The Disordered Mind

by Eric R. Kandel

  LOOKING AHEAD

  Studies of emotion from Darwin and James onward support Damasio’s contention that the philosopher René Descartes was in error when he claimed that emotion and reason, body and mind are separate. Fear is a case in point: we cannot simply put mind over matter and reason our way out of post-traumatic stress disorder or chronic anxiety. Studies of how animals learn fear, coupled with imaging studies of the human brain, have given us an understanding of where and how fear operates, including how our brain consolidates the memory of fear. Now innovative psychotherapy and drugs are beginning to help people with anxiety disorders unlearn fear.

  Emotion is integral to any personal, social, or moral decision we make. Scientists have found that people with damage to regions of the brain that integrate emotional signals into decision making have great difficulty reaching even simple, everyday decisions. And because they are also unable to engage emotion in moral decision making, these people often make different choices in moral quandaries than people without such brain damage.

  Imaging studies have revealed that people who exhibit psychopathic behavior have abnormalities in several areas of the brain concerned with emotional processing and moral functioning. These abnormalities lead to a profound lack of empathy and connection to others. Research in this area is complicated by society’s reaction to the crimes committed by the psychopathic prisoners being studied, but if scientists can identify biological and genetic markers of the disorder, treatment and possibly prevention may follow—and along with them a greater understanding of the basic biological mechanisms underlying our moral functioning.

  9

  THE PLEASURE PRINCIPLE AND FREEDOM OF CHOICE: ADDICTIONS

  We have seen that normal fear can spiral into post-traumatic stress disorder, leaving people unable to cope with everyday life. Likewise, our normal attraction to pleasure can go into overdrive, causing the brain to produce an excess of dopamine and resulting in addiction. That addiction may be to substances, such as drugs, alcohol, or tobacco, or to activities, such as gambling, eating, or shopping.

  Addiction creates havoc in people’s lives. It may cost them their job, their health, or their spouse. They may end up in poverty or in prison. Sometimes, addiction leads to death. People who are addicted do not want to keep doing what they are doing, yet they cannot stop—repeated abuse has eroded the brain’s ability to control desires and emotion. Thus, addiction robs us of our will, our ability to select freely among several possible courses of action.

  Addiction to substances takes an enormous toll on our society, with an estimated economic cost of over $740 billion annually in the United States. That economic cost climbs far higher if we consider compulsive disorders that are similar to addiction, such as pathological gambling and overeating. The human cost of addiction, for individuals and for society, is incalculable. While we have made progress over the past several decades in treating people with certain kinds of addictions, such as alcoholism, available therapies for most addictions, whether behavioral approaches or medications, have proved inadequate. Fortunately, scientists have made important advances over the last thirty years in understanding the biology of addiction, raising the hope that new treatments will emerge from these new insights.

  In the past, addiction was considered to be a manifestation of weak moral character. Today, we understand that it is a mental disorder, a malfunction of the brain’s reward system, the neural circuitry responsible for positive emotions and the anticipation of rewards. This chapter introduces us to the brain’s reward system and explains how addiction manipulates it. We learn about the stages of addiction and explore various avenues of research. Finally, we learn about new methods of treating people with these chronic disorders.

  THE BIOLOGICAL BASIS OF PLEASURE

  All of our positive emotions, our feelings of pleasure, can be traced to the neurotransmitter dopamine. Although our brain contains relatively few dopamine-producing neurons, they play an outsized role in the regulation of behavior, largely because of their intimate involvement with the production of pleasure.

  First discovered in the 1950s by the Swedish pharmacologist Arvid Carlsson, dopamine is released primarily by neurons in two regions of the brain: the ventral tegmental area and the substantia nigra (fig. 9.1). Neurons in the ventral tegmental region extend their axons to the hippocampus, which is involved in the memory of people, places, and things, and to the three most important brain structures for regulating emotion: the amygdala, which orchestrates emotion; the nucleus accumbens, a region of the striatum that mediates the impact of emotion; and the prefrontal cortex, which imposes will and control on the amygdala. This communications network, known as the mesolimbic pathway, is the major network in the brain’s reward system. It puts dopamine-producing neurons in a position to broadcast information widely, including to regions throughout the cerebral cortex.

  Soon after Carlsson discovered dopamine, James Olds and Peter Milner, two neuroscientists at McGill University, explored the neurotransmitter’s function further.1 They began by implanting an electrode deep in the center of a rat’s brain. The placement of the electrode was largely happenstance, but it turned out that Olds and Milner had inserted it right next to the nucleus accumbens, a crucial component of the mesolimbic pathway (fig. 9.1). They then installed a lever in the cage of the rats that would allow the animals to administer a small jolt of electricity to their brain in the neighborhood of the nucleus accumbens.

  Figure 9.1. The communications network formed by dopamine-producing neurons in the mesolimbic pathway is the key pathway in the brain’s reward system.

  The current was so weak that the scientists could not feel it when they applied it to their skin, yet it was pleasurable to the rats when applied to the nucleus accumbens. They would press the lever over and over and over again to produce the desired stimulus. In fact, the pleasure from the electrode was so intense that the animals soon lost interest in everything else. They stopped eating and drinking. They stopped all courtship behavior. They just crouched in the corner of their cage, transfixed by their bliss. Within days, many of the rats died of thirst.

  It took several decades of painstaking research before Olds and Milner, and eventually others, discovered that the rats were suffering from an excess of dopamine. Electrical stimulation of the nucleus accumbens had triggered the release of massive amounts of this neurotransmitter, overwhelming the animals with pleasure.

  THE BIOLOGY OF ADDICTION

  The standard view of a reward is that it is something that makes us feel happy or feel good. Maybe it’s chocolate cake, or a new gadget, or a beautiful work of art. Neuroscientists take a slightly different view: a reward is basically any object or event that produces “approach” behavior and leads us to spend attention and energy on it. By reinforcing approach behavior, rewards help us learn.

  Specialized regions in the brain appeared early in evolution to regulate our responses to pleasurable stimuli in the environment, such as food, water, sex, and social interactions. All drugs of abuse act on this reward system. Each drug acts on a different target, but in every case the net effect is to increase the amount and persistence of dopamine in the brain. Activation of dopamine signaling, along with activation of several other important reward signals that vary from drug to drug, is responsible for the initial high that people experience on drugs.

  Wolfram Schultz, a neuroscientist at the University of Cambridge, has studied the role of rewards in learning.2 Schultz’s experiments with monkeys drew on Pavlov’s early experiments with conditioned learning in dogs. Schultz would play a loud tone to monkeys, wait for a few seconds, and then squirt some drops of apple juice into their mouths. While the experiment was unfolding, Schultz monitored the electrical activity inside individual dopamine-producing neurons in the animals’ brains. At first, the neurons didn’t fire until the juice was delivered. However, once the animals learned that the tone predicted the arrival of juice, the same neurons began firing at the sound of the tone—th
at is, at the prediction of reward instead of the reward itself. To Schultz, the interesting feature about this dopamine learning system was that it is all about expectation.

  The expectation of reward helps us form habits. A good habit, one that is adaptive, helps us survive by enabling us to perform many important behaviors automatically, without thinking about them. Adaptive habits are promoted by the release of dopamine into the prefrontal cortex and the striatum, the areas of the brain involved with control and with reward and motivation. The release of dopamine not only creates a feeling of pleasure, it also conditions us. Conditioning, as we know, creates a long-term memory that enables us to recognize a stimulus the next time we see it and to respond accordingly. If the stimulus is positive, as in the case of adaptive habits, conditioning motivates us to pursue it. For example, if you eat a banana and find it delicious, the next time you see a banana you will feel motivated to eat it.

  Addictive drugs, whether legal or illegal—our body doesn’t make a distinction—also stimulate dopamine-producing neurons in the brain’s reward system. In this case, however, the result is greatly increased dopamine concentrations in the prefrontal cortex and the striatum. The excess dopamine generates intense pleasure and creates a conditioned response to the environmental cues that predict pleasure. Such cues—say, the smell of cigarette smoke or the sight of a needle—elicit an intense craving for the drug, which, in turn, elicits drug-seeking behavior.

  Why do some substances, such as cocaine, produce addiction rather than an adaptive habit? Normally, when dopamine binds to receptors on target cells it is taken up and removed from the synapse within a short period of time. However, brain imaging reveals that cocaine, a highly addictive drug, interferes with the removal of dopamine from the synapse. As a result, dopamine lingers there and continues to produce pleasurable feelings that persist beyond those produced by ordinary physiological stimuli. In this way cocaine hijacks the brain’s reward system.

  This hijacking takes place in several well-defined stages, beginning with the addictive process itself, in which a drug takes over the brain’s reward system, and ending with an inability to resist taking the drug. Every drug of abuse that we are aware of increases concentrations of dopamine in the pleasure centers of the cortex, and this increased dopamine is believed to produce the rewarding effects that define the drug experience. Many addictive drugs release additional chemicals that mediate reward.

  As a person continues to take the drug, however, he or she builds up a tolerance to it. The dopamine receptors no longer respond as effectively as they did before. The same amount of the drug that initially produced a high—the pleasurable feeling—now produces a normal feeling. As a result, the person needs more of the drug to produce an equivalent high. Nora Volkow, director of the National Institute on Drug Abuse and a pioneer in the study of how addiction affects the human brain, has documented this process in a series of imaging studies showing that the striatum stops responding once a person has used cocaine for some time.3

  At first glance, drug tolerance doesn’t seem to make sense. If a person takes a drug to feel good but that drug is not effective at increasing dopamine (which causes the pleasurable feeling), then what is the point of taking the drug? This is where positive associations come into play. An addicted person has learned to associate the drug with a certain place, certain people, certain music, and a certain time of day. Paradoxically, these associations rather than the drug itself often lead to the most tragic aspect of addiction: relapse.

  Relapse is possible even after a person has given up drugs for weeks, months, or even years. The memory of the pleasurable drug experience and the cues associated with it essentially persist forever. Exposure to those cues—the sight or smell of the drug, walking down a street where the person used to buy the drug, or bumping into people who used the drug—triggers a tremendous urge to use the drug again.

  A particularly interesting study of addiction by Lee Robins, a sociologist at Washington University in St. Louis, involves Vietnam veterans who had become hooked on very high quality heroin while overseas. Amazingly, most of them were able to conquer their addiction when they returned to the United States because none of the cues that had encouraged them to use heroin in Vietnam were present at home.4

  RESEARCH ON ADDICTION

  Because of the ease with which addicted people relapse, we now know that addiction is a chronic disease, like diabetes. People can be helped to avoid relapse, but recovery is a lifelong process requiring great effort and vigilance on the part of the addicted person. To date, there is no cure for addiction, but in recent years scientists have made progress in understanding the disorder.

  The first important avenue of investigation is brain imaging, as pioneered by Volkow. Imaging enables us to look inside the brain of an addicted person and see what areas are disrupted. These abnormal patterns of activity help to explain why some people cannot control the urge to take drugs, even though the drugs themselves are no longer pleasurable.5

  In one study, Volkow gave cocaine to addicted people and to people who were not addicted and then compared images of their brains, using positron emission tomography (PET). She expected to see a lot of activity in the main reward areas of the brain, and that’s exactly what she did see—in the brains of people who were not addicted. As dopamine concentrations increased, activity in their reward system spiked dramatically. To her surprise, however, she saw almost no activity in the brains of addicted people. These findings explain how our brain builds up a tolerance to drugs.6

  Volkow was drawn to the study of addiction because of the insights it offers into the normal workings of the brain. As she has pointed out in a personal communication, she has always been interested in understanding how the human brain controls and sustains its behavior.

  The study of drugs of abuse and addiction enabled her to investigate a condition in which the capacity to control oneself is disrupted. Brain imaging, in turn, enabled her to carry out studies in human beings afflicted by addiction. By studying the effects of drugs in the brain, she was able to gain insights into the neural circuits that shape behavior in response to environmental contexts and exposures and how these are subjectively experienced by the individual. In particular, she was interested in changes that are associated with pleasure, fear, and cravings.

  Similarly, by studying the brain of a person who is addicted and comparing it with the brain of someone who is not, she could identify the neural circuits that are disrupted and explore how this disruption relates to the disruption of self-control. From these studies, it became clear that addiction is a disease of the brain and that the changes triggered by drug exposure influence circuits in the brain that process motivation and reward.

  The second avenue of research into addiction, as Darwin might have predicted, involves experiments on animals. Because the dopamine system exists in similar form in many other animals, scientists can study craving and addiction in monkeys, rats, and even flies. While many advances in modern medicine have come about through the use of animal models, that is especially true in addiction.

  Animals readily become addicted to drugs, and the physiological and anatomical changes in their brains are similar to those in people. Addicted animals no longer show activity in the reward areas of the brain. Furthermore, the same factors that increase the likelihood of addiction in people also increase the likelihood of addiction in animals. We know, for example, that chronic stress will increase vulnerability to drug abuse in rats and in people because such drugs can transiently relieve some of the physiological and emotional consequences of stress. We also know that rats will choose to self-administer and addict themselves to the same range of drugs as people. Moreover, animals given unlimited access to a very potent drug like cocaine or heroin will overdose and kill themselves.

  We have also learned from animal models how repeated exposure to a drug of abuse changes the brain’s reward system. Some of the changes occur within the neurons that produce dopamine, impairi
ng their function and their ability to send dopamine signals to other regions of the brain. These changes are linked to drug tolerance—the reduced reward that individuals obtain from drugs as they take them repeatedly—as well as to the diminished responsiveness to rewards that people experience during withdrawal (fig. 9.2).

  Eric Nestler, at Icahn School of Medicine at Mount Sinai Hospital in New York City, notes that this diminished responsiveness is similar to the inability of people with depression to experience pleasure. In studies of mice addicted to cocaine, Nestler and his colleagues found that “by manipulating the reward pathway in these mice, we were not only able to prevent the rewarding effects of cocaine, but surprisingly, we could push these animals to a point where they were anhedonic—unable to experience pleasure.” Nestler has since studied the role of the brain’s reward system in depression as well as in addiction.7

  Scientists have identified the numerous chemical changes in animals’ brains that are induced by addictive drugs. Some of the changes are related to a drug’s ability to diminish the reward system’s sensitivity to dopamine. Other changes are related to a drug’s ability to promote compulsive, repetitive behavior. For example, scientists have found a molecule that modifies the expression of certain genes in a way that helps perpetuate memory. By disrupting the activity of this molecule in rats that are addicted to morphine, the scientists could eliminate the animals’ cravings for the drug.8 Such research raises the intriguing possibility that future treatments for addiction will focus not just on the pleasure pathway, but on our memory of pleasure as well.