normally activate the prefrontal cortex, their medial prefrontal cortex is less activated than that of healthy control subjects, and they perform more poorly on the tasks (Bolla et al., 2004 ; Garavan and Stout, 2005 ). In fact, Bolla and her colleagues found that the amount of activation of the medial prefrontal cortex was inversely related to the amount of cocaine that cocaine abusers normally took each week: The lower the brain activity, the more cocaine the person took. (See Figure 18.4 . )

People with a long history of drug abuse not only show the same deficits on tasks that involve the prefrontal cortex as do people with lesions of this region, they also show structural abnormalities of this region. For example, Franklin et al. ( 2002 ) reported an average decrease of 5–11 percent in the gray matter of various regions of the prefrontal cortex of chronic cocaine abusers. Thompson et al. ( 2004 ) found decreases in the gray matter volume of the cingulate cortex and limbic cortex of methamphetamine users, and Ersche et al. ( 2011 ) found similar decreases in the brains of cocaine users. de Ruiter et al. ( 2011 ) found evidence of loss of behavioral control caused by decreased activation of the dorsomedial PFC in both heavy smokers and pathological gamblers, which supports the assertion of some investigators that pathological gambling should be regarded as a form of addiction (Thomas et al., 2011 ). Zhang et al. ( 2011 ) found decreased gray matter in the prefrontal cortex that was proportional to the amount of people’s lifetime tobacco use. Of course, the results of these studies do not permit us to determine whether abnormalities in the prefrontal cortex predispose people to become addicted or whether drug taking causes these abnormalities (or both).

FIGURE 18.4 Cocaine Intake and the Medial Prefrontal Cortex

The graph shows the relative activation of the medial prefrontal cortex as a function of the amount of cocaine normally taken each week by cocaine abusers.

(Based on data from Bolla et al., 2004 .)

As we saw in Chapter 16 , the negative and cognitive symptoms of schizophrenia appear to be a result of hypofrontality—decreased activity of the prefrontal cortex. These symptoms are very similar to those that accompany long-term drug abuse. In fact, studies have shown a high level of comorbidity of schizophrenia and substance abuse. (Comorbidity refers to the simultaneous presence of two or more disorders in the same person.) For example, up to half of all people with schizophrenia have a substance abuse disorder (alcohol or illicit drugs), and 70–90 percent are nicotine dependent (Brady and Sinha, 2005 ). In fact, in the United States, smokers with psychiatric disorders, who constitute approximately 7 percent of the population, consume 34 percent of all cigarettes (Dani and Harris, 2005 ). Mathalon et al. ( 2003 ) found that prefrontal gray matter volumes were 10.1 percent lower in alcoholic patients, 9.0 percent lower in schizophrenic patients, and 15.6 percent lower in patients with both disorders. (See Figure 18.5 . )

Weiser et al. ( 2004 ) administered a smoking questionnaire to a random sample of adolescent military recruits each year. Over a four- to sixteen-year follow-up period, they found that, compared with nonsmokers, the prevalence of hospitalization for schizophrenia was 2.3 times higher in recruits who smoked at least ten cigarettes per day. (See Figure 18.6 . ) These results suggest that abnormalities in the prefrontal cortex may be a common factor in schizophrenia and substance abuse disorders. Again, I must note that research has not yet determined whether preexisting abnormalities increase the risk of these disorders or whether the disorders cause the abnormalities.

As we have just seen, the presence of drug-related stimuli can trigger craving and drug-seeking behavior. In addition, clinicians have long observed that stressful situations can cause former drug addicts to relapse. These effects have been observed in rats that had previously learned to self-administer cocaine or heroin. For example, Covington and Miczek ( 2001 ) paired naïve rats with rats that had been trained to become dominant. After being defeated by the dominant rats, the socially stressed rats became more sensitive to the effects of cocaine and showed bingeing—self-administration of larger amounts of the drug. Kosten, Miserendino, and Kehoe ( 2000 ) showed that stress that occurs early in life can have long-lasting effects. They stressed infant rats by isolating them from their mother and littermates for one hour per day for eight days. When these rats were given the opportunity in adulthood to inject themselves with cocaine, they readily acquired the habit and took more of the drugs than did control rats that had not been stressed. (See Figure 18.7 . )

FIGURE 18.5 Alcoholism, Schizophrenia, and Prefrontal Gray Matter

The graph shows the volume of gray matter in the prefrontal cortex of healthy controls, alcoholic patients, schizophrenic patients, and patients comorbid for both disorders.

(Based on data from Mathalon et al., 2003 .)

FIGURE 18.6 Smoking and Schizophrenia

The graph shows the prevalence of schizophrenia during a four- to sixteen-year follow-up period as a function of number of cigarettes smoked each day at age eighteen.

(Based on data from Weiser et al., 2004 .)

FIGURE 18.7 Social Stress and Cocaine Intake

The graph shows the cocaine intake of control rats and rats subjected to isolation stress early in life.

(Based on data from Kosten et al., 2000 .)

An important link between stressful experiences and drug craving is provided by corticotropin releasing hormone, or CRH. (This peptide is also referred to as corticotropin releasing factor, or CRF.) As we saw in Chapter 17 , CRH plays an important role in development of adverse effects on health produced by stress and on the development of anxiety disorders. Just as administration of a drug or of stimuli previously associated with drug-taking behavior can cause relapse, so can stressful experiences (Shalev, Erb, and Shaham, 2010 ). For example, administration of CRH can reinstate drug-taking behavior, and administration of a drug that blocks CRH receptors can reduce the likelihood of relapse from drugs or drug cues. CRH receptors in the VTA appear to be particularly important. For example, infusion of CRH into the VTA causes relapse, and infusion of a CRH receptor antagonist prevents reinstatement of drug-taking by a stressful stimulus (B. Wang et al., 2007 ).

SECTION SUMMARY: Common Features of Addiction

Addictive drugs are those whose reinforcing effects are so potent that some people who are exposed to them are unable to go for very long without taking the drugs and whose lives become organized around taking them. Fortunately, most people who are exposed to drugs do not become addicted to them. Originally, most addictive drugs came from plants, which used them as a defense against insects or other animals that otherwise would eat them, but chemists have synthesized many other drugs that have even more potent effects. If a person regularly takes some addictive drugs (most notably, the opiates), the effects of the drug show tolerance, and the person must take increasing doses to achieve the same effect. If the person then stops taking the drug, withdrawal effects, opposite to the primary effects of the drug, will occur. However, withdrawal effects are not the cause of addiction; the abuse potential of a drug is related to its ability to reinforce drug-taking behavior.

Positive reinforcement occurs when a behavior is regularly followed by an appetitive stimulus—one that an organism will approach. Addictive drugs produce positive reinforcement; they reinforce drug-taking behavior. Laboratory animals will learn to make responses that result in the delivery of these drugs. The faster a drug produces its effects, the more quickly dependence will be established. All addictive drugs that produce positive reinforcement stimulate the release of dopamine in the NAC, a structure that plays an important role in reinforcement. Neural changes that begin in the VTA and NAC eventually involve the dorsal striatum, which plays a critical role in instrumental conditioning. The activity of inhibitory circuits in the prefrontal cortex promote resistance to addiction. The susceptibility of adolescents to the addictive potential of drugs may be associated with the relative immaturity of the prefrontal cortex. Orexin and MCH play a role in the establishment of addiction.

Negative reinforcement occurs when a behavior is followed by the reduction or termination of an aversive stimulus. If, because of a person’s social situation or personality characteristics, he or she feels unhappy or anxious, a drug that reduces these feelings can reinforce drug-taking behavior by means of negative reinforcement. Also, the reduction of unpleasant withdrawal symptoms by a dose of the drug undoubtedly plays a role in maintaining drug addictions, but it is not the sole cause of craving.

Craving—the urge to take a drug to which one has become addicted—cannot be completely explained by withdrawal symptoms, because it can occur even after an addict has refrained from taking the drug for a long time. In laboratory animals a “free” shot of cocaine or presentation of stimuli previously associated with cocaine reinstates drug-seeking behavior. The vmPFC plays an inhibitory role in reinstatement, and the dACC plays a facilitatory role. Functional-imaging studies find that craving for addictive drugs and natural reinforcers such as appetizing food increases the activity of the ACC, OFC, insula, and dorsolateral prefrontal cortex. Long-term drug abuse is associated with decreased activity of the prefrontal cortex and even with a decreased volume of prefrontal gray matter, which may impair people’s judgment and ability to inhibit inappropriate responses, such as further drug taking. Schizophrenia is seen in a higher proportion of drug addicts than in the general population. Stressful stimuli—even those that occur early in life—increase susceptibility to drug addiction. Release of CRH in the VTA plays an important role in this process.

■ THOUGHT QUESTION

Explain what it means to say that addictive drugs “hijack” the reinforcement system.

Commonly Abused Drugs

People have been known to abuse an enormous variety of drugs, including alcohol, barbiturates, opiates, tobacco, amphetamine, cocaine, cannabis, hallucinogens such as LSD, PCP, and volatile solvents such as glues or even gasoline, ether, and nitrous oxide. The pleasure that children often derive from spinning themselves until they become dizzy may even be similar to the effects of some of these drugs. Obviously, I cannot hope to discuss all these drugs in any depth and keep the chapter to a reasonable length, so I will restrict my discussion to the most important of them in terms of popularity and potential for addiction. Some drugs, such as caffeine, are both popular and addictive, but because they do not normally cause intoxication, impair health, or interfere with productivity, I will not discuss them here. ( Chapter 4 did discuss the behavioral effects and site of action of caffeine.) I will also not discuss the wide variety of hallucinogenic drugs such as LSD or PCP. Although some people enjoy the mind-altering effects of LSD, many people simply find them frightening; in any event, LSD use does not normally lead to addiction. PCP (phencyclidine) acts as an indirect antagonist at the NMDA receptor, which means that its effects overlap with those of alcohol. Rather than devoting space to this drug, I have chosen to say more about alcohol, which is abused far more than any of the hallucinogenic drugs.

Opiates

Opium, derived from a sticky resin produced by the opium poppy, has been eaten and smoked for centuries. Opiate addiction has several high personal and social costs. First, because heroin, the most commonly abused opiate, is an illegal drug in most countries, an addict becomes, by definition, a criminal. Second, because of tolerance, a person must take increasing amounts of the drug to achieve a “high.” The habit thus becomes more and more expensive, and the person often turns to crime to obtain enough money to support his or her habit. Third, an opiate addict often uses unsanitary needles; at present, a substantial percentage of people who inject illicit drugs have been exposed in this way to hepatitis or the AIDS virus. Fourth, if the addict is a pregnant woman, her infant will also become dependent on the drug, which easily crosses the placental barrier. The infant must be given opiates right after being born and then weaned off the drug with gradually decreasing doses. Fifth, the uncertainty about the strength of a given batch of heroin makes it possible for a user to receive an unusually large dose of the drug, with possibly fatal consequences. And some of the substances used to dilute heroin are themselves toxic.

NEURAL BASIS OF REINFORCING EFFECTS

As we saw earlier, laboratory animals will self-administer opiates. When an opiate is administered systemically, it stimulates opiate receptors located on neurons in various parts of the brain and produces a variety of effects, including analgesia, hypothermia (lowering of body temperature), sedation, and reinforcement. Opiate receptors in the periaqueductal gray matter are primarily responsible for the analgesia, those in the preoptic area are responsible for the hypothermia, and those in the mesencephalic reticular formation are responsible for the sedation. As we shall see, opiate receptors in the ventral tegmental area and the NAC appear to play a role in the reinforcing effects of opiates.

As we saw in Chapter 4 , there are three major types of opiate receptors: μ (mu), δ (delta), and κ (kappa). Evidence suggests that μ receptors and δ receptors are responsible for reinforcement and analgesia and that stimulation of κ receptors produces aversive effects. Evidence for the role of μ receptors comes from a study by Matthes et al. ( 1996 ), who performed a targeted mutation against the gene responsible for production of the μ opiate receptor in mice. These animals, when they grew up, were completely insensitive to the reinforcing or analgesic effects of morphine, and they showed no signs of withdrawal symptoms after having been given increasing doses of morphine for six days. (See Figure 18.8 . )

As we saw earlier, reinforcing stimuli cause the release of dopamine in the NAC. Injections of opiates are no exception to this general rule; Wise et al. ( 1995 ) found that the level of dopamine in the NAC increased by 150–300 percent while a rat was pressing a lever that delivered intravenous injections of heroin. Rats will also press a lever that delivers injections of an opiate directly into the ventral tegmental area (Devine and Wise, 1994 ) or the NAC (Goeders, Lane, and Smith, 1984 ). In other words, injections of opiates into both ends of the mesolimbic dopaminergic system are reinforcing.

The release of endogenous opioids may even play a role in the reinforcing effects of some addictive drugs. Studies have shown that administration of naloxone (a drug that blocks opiate receptors), reduces the reinforcing effects of alcohol in both humans and laboratory animals. Because the use of opiate blockers has recently been approved as a treatment for alcoholism, I will discuss relevant research later in this chapter.

naloxone A drug that blocks μ opiate receptors; antagonizes the reinforcing and sedative effects of opiates.

NEURAL BASIS OF TOLERANCE AND WITHDRAWAL

Several studies have investigated the neural systems that are responsible for the development of tolerance and subsequent withdrawal effects of opiates. Maldonado et al. ( 1992 ) made rats physically dependent on morphine and then injected naloxone into various regions of the brain to determine whether the sudden blocking of opiate receptors would stimulate symptoms of withdrawal. This technique—administering an addictive drug for a prolonged interval and then blocking its effects with an antagonist—is referred to as antagonist-precipitated withdrawal . The investigators found that the most sensitive site was the locus coeruleus, followed by the periaqueductal gray matter. Injection of naloxone into the amygdala produced a weak withdrawal syndrome. Using a similar technique (first infusing morphine into various regions of the brain and then precipitating withdrawal by giving the animals an intraperitoneal injection of naloxone), Bozarth ( 1994 ) confirmed the role of the locus coeruleus and the periaqueductal gray matter in the production of withdrawal symptoms.

antagonist-precipitated withdrawal Sudden withdrawal from long-term administration of a drug caused by cessation of the drug and administration of an antagonistic drug.

FIGURE 18.8 Effects of a Targeted Deletion of the μ Opiate Receptor

The graphs show a lack of responses to morphine in mice with targeted mutations against the μ opiate receptor. (a) Latency to tail withdrawal from a hot object (a measure of analgesia). (b) Wet-dog shakes (a prominent withdrawal symptom in rodents) after being withdrawn from long-term morphine administration. (c) Conditioned place preference for a chamber associated with an injection of morphine (a measure of reinforcement).

(Based on data from Matthes et al., 1996 .)

A single dose of an opiate decreases the firing rate of neurons in the locus coeruleus, but if the drug is administered chronically, the firing rate will return to normal. Then, if an opiate antagonist is administered (to precipitate withdrawal symptoms), the firing rate of these neurons increases dramatically, which increases the release of norepinephrine in the regions that receive projections from this nucleus (Koob, 1996 ; Nestler, 1996 ). In addition, lesions of the locus coeruleus reduce the severity of antagonist-precipitated withdrawal symptoms (Maldonado and Koob, 1993 ). A microdialysis study by Aghajanian, Kogan, and Moghaddam ( 1994 ) found that antagonist-precipitated withdrawal caused an increase in the level of glutamate, the major excitatory neurotransmitter, in the locus coeruleus.

Stimulant Drugs: Cocaine and Amphetamine

Cocaine and amphetamine have similar behavioral effects, because both act as potent dopamine agonists. However, their sites of action are different. Cocaine binds with and deactivates the dopamine transporter proteins, thus blocking the reuptake of dopamine after it is released by the terminal buttons. Amphetamine also inhibits the reuptake of dopamine, but its most important effect is to directly stimulate the release of dopamine from terminal buttons. Methamphetamine is chemically related to amphetamine but is considerably more potent. Freebase cocaine (“crack”), a particularly potent form of the drug, is smoked and thus enters the blood supply of the lungs and reaches the brain very quickly. Because its effects are so potent and so rapid, it is probably the most effective reinforcer of all available drugs.

When people take cocaine, they become euphoric, active, and talkative. They say that they feel powerful and alert. Some of them become addicted to the drug, and obtaining it becomes an obsession to which they devote more and more time and money. Laboratory animals, which will quickly learn to self-administer cocaine intravenously, also act excited and show intense exploratory activity. After receiving the drug for a day or two, rats start showing stereotyped movements, such as grooming, head bobbing, and persistent locomotion (Geary, 1987 ). If rats or monkeys are given continuous access to a lever that permits them to self-administer cocaine, they often self-inject so much cocaine that they die. In fact, Bozarth and Wise ( 1985 ) found that rats that self-administered cocaine were almost three times more likely to die than were rats that self-administered heroin. As we have seen, the mesolimbic dopamine system plays an essential role in all forms of reinforcement, except perhaps for the reinforcement that is mediated by stimulation of opiate receptors. Many studies have shown that intravenous injections of cocaine and amphetamine increase the concentration of dopamine in the NAC, as measured by microdialysis. For example, Figure 18.9 shows data collected by Di Ciano et al. ( 1995 ) in a study with rats that learned to press a lever that delivered intravenous injections of cocaine or amphetamine. The colored bars at the base of the graphs indicate the animals’ responses, and the line graphs indicate the level of dopamine in the NAC. (See Figure 18.9 . )

One of the alarming effects of cocaine and amphetamine seen in people who abuse these drugs regularly is psychotic behavior: hallucinations, delusions of persecution, mood disturbances, and repetitive behaviors. These symptoms so closely resemble those of paranoid schizophrenia that even a trained mental health professional cannot distinguish them unless he or she knows about the person’s history of drug abuse. However, these effects apparently disappear once people stop taking the drug. As we saw in Chapter 16 , the fact that these symptoms are provoked by dopamine agonists and reduced by drugs that block dopamine receptors suggests that overactivity of dopaminergic synapses is responsible for the positive symptoms of schizophrenia.

Some evidence suggests that the use of stimulant drugs may have adverse long-term effects on the brain. For example, a PET study by McCann et al. ( 1998 ) discovered that prior abusers of methamphetamine showed a decrease in the numbers of dopamine transporters in the caudate nucleus and putamen, despite the fact that they had abstained from the drug for approximately three years. The decreased number of dopamine transporters suggests that the number of dopaminergic terminals in these regions is diminished. As the authors note, these people might have an increased risk of Parkinson’s disease as they get older. (See Figure 18.10 . ) Studies with laboratory animals have also found that methamphetamine can damage terminals of serotonergic axons and trigger death of neurons through apoptosis in the cerebral cortex, striatum, and hippocampus (Cadet, Jayanthi, and Deng, 2003 ).

FIGURE 18.9 Release of Dopamine in the Nucleus Accumbens

The graphs show dopamine concentration in the nucleus accumbens, measured by microdialysis, during self-administration of intravenous cocaine or amphetamine by rats.

(Based on data from Di Ciano et al., 1995 .)

Nicotine

Nicotine might seem rather tame in comparison to opiates, cocaine, and amphetamine. Nevertheless, nicotine is an addictive drug, and it accounts for more deaths than the so-called hard drugs. The combination of nicotine and other substances in tobacco smoke is carcinogenic and leads to cancer of the lungs, mouth, throat, and esophagus. Approximately one-third of the adult population of the world smokes, and smoking is one of the few causes of death that is rising in developing countries. The World Health Organization estimates that 50 percent of the people who begin to smoke as adolescents and continue smoking throughout their lives will die from smoking-related diseases. Investigators estimate that, in just a few years, tobacco will be the largest single health problem worldwide, with over 6 million deaths per year (Mathers and Loncar, 2006 ). In fact, tobacco use is the leading cause of preventable death in developed countries (Dani and Harris, 2005 ). In the United States alone, tobacco addiction kills more than 430,000 people each year (Chou and Narasimhan, 2005 ). Smoking by pregnant women also has negative effects on the health of their fetuses—apparently worse than those of cocaine (Slotkin, 1998 ). Unfortunately, approximately 25 percent of pregnant women in the United States expose their fetuses to nicotine.

FIGURE 18.10 Dopamine Transporters, Methamphetamine Abuse, and Parkinson’s Disease

The scans show concentrations of dopamine transporters from a control subject, a subject who had previously abused methamphetamine, and a subject with Parkinson’s disease. Decreased concentrations of dopamine transporters indicate loss of dopaminergic terminals.

(From McCann, U. D., Wong, D. F., Yokoi, F., et al. Journal of Neuroscience, 1998, 18, 8417–8422. By permission.)

The addictive potential of nicotine should not be underestimated; many people continue to smoke even when doing so causes serious health problems. For example, Sigmund Freud, whose theory of psychoanalysis stressed the importance of insight in changing one’s behavior, was unable to stop smoking even after most of his jaw had been removed because of the cancer that this habit had caused (Brecher, 1972 ). He suffered severe pain and, as a physician, realized that he should have stopped smoking. He did not, and his cancer finally killed him.

Although executives of tobacco companies and others whose economic welfare is linked to the production and sale of tobacco products used to argue that smoking is a “habit” rather than an “addiction,” evidence suggests that the behavior of people who regularly use tobacco is that of compulsive drug users. In a review of the literature, Stolerman and Jarvis ( 1995 ) note that smokers tend to smoke regularly or not at all; few can smoke just a little. Males smoke an average of seventeen cigarettes per day, while females smoke an average of fourteen. Nineteen out of twenty smokers smoke every day, and only sixty out of 3500 smokers questioned smoke fewer than five cigarettes per day. Forty percent of people continue to smoke after having had a laryngectomy (which is usually performed to treat throat cancer). Indeed, physicians have reported that patients with tubes inserted into their tracheas so that they can breathe will sometimes press a cigarette against the opening of these tubes and try to smoke (Hyman and Malenka, 2001 ). More than 50 percent of heart attack survivors continue to smoke, and about 50 percent of people continue to smoke after submitting to surgery for lung cancer. Of those who attempt to quit smoking by enrolling in a special program, 20 percent manage to abstain for one year. The record is much poorer for those who try to quit on their own: One-third manage to stop for one day, one-fourth abstain for one week, but only 4 percent manage to abstain for six months. It is difficult to reconcile these figures with the assertion that smoking is merely a “habit” that is pursued for the “pleasure” that it produces.

Ours is not the only species willing to self-administer nicotine; so will laboratory animals (Donny et al., 1995 ). Nicotine stimulates nicotinic acetylcholine receptors, of course. It also increases the activity of dopaminergic neurons of the mesolimbic system (Mereu et al., 1987 ) and causes dopamine to be released in the NAC (Damsma, Day, and Fibiger, 1989 ). Figure 18.11 shows the effects of two injections of nicotine or saline on the extracellular dopamine level of the NAC, measured by microdialysis. (See Figure 18.11 . )

Injection of a nicotinic agonist directly into the ventral tegmental area will reinforce a conditioned place preference (Museo and Wise, 1994 ). Conversely, injection of a nicotinic antagonist into the VTA will block the ability of nicotine to cause the release of dopamine in the nucleus accumbens and reduce the reinforcing effect of intravenous injections of nicotine (Corrigall, Coen, and Adamson, 1994 ; Gotti et al., 2010 ). But although nicotinic receptors are found in both the VTA and the NAC, Corrigall and his colleagues found that injections of a nicotinic antagonist in the NAC have no effect on reinforcement. Consistent with these findings, Nisell, Nomikos, and Svensson ( 1994 ) found that infusion of a nicotinic antagonist into the VTA will prevent an intravenous injection of nicotine from triggering the release of dopamine in the NAC. Infusion of the antagonist into the NAC will not have this effect. Thus, the reinforcing effect of nicotine appears to be caused by activation of nicotinic receptors in the ventral tegmental area.

FIGURE 18.11 Nicotine and Dopamine Release in the Nucleus Accumbens

The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of nicotine or saline. The arrows indicate the time of the injections.

(Based on data from Damsma et al., 1989 .)

Studies have found that the endogenous cannabinoids play a role in the reinforcing effects of nicotine. Rimonabant, a drug that blocks cannabinoid CB1 receptors, reduces nicotine self-administration and nicotine-seeking behavior in rats (Cohen, Kodas, and Griebel, 2005 ), apparently by reducing the release of dopamine in the NAC (De Vries and Schoffelmeer, 2005 ). By blocking CB1 receptors, rimonabant decreases the reinforcing effects of nicotine. As we saw in Chapter 12 , rimonabant was used for antiobesity therapy for a short time but was withdrawn from the market because of dangerous side effects. Clinical trials have found that rimonabant appears to help prevent relapse in people who are trying to quit smoking, but it is not approved for this purpose, either. However, the effects of the drug in humans and laboratory animals suggest that craving for nicotine, like the craving for food, is enhanced by the release of endocannabinoids in the brain.

The nicotinic ACh receptor exists in three states. When a burst of ACh is released by an acetylcholinergic terminal button, the receptors open briefly, permitting the entry of calcium. (Most nicotinic receptors serve as heteroreceptors on terminal buttons that release another neurotransmitter. The entry of calcium stimulates the release of that neurotransmitter.) Within a few milliseconds, the enzyme AChE has destroyed the acetylcholine, and the receptors either close again or enter a desensitized state, during which they bind with, but do not react to, ACh. Normally, few nicotinic receptors enter the desensitized state. However, when a person smokes, the level of nicotine in the brain rises slowly and stays steady for a prolonged period because nicotine, unlike ACh, is not destroyed by AChE. At first, nicotinic receptors are activated, but the sustained low levels of the drug convert many nicotinic receptors to the desensitized state. Thus, nicotine has dual effects on nicotinic receptors: activation and then desensitization. In addition, probably in response to desensitization, the number of nicotinic receptors increases (Dani and De Biasi, 2001 ).

Most smokers report that their first cigarette in the morning brings the most pleasure, presumably because the period of abstinence during the night has allowed many of their nicotinic receptors to enter the closed state and become sensitized again. The first dose of nicotine in the morning activates these receptors and has a reinforcing effect. After that, a large proportion of the smoker’s nicotinic receptors become desensitized again; as a consequence, most smokers say that they smoke less for pleasure than to relax and gain relief from nervousness and craving. If smokers abstain for a few weeks, the number of nicotinic receptors in their brains returns to normal. However, as the high rate of relapse indicates, craving continues, which means that other changes in the brain must have occurred.

Cessation of smoking after long-term use causes withdrawal symptoms, including anxiety, restlessness, insomnia, and inability to concentrate (Hughes et al., 1989 ). Like the withdrawal symptoms of other drugs, these symptoms may increase the likelihood of relapse, but they do not explain why people become addicted to the drug in the first place.

Patient N. is a [38-year-old man who] started smoking at the age of 14. At the time of his stroke, he was smoking more than 40 unfiltered cigarettes per day and was enjoying smoking very much... [H]e used to experience frequent urges to smoke, especially upon waking, after eating, when he drank coffee or alcohol, and when he was around other people who were smoking. He often found it difficult to refrain from smoking in situations where it was inappropriate, e.g., at work or when he was sick and bedridden. He was aware of the health risks of smoking before his stroke but was not particularly concerned about those risks. Before his stroke, he had never tried to stop smoking, and he had had no intention of doing so. N. smoked his last cigarette on the evening before his stroke. When asked about his reason for quitting smoking, he stated simply, “I forgot that I was a smoker.” When asked to elaborate, he said that he did not forget the fact that he was a smoker but rather that “my body forgot the urge to smoke.” He felt no urge to smoke during his hospital stay, even though he had the opportunity to go outside to smoke. His wife was surprised by the fact that he did not want to smoke in the hospital, given the degree of his prior addiction. N. recalled how his roommate in the hospital would frequently go outside to smoke and that he was so disgusted by the smell upon his roommate’s return that he asked to change rooms. He volunteered that smoking in his dreams, which used to be pleasurable before his stroke, was now disgusting. N. stated that, although he ultimately came to believe that his stroke was caused in some way by smoking, suffering a stroke was not the reason why he quit. In fact, he did not recall ever making any effort to stop smoking. Instead, it seemed to him that he had spontaneously lost all interest in smoking. When asked whether his stroke might have destroyed some part of his brain...that made him want to smoke, he agreed that this was likely to have been the case. (Naqvi et al., 2007 , p. 534)

As Naqvi et al. ( 2007 ) report, Mr. N. sustained a stroke that damaged his insula. In fact, several other patients with insular damage had the same experience. Naqvi and his colleagues identified nineteen cigarette smokers with damage to the insula and fifty smokers with brain damage that spared this region. Of the nineteen patients who had damage to the insula, twelve “quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke” (Naqvi et al., 2007 , p. 531). One patient with insula damage quit smoking but still reported feeling an urge to smoke. Figure 18.12 shows computer-generated images of brain damage that showed a statistically significant correlation with disruption of smoking. As you can see, the insula, which is colored red, showed the highest association with cessation of smoking. (See Figure 18.12 . )

Other studies have corroborated the report by Naqvi and his colleagues (Hefzy, Silver, and Silver, 2011 ). In addition, Forget et al. ( 2010 ) found that infusion of an inhibitory drug into the insula of rats reduced the reinforcing effects of nicotine. (See Figure 18.13 . ) I mentioned earlier that Zhang et al. ( 2011 ) found decreased gray matter in the frontal cortex of smokers, which may be at least partly responsible for the difficulty that smokers have in breaking their habit. These investigators also found that the insula was larger in smokers, which is consistent with the apparent role of the insula in nicotine addiction.

FIGURE 18.12 Damage to the Insula and Smoking Cessation

The diagrams show the regions of the brain (shown in red) where damage was most highly correlated with cessation of smoking.

(From Naqvi, N. H., Rudrauf, D., Damasio, H., and Bechara, A. Science, 2007, 315, 531–534. By permission.)

FIGURE 18.13 Effect of Inactivation of the Insula on Reinstatement of Drug-Seeking Behavior in Rats

Rats were trained to work for injections of nicotine, and then the behavior was extinguished. The graph shows that inactivation of the insula substantially reduced drug-seeking behavior elicited by nicotine or cues previously associated with nicotine.

(Based on data of Forget et al., 2010 .)

One of the several deterrents to cessation of smoking is the fact that overeating and weight gain frequently occur when people stop smoking. As I mentioned earlier in this chapter and in Chapter 12 , eating and a reduction in metabolic rate are stimulated by the release of MCH and orexin in the brain. Jo, Wiedl, and Role ( 2005 ) found that nicotine inhibits MCH neurons, thus suppressing appetite. When people try to quit smoking, they are often discouraged by the fact that the absence of nicotine in their brains releases their MCH neurons from this inhibition, increasing their appetite. Nicotine also stimulates the release of orexin, which, as we saw earlier in this chapter, is involved in drug-seeking behavior (Huang, Xu, and van den Pol, 2011 ). Orexin is released in many parts of the brain, but one region may play an especially important role in smoking: the insula. Hollander et al. ( 2008 ) found that infusion of a drug into the insula that blocks orexin receptors decreased the responding of rats for injections of nicotine.

Researchers have discovered a pathway in the brain that inhibits the reinforcing effects of nicotine. Neurons in the medial habenula, a region of the midbrain, contain a special type of nicotinic ACh receptor that includes an α5 subunit. The neurons that contain these receptors send their axons to the interpeduncular nucleus, located in the midline of the midbrain, caudal to the medial habenula. This pathway appears to be part of a system that inhibits the reinforcing effects of nicotine. Fowler et al. ( 2011 ) prepared a targeted mutation against the gene responsible for synthesis of α5 ACh receptors in the medial habenula of mice. They found that the knockout increased self-administration of high doses of nicotine. They also found that the procedure decreased the ability of nicotine to activate the interpeduncular nucleus, and that disruption of activity in this nucleus increased nicotine self-administration. The medial habenula-interpeduncular nucleus circuit appears to protect the animals (and presumably, our own species) against intake of large quantities of nicotine. A normal mouse will increase its response rate when the amount of nicotine contained in each injection increases—up to a point, that is. Eventually, larger injections will suppress the animal’s response rate so that it will not receive too much nicotine. But if α5 ACh receptors in the habenula are deactivated, this inhibitory effect does not occur. (See Figure 18.14 . )

Alcohol

Alcohol has enormous costs to society. A large percentage of deaths and injuries caused by motor vehicle accidents are related to alcohol use, and alcohol contributes to violence and aggression. Chronic alcoholics often lose their jobs, their homes, and their families; and many die of cirrhosis of the liver, exposure, or diseases caused by poor living conditions and abuse of their bodies. As we saw in Chapter 15 , women who drink during pregnancy run the risk of giving birth to babies with fetal alcohol syndrome, which includes malformation of the head and the brain and accompanying mental retardation. In fact, alcohol consumption by pregnant women is one of the leading causes of mental retardation in the Western world today. Therefore, understanding the physiological and behavioral effects of this drug is an important issue.

FIGURE 18.14 Effect of Knockout of the α5 ACh Receptor Gene in Mice

The graph shows that mice with a targeted mutation against α5 ACh receptors in the medial habenula self-administer increasing doses of nicotine, whereas normal mice limit their intake.

(Based on data of Fowler et al., 2011 .)

Alcohol has the most serious effects on fetal development during the brain growth spurt period, which occurs during the last trimester of pregnancy and for several years after birth. Ikonomidou et al. ( 2000 ) found that exposure of the immature rat brain triggered widespread cell death through apoptosis. The investigators exposed immature rats to alcohol at different times during the period of brain growth and found that different regions were vulnerable to the effects of the alcohol at different times. Alcohol has two primary sites of action: It serves as an indirect agonist at GABAA receptors and as an indirect antagonist at NMDA receptors. Apparently, both of these actions trigger apoptosis. Ikonomidou and her colleagues found that administration of a GABAA agonist (phenobarbital, a barbiturate) or an NMDA antagonist (MK-801) to seven-day-old rats caused brain damage by means of apoptosis. (See Figure 18.15 . )

At low doses, alcohol produces mild euphoria and has an anxiolytic effect—that is, it reduces the discomfort of anxiety. At higher doses, it produces incoordination and sedation. In studies with laboratory animals, the anxiolytic effects manifest themselves as a release from the punishing effects of aversive stimuli. For example, if an animal is given electric shocks whenever it makes a particular response (say, one that obtains food or water), it will stop doing so. However, if it is then given some alcohol, it will begin making the response again (Koob et al., 1984 ). This phenomenon explains why people often do things they normally would not when they have had too much to drink; the alcohol removes the inhibitory effect of social controls on their behavior.

FIGURE 18.15 Early Exposure to Alcohol and Apoptosis

The photomicrographs of sections of rat brain show degenerating neurons (black spots). Exposure to alcohol during the period of rapid brain growth causes cell death by inducing apoptosis. These effects are mediated by the actions of alcohol as an NMDA antagonist and a GABAA agonist. MK-801, an NMDA antagonist, and phenobarbital, a GABAA agonist, also induce apoptosis.

(From Ikonomidou, C., Bittigau, P., Ishimaru, M. J., et al. Science, 2000, 287, 1056–1060. By permission.)

Alcohol produces both positive and negative reinforcement. The positive reinforcement manifests itself as mild euphoria. As we saw earlier, negative reinforcement is caused by the termination of an aversive stimulus. If a person feels anxious and uncomfortable, then an anxiolytic drug that relieves this discomfort provides at least a temporary escape from an unpleasant situation.

The negative reinforcement provided by the anxiolytic effect of alcohol is probably not enough to explain the drug’s addictive potential. Other drugs, such as the benzodiazepines (tranquilizers such as Valium), are even more potent anxiolytics than alcohol, yet such drugs are abused less often. It is probably the unique combination of stimulating and anxiolytic effects—of positive and negative reinforcement—that makes alcohol so difficult for some people to resist.

Alcohol, like other addictive drugs, increases the activity of the dopaminergic neurons of the mesolimbic system and increases the release of dopamine in the NAC as measured by microdialysis (Gessa et al., 1985 ; Imperato and Di Chiara, 1986 ). The release of dopamine appears to be related to the positive reinforcement that alcohol can produce. An injection of a dopamine antagonist directly into the NAC decreases alcohol intake in rats (Samson et al., 1993 ), as does the injection of a drug into the ventral tegmental area that decreases the activity of the dopaminergic neurons there (Hodge et al., 1993 ). In a double-blind study, Enggasser and de Wit ( 2001 ) found that haloperidol, an antischizophrenic drug that blocks DA receptors, decreased the amount of alcohol that nonalcoholic subjects subsequently drank. Presumably, the drug reduced the reinforcing effect of the alcohol. In addition, the subjects who normally feel stimulated and euphoric after having a drink reported a reduction in these effects after taking haloperidol.

As I just mentioned, alcohol has two major sites of action in the nervous system, acting as an indirect antagonist at NMDA receptors and an indirect agonist at GABAA receptors (Chandler, Harris, and Crews, 1998 ). That is, alcohol enhances the action of GABA at GABAA receptors and interferes with the transmission of glutamate at NMDA receptors.

As we saw in Chapter 13 , NMDA receptors are involved in long-term potentiation, a phenomenon that plays an important role in learning. Therefore, it will not surprise you to learn that alcohol, which antagonizes the action of glutamate at NMDA receptors, disrupts long-term potentiation and interferes with the spatial receptive fields of place cells in the hippocampus (Givens and McMahon, 1995 ; Matthews, Simson, and Best, 1996 ). Presumably, this effect at least partly accounts for the deleterious effects of alcohol on memory and other cognitive functions.

Withdrawal from long-term alcohol intake (like that of heroin, cocaine, amphetamine, and nicotine) decreases the activity of mesolimbic neurons and their release of dopamine in the NAC (Diana et al., 1993 ). If an indirect antagonist for NMDA receptors is then administered, dopamine secretion in the NAC recovers. The evidence suggests the following sequence of events: Some of the acute effects of a single dose of alcohol are caused by the antagonistic effect of the drug on NMDA receptors. Long-term suppression of NMDA receptors causes up-regulation—a compensatory increase in the sensitivity of the receptors. Then, when alcohol intake suddenly ceases, the increased activity of NMDA receptors inhibits the activity of ventral tegmental neurons and the release of dopamine in the NAC.

Although the effects of heroin withdrawal have been exaggerated, those produced by barbiturate or alcohol withdrawal are serious and can even be fatal. The increased sensitivity of NMDA receptors as they rebound from the suppressive effect of alcohol can trigger seizures and convulsions. Convulsions caused by alcohol withdrawal are considered to be a medical emergency and are usually treated with benzodiazepines. Confirming the cause of these reactions, Liljequist ( 1991 ) found that seizures caused by alcohol withdrawal could be prevented by giving mice a drug that blocks NMDA receptors.

The second site of action of alcohol is the GABAA receptor. Alcohol binds with one of the many binding sites on this receptor and increases the effectiveness of GABA in opening the chloride channel and producing inhibitory postsynaptic potentials. Proctor et al. ( 1992 ) recorded the activity of single neurons in the cerebral cortex of slices of rat brains. They found that the presence of alcohol significantly increased the postsynaptic response produced by the action of GABA at the GABAA receptor. As we saw in Chapter 4 , the anxiolytic effect of the benzodiazepine tranquilizers is caused by their action as indirect agonists at the GABAA receptor. Because alcohol has this effect also, we can surmise that the anxiolytic effect of alcohol is a result of this action of the drug.

The sedative effect of alcohol also appears to be exerted at the GABAA receptor. Suzdak et al. ( 1986 ) discovered a drug (Ro15-4513) that reverses alcohol intoxication by blocking the alcohol binding site on this receptor. Figure 18.16 shows two rats that received injections of enough alcohol to make them pass out. The one facing us also received an injection of the alcohol antagonist and appears completely sober. (See Figure 18.16 . )

This wonder drug has not been put on the market, nor is it likely to be. Although the behavioral effects of alcohol are mediated by their action on GABAA receptors and NMDA receptors, high doses of alcohol have other, potentially fatal effects on all cells of the body, including destabilization of cell membranes. Thus, people taking some of the alcohol antagonist could then go on to drink themselves to death without becoming drunk in the process. Drug companies naturally fear possible liability suits stemming from such occurrences.

FIGURE 18.16 Effects of Ro15-4513, an Alcohol Antagonist

Both rats received an injection of alcohol, but the one facing us also received an injection of the alcohol antagonist.

(Photograph courtesy of Steven M. Paul, National Institute of Mental Health, Bethesda, Md.)

I mentioned earlier that opiate receptors appear to be involved in a reinforcement mechanism that does not directly involve dopaminergic neurons. The reinforcing effect of alcohol is at least partly caused by its ability to trigger the release of the endogenous opioids. Several studies have shown that the opiate receptor blockers such as naloxone or naltrexone block the reinforcing effects of alcohol in a variety of species, including rats, monkeys, and humans (Altschuler, Phillips, and Feinhandler, 1980 ; Davidson, Swift, and Fitz, 1996 ; Reid, 1996 ). In addition, endogenous opioids may play a role in craving in abstinent alcoholics. Heinz et al. ( 2005 ) found that one to three weeks of abstinence increased the number of μ opiate receptors in the NAC. The greater the number of receptors, the more intense the craving was. Presumably, the increased number of μ receptors increased the effects of endogenous opiates on the brain and served as a contributing factor to the craving for alcohol. (See Figure 18.17 . )

Because naltrexone has become a useful adjunct to treatment of alcoholism, I will discuss this topic further in the last section of this chapter.

Cannabis

Another drug that people regularly self-administer—almost exclusively by smoking—is THC, the active ingredient in marijuana. As you learned in Chapter 4 , the site of action of the endogenous cannabinoids in the brain is the CB1 receptor. The endogenous ligands for the CB1 receptor, anandamide and 2-AG, are lipids. Administration of a drug that blocks CB1 receptors abolishes the “high” produced by smoking marijuana (Huestis et al., 2001 ).

By the way, di Tomaso, Beltramo, and Piomelli ( 1996 ) discovered that chocolate contains three anandamide-like chemicals. Whether the existence of these chemicals is related to the great appeal that chocolate has for many people is not yet known. (I suppose that this is the place for a chocoholic joke.)

THC, like other drugs with abuse potential, has a stimulating effect on dopaminergic neurons. Chen et al. ( 1990 ) injected rats with low doses of THC and measured the release of dopamine in the NAC by means of microdialysis. Sure enough, they found that the injections caused the release of dopamine. (See Figure 18.18 . ) Chen et al. ( 1993 ) found that local injections of small amounts of THC into the ventral tegmental area had no effect on the release of dopamine in the NAC. However, injection of THC into the NAC didcause dopamine release there. Thus, the drug appears to act directly on dopaminergic terminal buttons—presumably on presynaptic heteroreceptors, where it increases the release of dopamine.

FIGURE 18.17 Craving for Alcohol and μ opiate Receptors

The drawings of the results of PET scans show the presence of μ opiate receptors in the dorsal striatum of detoxified alcoholic patients and healthy control subjects. The graph shows the relative alcohol craving score as a function of relative numbers of μ opiate receptors.

(Based on data from Heinz et al., 2005 .)

A variety of laboratory animals, including mice, rats, and monkeys, will self-administer drugs that stimulate CB1 receptors, including THC (Maldonado and Rodriguez de Fonseca, 2002 ). A targeted mutation that blocks the production of CB1 receptors abolishes the reinforcing effect not only of cannabinoids but also of morphine and heroin (Cossu et al., 2001 ). This mutation also decreases the reinforcing effects of alcohol and the acquisition of self-administration of cocaine (Houchi et al., 2005 ; Soria et al., 2005 ). In addition, as we saw in the previous section, rimonabant, a drug that blocks CB1 receptors, decreases the reinforcing effects of nicotine.

FIGURE 18.18 THC and Dopamine Secretion in the Nucleus Accumbens

The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of THC or an inert placebo.

(Based on data from Chen et al., 1990 .)

The primary reinforcing component of marijuana, THC, is one of approximately seventy different chemicals produced only by the cannabis plant. Another chemical, cannabidiol (CBD), plays an entirely different role. Unlike THC, which produces anxiety and psychotic-like behavior in large doses, CBD had antianxiety and antipsychotic effects. THC is a partial agonist of cannabinoid receptors, whereas CBD is an antagonist. Also unlike THC, CBD does not produce psychotropic effects: It is not reinforcing, and it does not produce a “high.” In recent years, levels of THC in marijuana have increased greatly, while levels of CBD have decreased. During the past decade, the numbers of people who seek treatment for dependence on cannabis has also increased (Morgan et al., 2010 ). Morgan and her colleagues recruited ninety-four people who used marijuana regularly for a study on the effects of THC and CBD. The investigators measured the concentration of THC and CBD in a sample of their marijuana and in a sample of their urine. They found that people smoking their customary marijuana with low levels of CBD and high levels of THC paid more attention to photographs of cannabis-related stimuli and said that they liked them better than those smoking their customary marijuana with higher levels of CBD. Both groups gave high ratings to food-related photographs, so CBD had no effect on their interest in food. (See Figure 18.19 . ) A study by Ren et al. ( 2009 ) found that an injection of CBD reduced heroin-seeking behavior in rats, even up to two weeks later, which indicates that the effects of this drug are not limited to marijuana. CBD did not affect the animals’ intake of heroin, but it did decrease the reinforcing effect of stimuli that had previously been associated with heroin.

FIGURE 18.19 Effects of Varying Ratios of Cannabidiol and THC in Marijuana

The graph shows that smoking marijuana with high levels of CBD decreases the pleasantness of photographs associated with marijuana smoking.

(Based on data of Morgan et al., 2010 .)

As we saw in Chapter 4 , the hippocampus contains a large concentration of THC receptors. Marijuana is known to affect people’s memory. Specifically, it impairs their ability to keep track of a particular topic; they frequently lose the thread of a conversation if they are momentarily distracted. Evidence indicates that the drug does so by disrupting the normal functions of the hippocampus, which plays such an important role in memory. Pyramidal cells in the CA1 region of the hippocampus release endogenous cannabinoids, which provide a retrograde signal that inhibits GABAergic neurons that normally inhibit them. In this way the release of endogenous cannabinoids facilitates the activity of CA1 pyramidal cells and facilitates long-term potentiation (Kunos and Batkai, 2001 ).

We might expect that facilitating long-term potentiation in the hippocampus would enhance its memory functions. However, the reverse is true; Hampson and Deadwyler ( 2000 ) found that the effects of cannabinoids on a spatial memory task were similar to those produced by hippocampal lesions. Thus, excessive activation of CB1 receptors in field CA1 appears to interfere with normal functioning of the hippocampal formation.

Three articles (Moore et al., 2007 ; Le Bec et al., 2009 ; Minozzi et al., 2010 ) report a disturbing finding: The incidence of psychotic disorders such as schizophrenia is increased in cannabis users—especially those who have used cannabis frequently. Of course, a correlational study cannot prove the existence of a cause-and-effect relationship. It is possible that people who are more likely to develop psychotic symptoms are also more likely to use cannabis. However, statistical adjustments suggest that a cause-and-effect relationship between cannabis use and psychosis cannot be ruled out. Moore et al. ( 2007 ) conclude “that there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life” (p. 319). This issue certainly deserves further study.

SECTION SUMMARY: Commonly Abused Drugs

Opiates produce analgesia, hypothermia, sedation, and reinforcement. Opiate receptors in the periaqueductal gray matter are responsible for the analgesia, those in the preoptic area for the hypothermia, those in the mesencephalic reticular formation for the sedation, and those in the ventral tegmental area and NAC at least partly for the reinforcement. A targeted mutation in mice indicates that μ opiate receptors are responsible for analgesia, reinforcement, and withdrawal symptoms. The release of the endogenous opioids may play a role in the reinforcing effects of natural stimuli or even other addictive drugs such as alcohol.

The symptoms that are produced by antagonist-precipitated withdrawal from opiates can be elicited by injecting naloxone into the periaqueductal gray matter and the locus coeruleus, which implicates these structures in these symptoms.

Cocaine inhibits the reuptake of dopamine by terminal buttons, and amphetamine causes the dopamine transporters in terminal buttons to run in reverse, releasing dopamine from terminal buttons. Besides producing alertness, activation, and positive reinforcement, cocaine and amphetamine can produce psychotic symptoms that resemble those of paranoid schizophrenia. The reinforcing effects of cocaine and amphetamine are mediated by an increase in dopamine in the NAC. Chronic methamphetamine abuse is associated with reduced numbers of dopaminergic axons and terminals in the striatum (revealed as a decrease in the numbers of dopamine transporters located there).

The status of nicotine as a strongly addictive drug (for both humans and laboratory animals) was long ignored, primarily because it does not cause intoxication and because the ready availability of cigarettes and other tobacco products does not make it necessary for addicts to engage in illegal activities. However, the craving for nicotine is extremely motivating. Nicotine stimulates the release of mesolimbic dopaminergic neurons, and injection of nicotine into the ventral tegmental area is reinforcing. Cannabinoid CB1 receptors are involved in the reinforcing effect of nicotine as well. Nicotine from smoking excites nicotinic acetylcholine receptors but also desensitizes them, which leads to unpleasant withdrawal effects. The activation of nicotinic receptors on presynaptic terminal buttons in the ventral tegmental area also produced long-term potentiation. Damage to the insula is associated with cessation of smoking, which suggests that this region plays a role in the maintenance of cigarette addiction. Suppression of its activity with inhibitory drugs reduces nicotine intake in laboratory animals. Nicotine stimulation of the release of GABA in the lateral hypothalamus decreases the activity of MCH neurons and reduces food intake, which explains why cessation of smoking often leads to weight gain. Infusion of an orexin antagonist in the insula suppresses nicotine intake. Activity of a circuit from the medial habenula to the interpeduncular nucleus does the same. This effect depends on the presence of neurons with α5 ACh receptors in the habenula.

Exposure to alcohol during the period of rapid brain development has devastating effects and is the leading cause of mental retardation. This exposure causes neural destruction through apoptosis. Alcohol and barbiturates have similar effects. Alcohol has positively reinforcing effects and, through its anxiolytic action, has negatively reinforcing effects as well. It serves as an indirect antagonist at NMDA receptors and an indirect agonist at GABAA receptors. It stimulates the release of dopamine in the NAC. Withdrawal from long-term alcohol abuse can lead to seizures, an effect that seems to be caused by compensatory up-regulation of NMDA receptors. Release of the endogenous opioids also plays a role in the reinforcing effects of alcohol. Increases in the numbers of μ opiate receptors during abstinence from alcohol may intensify craving.

The active ingredient in cannabis, THC, stimulates receptors whose natural ligand is anandamide. THC, like other addictive drugs, stimulates the release of dopamine in the NAC. The presence of cannabidiol (CBD) in marijuana has a protective effect against dependence on cannabis. The CB1 receptor is responsible for the physiological and behavioral effects of THC and the endogenous cannabinoids. A targeted mutation against the CB1 receptor reduces the reinforcing effect of alcohol, cocaine, and the opiates as well as that of the cannabinoids. Blocking CB1 receptors also decreases the reinforcing effects of nicotine. Cannabinoids produce memory deficits by acting on inhibitory GABAergic neurons in the CA1 field of the hippocampus. Two disturbing reports indicate that cannabis use is associated with the incidence of schizophrenia.

■ THOUGHT QUESTIONS

· 1. Although executives of tobacco companies used to insist that cigarettes were not addictive and asserted that people smoked simply because of the pleasure the act gave them, research indicates that nicotine is indeed a potent addictive drug. Why do you think it took so long to recognize this fact?

· 2. In most countries, alcohol is legal and marijuana is not. In your opinion, why? What criteria would you use to decide whether a newly discovered drug should be legal or illegal? Danger to health? Effects on fetal development? Effects on behavior? Potential for dependence? If you applied these criteria to various substances in current use, would you have to change the legal status of any of them?

Heredity and Drug Abuse

Not everyone is equally likely to become addicted to a drug. Many people manage to drink alcohol moderately, and most users of potent drugs such as cocaine and heroin use them “recreationally” without becoming dependent on them. Evidence indicates that both genetic and environmental factors play a role in determining a person’s likelihood of consuming drugs and of becoming dependent on them. In addition, there are both general factors (likelihood of taking and becoming addicted to any of a number of drugs) and specific factors (likelihood of taking and becoming addicted to a particular drug).

Tsuang et al. ( 1998 ) studied 3372 male twin pairs to estimate the genetic contributions to drug abuse. They found strong general genetic and environmental factors: Abusing any category of drug was associated with abusing drugs in all other categories: sedatives, stimulants, opiates, marijuana, and psychedelics. Abuse of marijuana was especially influenced by family environmental factors. Abuse of every category except psychedelics was influenced by genetic factors peculiar to that category. Abuse of heroin had a particularly strong unique genetic factor. Another study of male twin pairs (Kendler et al., 2003 ) found a strong common genetic factor for the use of all categories of drugs and found in addition that shared environmental factors had a stronger effect on use than on abuse. In other words, environment plays a strong role in influencing a person to try a drug and perhaps continue to use it recreationally, but genetics plays a stronger role in determining whether the person becomes addicted.

Goldman, Oroszi, and Ducci ( 2005 ) reviewed twin studies that attempted to measure the heritability of various classes of addictive disorders. Heritability (h2) is the percentage of variability in a particular population that can be attributed to genetic variability. The average value of h2 ranged from approximately 0.4 for hallucinogenic drugs to just over 0.7 for cocaine. As you will see in Figure 18.20 , the authors included addiction to gambling. (See Figure 18.20 . )

The genetic basis of addiction to alcohol has received more attention than addiction to other drugs. Alcohol consumption is not distributed equally across the population; in the United States, 10 percent of the people drink 50 percent of the alcohol (Heckler, 1983 ). Many twin studies and adoption studies confirm that the primary reason for this disparity is genetic.

FIGURE 18.20 Heritability (h2) of Addiction to Specific Addictive Agents

(Adapted from Goldman et al., 2005 .)

A susceptibility to alcoholism could conceivably be caused by differences in the ability to digest or metabolize alcohol or by differences in the structure or biochemistry of the brain. There is evidence that variability in the gene responsible for the production of alcohol dehydrogenase, an enzyme involved in metabolism of alcohol, plays a role in susceptibility to alcoholism. A particular variant of this gene, which is especially prevalent in eastern Asia, is responsible for a reaction to alcohol intake that most people find aversive and that discourages further drinking (Goldman, Oroszi, and Ducci, 2005 ). However, most investigators believe that differences in brain physiology—for example, those that control sensitivity to the reinforcing effects of drugs or sensitivity to various environmental stressors—are more likely to play a role. For example, increased sensitivity to environmental stressors might encourage the use of alcohol as a means to reduce the stress-related anxiety.

Investigators have also focused on the possibility that susceptibility to addiction may involve differences in functions of specific neurotransmitter systems. As we saw earlier, nicotinic ACh receptors that contain the α5 subunit, found on neurons in the medial habenula, play a role in inhibiting the reinforcing effects of nicotine. Genetic studies found that a particular allele of the gene responsible for the production of this receptor is associated with increased susceptibility to nicotine addiction and consequent development of lung cancer (Bierut, 2008 ). A study by Kuryatov, Berrettini, and Lindstrom ( 2011 ) found that the presence of this allele reduces the sensitivity of the α5 ACh receptors, and hence reduces the inhibitory effect of large doses of nicotine. The result would be increased susceptibility to the addictive effects of nicotine.

Renthal et al. ( 2009 ) performed a genomewide analysis of the effects of cocaine on genetic material in the mouse DNA. They found that cocaine turned on hundreds of genes, many of which were already known to be involved in the behavioral effects of the drug. One of their most interesting discoveries was that cocaine turns on the genes that produce sirtuins, proteins that play important regulatory roles in cells. They also found that a sirtuin agonist increased the reinforcing effects of cocaine and that a sirtuin antagonist decreased it. As other investigators have noted, their approach holds promise for discovering the molecular biology of addictive drugs and identifying potential treatments for people who abuse them.

SECTION SUMMARY: Heredity and Drug Abuse

Most people who are exposed to addictive drugs—even drugs with a high abuse potential—do not become addicts. Evidence suggests that the likelihood of addiction, especially to alcohol and nicotine, is strongly affected by heredity. Drug taking and addiction are affected by general hereditary and environmental factors that apply to all drugs and specific factors that apply to particular drugs. A better understanding of the physiological basis of reinforcement and punishment will help us to understand the effects of heredity on susceptibility to addiction. Some individual genes have been shown to affect abuse of particular drugs. For example, variations in the genes for alcohol dehydrogenase play a role in susceptibility to alcoholism, variations in the gene for the α5 ACh receptor affect the likelihood of nicotine addiction, and the genes that produce sirtuins modify responsiveness to the addictive potential of cocaine.

■ THOUGHT QUESTION

Can you think of any genetic factors besides the ones I’ve described in the previous section that might affect a person’s susceptibility to drug abuse? For example, what kinds of individual differences might affect the likelihood that a person tries a drug, likes the effects of the drug, is able to resist taking more of the drug, etc.?

Therapy for Drug Abuse

There are many reasons for engaging in research on the physiology of drug abuse, including an academic interest in the nature of reinforcement and the pharmacology of psychoactive drugs. But most researchers entertain the hope that the results of their research will contribute to the development of ways to treat and—better yet—prevent drug abuse in members of our own species. As you well know, the incidence of drug abuse is far too high; obviously, research has not yet solved the problem. However, real progress is being made.

The most common treatment for opiate addiction is methadone maintenance. Methadone is a potent opiate, just like morphine or heroin. If it were available in a form suitable for injection, it would be abused. (In fact, methadone clinics must control their stock of methadone carefully to prevent it from being stolen and sold to opiate abusers.) Methadone maintenance programs administer the drug to their patients in the form of a liquid, which they must drink in the presence of the personnel supervising this procedure. Because the oral route of administration increases the opiate level in the brain slowly, the drug does not produce a high, the way an injection of heroin will. In addition, because methadone is long lasting, the patient’s opiate receptors remain occupied for a long time, which means that an injection of heroin has little effect. Of course, a very large dose of heroin will still produce a “rush,” so the method is not foolproof.

A newer drug, buprenorphine, shows promise of being an even better therapeutic agent for opiate addiction than methadone (Vocci, Acri, and Elkashef, 2005 ). Buprenorphine is a partial agonist for the μ opiate receptor. (You will recall from Chapter 16 that a partial agonist is a drug that has a high affinity for a particular receptor but activates that receptor less than the normal ligand does. This action reduces the effects of a receptor ligand in regions of high concentration and increases it in regions of low concentration, as shown in Figure 16.14 .) Buprenorphine blocks the effects of opiates and itself produces only a weak opiate effect. Unlike methadone, it has little value on the illicit drug market. A randomized placebo-controlled trial compared the effectiveness of buprenorphine and buprenorphine plus naloxone in recovering opiate addicts (Fudala et al., 2003 ). People in the two drug-treatment groups reported less craving than those in the control group. The proportion of people who continued to be abstinent was 17.8 percent for people treated with buprenorphine, 20.7 percent for people treated with the combination of the two drugs, and only 5.8 percent for people receiving a placebo. (See Figure 18.21 . ) After one month, all subjects were given buprenorphine plus naloxone for eleven months. The percentage of people who abstained (indicated by the absence of opiates in urine samples) ranged from 35.2 to 67.4 percent at various times during the eleven-month period.

A major advantage of buprenorphine, besides its efficacy, is the fact that it can be used in office-based treatment. The addition of a small dose of naloxone ensures that the combination drug has no abuse potential—and will, in fact, cause withdrawal symptoms if it is taken by an addict who is currently taking an opiate.

FIGURE 18.21 Buprenorphine as a Treatment for Opiate Addiction

The graph shows the effects of treatment with buprenorphine, buprenorphine + naloxone, and a placebo on opiate craving in recovering opiate addicts.

(Based on data from Fudala et al., 2003 .)

As we saw, opiate receptor blockers such as naloxone and naltrexone interfere with the action of opiates. Emergency rooms always have one of these drugs available to rescue patients who have taken an overdose of heroin, and many lives have been saved by these means. But although an opiate antagonist will block the effects of heroin, the research reviewed earlier in this chapter suggests that it should increase the craving for heroin.

As we saw earlier, the reinforcing effects of cocaine and amphetamine are primarily a result of the sharply increased levels of dopamine that these drugs produce in the NAC. Drugs that block dopamine receptors certainly block the reinforcing effects of cocaine and amphetamine, but they also produce dysphoria and anhedonia. People will not tolerate the unpleasant feelings these drugs produce, so they are not useful treatments for cocaine and amphetamine abuse. Drugs that stimulate dopamine receptors can reduce a person’s dependence on cocaine or amphetamine, but these drugs are just as addictive as the drugs they replace and have the same deleterious effects on health.

An interesting approach to cocaine addiction was suggested by a study by Carrera et al. ( 1995 ), who conjugated cocaine to a foreign protein and managed to stimulate rats’ immune systems to develop antibodies to cocaine. The antibodies bound with molecules of cocaine and prevented them from crossing the blood–brain barrier. As a consequence, these “cocaine-immunized” rats were less sensitive to the activating effects of cocaine, and brain levels of cocaine in these animals were lower after an injection of cocaine. Since this study was carried out, animal studies with vaccines against cocaine, heroin, methamphetamine, and nicotine have been carried out, and several human clinical trials with vaccines for cocaine and nicotine have taken place (Cerny and Cerny, 2009 ; Carroll et al., 2011 ; Hicks et al., 2011 ; Stowe et al., 2011 ). The results of these animal studies and human trials are promising, and more extensive human trials are in progress. Theoretically, at least, treatment of addictions with immunotherapy should interfere only with the action of an abused drug and not with the normal operations of people’s reinforcement mechanisms. Thus, the treatment should not decrease their ability to experience normal pleasure.

Yet another approach to addiction is being investigated. As we saw in Chapters 13 , 16 , and 17 , deep brain stimulation (DBS) has been shown to have therapeutic effects on the symptoms of Parkinson’s disease, depression, anxiety disorders, and obsessive-compulsive disorder. A review by Luigjes et al. ( 2011 ) reported that seven animal studies have investigated the effectiveness of stimulation of the NAC, subthalamic nucleus (STN), dorsal striatum, habenula, medial PFC, and hypothalamus. Eleven studies with human subjects have targeted the NAC or the STN. So far, the authors report, the NAC appears to be the most promising target. For example, Mantione et al. ( 2010 ) stimulated the NAC of a forty-seven-year-old male smoker. The investigators reported that the man effortlessly stopped smoking and lost weight (he was obese).

Deep brain stimulation is not a procedure to take lightly. It involves brain surgery, which runs a risk of complications such as hemorrhage and infection. Of course, addictions include significant health risks, including death from infections or lung cancer, so each case requires an analysis of the potential risks and benefits. In any event, the use of DBS is currently experimental, and we must consider the strong possibility that such a dramatic procedure will produce placebo effects. (Yes, surgical procedures are susceptible to placebo effects.) A less invasive procedure, transcranial magnetic stimulation, is also being investigated as a treatment for addictions. For example, Amiaz et al. ( 2009 ) applied TMS over the left dorsolateral PFC of nicotine addicts. The treatment reduced tobacco use (verified by urinalysis), but the therapeutic effects eventually diminished over time.

A treatment similar to methadone maintenance has been used successfully as an adjunct to treatment for nicotine addiction. For several years, chewing gum containing nicotine has been available, and more recently, transdermal patches that release nicotine through the skin have been marketed. Both methods maintain a sufficiently high level of nicotine in the brain to decrease a person’s craving for nicotine. Once the habit of smoking has subsided, the dose of nicotine can be decreased to wean the person from the drug. Carefully controlled studies have shown that nicotine maintenance therapy, and not administration of a placebo, is useful in treatment for nicotine dependence (Raupach and van Schayck, 2011 ). However, nicotine maintenance therapy is most effective if it is part of a counseling program.

One of the limitations of treating a smoking addiction with nicotine maintenance is that this procedure does not provide an important non-nicotine component of smoking: the sensations produced by the action of cigarette smoke on the airways. As we saw earlier in this chapter, stimuli associated with the administration of addictive drugs play an important role in sustaining an addictive habit. Smokers who rate the pleasurability of puffs of normal and denicotinized cigarettes within seven seconds, which is less time than it takes for nicotine to leave the lungs, enter the blood, and reach the brain, reported that puffing denicotinized cigarettes produced equally strong feelings of euphoria and satisfaction and reductions in the urge to smoke. Furthermore, blocking the sensations of cigarette smoke on the airways by first inhaling a local anesthetic diminishes smoking satisfaction. Denicotinized cigarettes are not a completely adequate substitute for normal cigarettes, because nicotine itself, not just the other components of smoke, makes an important contribution to the sensations felt in the airways. In fact, trimethaphan, a drug that blocks nicotinic receptors but does not cross the blood–brain barrier, decreases the sensory effects of smoking and reduces satisfaction. Because trimethaphan does not interfere with the effects of nicotine on the brain, this finding indicates that the central effects of nicotine are not sufficient by themselves to maintain an addiction to nicotine. Instead, the combination of an immediate cue from the sensory effects of components of cigarette smoke on the airways and a more delayed, and more continuous, effect of nicotine on the brain serves to make smoking so addictive (Naqvi and Bechara, 2005 ; Rose, 2006 ).

As we saw earlier in this chapter, studies with laboratory animals have found that the endogenous cannabinoids are involved in the reinforcing effects of nicotine as well as those of marijuana. A recent clinical trial reported that rimonabant, a drug that blocks CB1 receptors, was effective in helping smokers to quit their habit (Henningfield et al., 2005 ). One significant benefit of the drug was a decrease in the weight gain that typically accompanies cessation of smoking and often discourages smokers who are trying to quit. As we saw in Chapter 12 , the endocannabinoids stimulate eating, apparently by increasing the release of MCH and orexin. Blocking CB1 receptors abolishes this effect and helps to counteract the effects of withdrawal from nicotine on these neurons. But the problem with rimonabant is that some clinical trials have found that the drug can cause anxiety and depression, which provoked the withdrawal of its approval as an antiobesity medication. At the present time, approval of rimonabant to treat nicotine addiction seems unlikely.

Another drug, varenicline, has been approved for therapeutic use to treat nicotine addiction. Varenicline was developed especially as a treatment for nicotine addiction. The drug serves as a partial agonist for the nicotinic receptor, just as buprenorphine serves as a partial agonist for the μ opiate receptor. As a partial nicotinic agonist, varenicline maintains a moderate level of activation of nicotinic receptors but prevents high levels of nicotine from providing excessive levels of stimulation. Figure 18.22 shows the effects of treatment with varenicline and bupropion on continuous abstinence rates of smokers enrolled in a randomized, double-blind, placebo control study (Nides et al., 2006 ). By the end of the fifty-two-week treatment program, 14.4 percent of the smokers treated with varenicline were still abstinent, compared with 6.3 percent and 4.9 percent of the smokers who received bupropion and placebo, respectively. (See Figure 18.22 . )

FIGURE 18.22 Varenicline as a Treatment for Smoking

The graph shows the percentage of smokers treated with varenicline, bupropion, or placebo who abstained from cigarette smoking.

(Based on data from Nides et al., 2006 .)

As I mentioned earlier, several studies have shown that opiate antagonists decrease the reinforcing value of alcohol in a variety of species, including our own. This finding suggests that the reinforcing effect of alcohol—at least in part—is produced by the secretion of endogenous opioids and the activation of opiate receptors in the brain. A study by Davidson, Swift, and Fitz ( 1996 ) clearly illustrates this effect. The investigators arranged a double-blind, placebo-controlled study with sixteen college-age men and women to investigate the effects of naltrexone on social drinkers. None of the participants were alcohol abusers, and pregnancy tests ensured that the women were not pregnant. They gathered around a table in a local restaurant/bar for three two-hour drinking sessions, two weeks apart. For several days before the meeting, they swallowed capsules that contained either naltrexone or an inert placebo. The results showed that naltrexone increased the latency to take the first sip and to take a second drink and that the blood alcohol levels of the naltrexone-treated participants were lower at the end of the session. In general, the people who had taken naltrexone found that their drinks did not taste very good—in fact, some of them asked for a different drink after taking the first sip.

These results are consistent with reports of the effectiveness of naltrexone as an adjunct to programs designed to treat alcohol abuse. For example, O’Brien, Volpicelli, and Volpicelli ( 1996 ) reported the results of two long-term programs using naltrexone along with more traditional behavioral treatments. Both programs found that administration of naltrexone significantly increased the likelihood of success. As Figure 18.23 shows, naltrexone decreased the participants’ craving for alcohol and increased the number of participants who managed to abstain from alcohol. (See Figure 18.23 . ) Currently, many treatment programs are using a sustained-release form of naltrexone to help treat alcoholism, and results with the drug have been encouraging (Gastfriend, 2011 ).

One more drug has shown promise for treatment of alcoholism. As we saw earlier in this chapter, alcohol serves as an indirect agonist at the GABAA receptor and an indirect antagonist at the NMDA receptor. Acamprosate, an NMDA-receptor antagonist that has been used in Europe to treat seizure disorders, was tested for its ability to stop seizures induced by withdrawal from alcohol. The researchers discovered that the drug had an unexpected benefit: Alcoholic patients who received the drug were less likely to start drinking again (Wickelgren, 1998 ). Several double-blind studies have confirmed the therapeutic benefits of acamprosate, but these benefits appear to be modest (Rösner et al., 2010 ).

FIGURE 18.23 Naltrexone as a Treatment for Alcoholism

The graphs show mean craving score and proportion of patients who abstained from drinking while receiving naltrexone or a placebo.

(Based on data from O’Brien et al., 1996 .)

SECTION SUMMARY: Therapy for Drug Abuse

Although drug abuse is difficult to treat, researchers have developed several useful therapies. Methadone maintenance replaces addiction to heroin by addiction to an opiate that does not produce euphoric effects when administered orally. Buprenorphine, a partial agonist for the μ opiate receptor, reduces craving for opiates. Because it is not of interest to opiate addicts (especially when it is combined with naltrexone), it can be administered by a physician at an office visit. The development of antibodies to cocaine and nicotine in humans and to several other drugs in rats holds out the possibility that people may someday be immunized against addictive drugs, preventing the entry of the drugs into the brain. Deep brain stimulation of the NAC and STN and TMS of the prefrontal cortex show promise as a treatment for addiction. Nicotine-containing gum and transdermal patches help smokers to combat their addiction. However, sensations from the airways produced by the presence of cigarette smoke play an important role in addiction, and oral and transdermal administration do not provide these sensations. Rimonabant, a CB1 receptor antagonist, aids in smoking cessation and reduces the likelihood of weight gain, but it may produce adverse emotional effects. Bupropion, an antidepressant drug, has also been shown to help smokers stop their habit. Varenicline, a partial agonist for the nicotinic receptor, may be even more effective. The most effective pharmacological adjunct to treatment for alcoholism appears to be naltrexone, an opiate receptor blocker that reduces the drug’s reinforcing effects. Acamprosate, an NMDA-receptor antagonist, appears to facilitate treatment of alcoholism.

A personal note: You are now at the end of the book (as you well know), and you have spent a considerable amount of time reading my words. While working on this book, I have tried to imagine myself talking to someone who is interested in learning something about the physiology of behavior. As I mentioned in the preface, writing is often a lonely activity, and the imaginary audience helped to keep me company. If you would like to turn this communication into a two-way conversation, write to me: [email protected]

■ THOUGHT QUESTION

Consider the experimental studies with laboratory animals described in this chapter that have revealed ways that addictive drugs interact with the brain. For example, we saw that orexin and MCH are involved in the reinforcing effects of drugs, and that the insula is specifically involved in the reinforcing effects of nicotine. Can you think of ways that these findings might lead to new ways to treat drug addiction?

Review Questions

Study and Review on MyPsychLab

Describe two common features of addition: positive and negative reinforcement.

Describe the neural mechanisms responsible for craving and relapse.

Review the neural basis of the reinforcing effects and withdrawal effects of opiates.

Describe the behavioral and physical effects of cocaine and amphetamine.

Describe the behavioral and physical effects of nicotine.

Describe the behavioral and physical effects of alcohol and cannabis.

Describe research on the role that heredity plays in addiction.

Discuss different methods of therapy for drug abuse.

Explore the Virtual Brain in MyPsychLab

■ DRUG ADDICTION AND BRAIN REWARD CIRCUITS

The brain circuitry thought to be involved in drug abuse is shown in the Drug Addiction and Brain Reward Circuits module of the virtual brain.