Drug addiction dramatically shifts a person's attention, priorities, and behaviors towards a focus almost entirely on seeking out and taking drugs. Now, an animal study funded by the National Institute on Drug Abuse, part of the National Institutes of Health, has identified some of the specific long-term adaptations in the brain's reward system that may contribute to this shift. These long-lasting brain changes may underlie the maladaptive learning that contributes to addiction and to the propensity for relapse, even after years of abstinence from the drug. The study was published in Neuron on July 30, 2008.

Investigators from the University of California, San Francisco (UCSF) using an animal model of addiction, were able to distinguish brain changes in rats trained to self-administer cocaine, versus those animals that were trained to self-administer natural rewards such as food, or sucrose for several weeks. The investigators also were able to look at how much the "expectation" of receiving the drug influenced those brain changes by comparing rats trained to self-administer the drug versus animals who received the same amount of cocaine, but received it passively, i.e. they could not control their own drug taking by self-administration.

It has been hypothesized that persistent drug seeking alters the brain's natural reward and motivational system. The current study focuses on how drug seeking alters the communication between brain cells in this critical circuitry. In the normal processes of learning and memory formation there is a well documented strengthening of communication between brain cells, this process is known as "long-term potentiation" (LTP). The new study reports that LTP was similar in the rats that had learned to self administer cocaine, food or sucrose, but with a critical distinction. The increase in LTP due to cocaine persisted for up to three months of abstinence, but the increase in response to natural rewards dissipated after only three weeks. Importantly, the nature of the cocaine experience had a strong effect on the outcome, since rats exposed to cocaine when they did not expect it (passive infusions) displayed no LTP, neither transient nor long lasting. Finally, the study showed that LTP in rats that self-administered cocaine persisted after they were trained to stop drug self-administration behaviors. This indicates that, once established, it is very difficult to reverse the "memory trace" associated with drug reward.

"This research provides a better characterization of the variables, at the cellular, circuit, and behavioral level that contribute to the persistent nature of addictive disorders," said Dr. Elias A. Zerhouni, NIH director.
"The researchers were able to illuminate why drug related memories are so stable," said NIDA Director Dr. Nora Volkow. "Their persistence is highly refractory to new learning, which makes our jobs that much tougher, and reminds us that treatment must recognize and address the high propensity for relapse almost anywhere down the road."

"These results indicate that the LTP induced by self administered cocaine is more persistent than that produced by natural rewards, such as food; and that the LTP is not just a result of exposure to cocaine, but also is linked to the drug's effects and the animal's learning to obtain the drug," said Dr. Billy Chen, postdoctoral fellow at UCSF's Ernest Gallo Clinic and Research Center and lead author of the study. "These are important distinctions that will help us better understand how addiction develops, and why drugs can overshadow other natural rewards and become the mainstay of an addicted person's life."

In 2006, six million Americans age 12 and older had abused cocaine in any form. There are currently no medications for cocaine addiction, therefore standard treatments typically rely on behavioral interventions. However, relapse after treatment for cocaine addiction is common.

READ THIS IMPORTANT REPORT WRITTEN BY THE DIRECTOR OF NIDA. IT PRESENTS A COMPREHENSIVE PICTURE OF ADDICTION, ADDICTION TREATMENT, AND THE BRAIN


How Science Has Revolutionized the Understanding of Drug Addiction

Throughout much of the last century, scientists studying drug abuse labored in the shadows of powerful myths and misconceptions about the nature of addiction. When science began to study addictive behavior in the 1930s, people addicted to drugs were thought to be morally flawed and lacking in willpower. Those views shaped society's responses to drug abuse, treating it as a moral failing rather than a health problem, which led to an emphasis on punitive rather than preventative and therapeutic actions. Today, thanks to science, our views and our responses to drug abuse have changed dramatically. Groundbreaking discoveries about the brain have revolutionized our understanding of drug addiction, enabling us to respond effectively to the problem.

As a result of scientific research, we know that addiction is a disease that affects both brain and behavior. We have identified many of the biological and environmental factors and are beginning to search for the genetic variations that contribute to the development and progression of the disease. Scientists use this knowledge to develop effective prevention and treatment approaches that reduce the toll drug abuse takes on individuals, families, and communities.

Despite these advances, many people today do not understand why individuals become addicted to drugs or how drugs change the brain to foster compulsive drug abuse. This booklet aims to fill that knowledge gap by providing scientific information about the disease of drug addiction, including the many harmful consequences of drug abuse and the basic approaches that have been developed to prevent and treat the disease. At the National Institute on Drug Abuse (NIDA), we believe that increased understanding of the basics of addiction will empower people to make informed choices in their own lives, adopt science-based policies and programs that reduce drug abuse and addiction in their communities, and support scientific research that improves the Nation's well-being.


Why study drug abuse and addiction?

Abuse and addiction to alcohol, nicotine, and illegal substances cost Americans upwards of half a trillion dollars a year, considering their combined medical, economic, criminal, and social impact.1,2,3. Every year, abuse of illicit drugs and alcohol contributes to the death of more than 100,000 Americans, while tobacco is linked to an estimated 440,000 deaths per year.


People of all ages suffer the harmful consequences of drug abuse and addiction.

- Babies exposed to legal and illegal drugs in the womb may be born premature and underweight. This drug exposure can slow the child's intellectual development and affect behavior later in life.

- Adolescents who abuse drugs often act out, do poorly academically, and drop out of school. They are at risk of unplanned pregnancies, violence, and infectious diseases.

- Adults who abuse drugs often have problems thinking clearly, remembering, and paying attention. They often develop poor social behaviors as a result of their drug abuse, and their work performance and personal relationships suffer.

- Parents' drug abuse often means chaotic, stress-filled homes and child abuse and neglect. Such conditions harm the well-being and development of children in the home and may set the stage for drug abuse in the next generation.


How does science provide solutions for drug abuse and addiction?

Scientists study the effects that drugs have on the brain and on people's behavior. They use this information to develop programs for preventing drug abuse and for helping people recover from addiction. Further research helps transfer these ideas into practice in our communities.


What is drug addiction?

Addiction is defined as a chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences. It is considered a brain disease because drugs change the brain - they change its structure and how it works. These brain changes can be long lasting, and can lead to the harmful behaviors seen in people who abuse drugs.


Why do people take drugs?

In general, people begin taking drugs for a variety of reasons:

- To feel good. Most abused drugs produce intense feelings of pleasure. This initial sensation of euphoria is followed by other effects, which differ with the type of drug used. For example, with stimulants such as cocaine, the "high" is followed by feelings of power, self-confidence, and increased energy. In contrast, the euphoria caused by opiates such as heroin is followed by feelings of relaxation and satisfaction.

- To feel better. Some people who suffer from social anxiety, stress-related disorders, and depression begin abusing drugs in an attempt to lessen feelings of distress. Stress can play a major role in beginning drug use, continuing drug abuse, or relapse in patients recovering from addiction.

- To do better. The increasing pressure that some individuals feel to chemically enhance or improve their athletic or cognitive performance can similarly play a role in initial experimentation and continued drug abuse.

- Curiosity and "because others are doing it." In this respect adolescents are particularly vulnerable because of the strong influence of peer pressure; they are more likely, for example, to engage in "thrilling" and "daring" behaviors.


If taking drugs makes people feel good or better, what's the problem?

At first, people may perceive what seem to be positive effects with drug use. They also may believe that they can control their use; however, drugs can quickly take over their lives. Consider how a social drinker can become intoxicated, put himself behind a wheel and quickly turn a pleasurable activity into a tragedy for him and others. Over time, if drug use continues, pleasurable activities become less pleasurable, and drug abuse becomes necessary for abusers to simply feel "normal." Drug abusers reach a point where they seek and take drugs, despite the tremendous problems caused for themselves and their loved ones. Some individuals may start to feel the need to take higher or more frequent doses, even in the early stages of their drug use.


Is continued drug abuse a voluntary behavior?

The initial decision to take drugs is mostly voluntary. However, when drug abuse takes over, a person's ability to exert self control can become seriously impaired. Brain imaging studies from drug-addicted individuals show physical changes in areas of the brain that are critical to judgment, decision-making, learning and memory, and behavior control. Scientists believe that these changes alter the way the brain works, and may help explain the compulsive and destructive behaviors of addiction.


Why do some people become addicted to drugs, while others do not?

As with any other disease, vulnerability to addiction differs from person to person. In general, the more risk factors an individual has, the greater the chance that taking drugs will lead to abuse and addiction. "Protective" factors reduce a person's risk of developing addiction.


What factors determine if a person will become addicted?

No single factor determines whether a person will become addicted to drugs. The overall risk for addiction is impacted by the biological makeup of the individual - it can even be influenced by gender or ethnicity, his or her developmental stage, and the surrounding social environment (e.g., conditions at home, at school, and in the neighborhood).


Which biological factors increase risk of addiction?

Scientists estimate that genetic factors account for between 40 and 60 percent of a person's vulnerability to addiction, including the effects of environment on gene expression and function. Adolescents and individuals with mental disorders are at greater risk of drug abuse and addiction than the general population.


What environmental factors increase the risk of addiction?

Home and Family. The influence of the home environment is usually most important in childhood. Parents or older family members who abuse alcohol or drugs, or who engage in criminal behavior, can increase children's risks of developing their own drug problems.

Peer and School. Friends and acquaintances have the greatest influence during adolescence. Drug-abusing peers can sway even those without risk factors to try drugs for the first time. Academic failure or poor social skills can put a child further at risk for drug abuse.


What other factors increase the risk of addiction?

- Early Use. Although taking drugs at any age can lead to addiction, research shows that the earlier a person begins to use drugs the more likely they are to progress to more serious abuse. This may reflect the harmful effect that drugs can have on the developing brain; it also may result from a constellation of early biological and social vulnerability factors, including genetic susceptibility, mental illness, unstable family relationships, and exposure to physical or sexual abuse. Still, the fact remains that early use is a strong indicator of problems ahead, among them, substance abuse and addiction.

- Method of Administration. Smoking a drug or injecting it into a vein increases its addictive potential. Both smoked and injected drugs enter the brain within seconds, producing a powerful rush of pleasure. However, this intense "high" can fade within a few minutes, taking the abuser down to lower, more normal levels. It is a starkly felt contrast, and scientists believe that this low feeling drives individuals to repeated drug abuse in an attempt to recapture the high pleasurable state.


The brain continues to develop into adulthood and undergoes dramatic changes during adolescence.

One of the brain areas still maturing during adolescence is the prefrontal cortex11 - the part of the brain that enables us to assess situations, make sound decisions, and keep our emotions and desires under control. The fact that this critical part of an adolescent's brain is still a work-in-progress puts them at increased risk for poor decisions (such as trying drugs or continued abuse). Thus, introducing drugs while the brain is still developing may have profound and long-lasting consequences.


Drugs and the Brain


Introducing the Human Brain

The human brain is the most complex organ in the body. This three-pound mass of gray and white matter sits at the center of all human activity - you need it to drive a car, to enjoy a meal, to breathe, to create an artistic masterpiece, and to enjoy everyday activities. In brief, the brain regulates your basic body functions; enables you to interpret and respond to everything you experience; and shapes your thoughts, emotions, and behavior.

The brain is made up of many parts that all work together as a team. Different parts of the brain are responsible for coordinating and performing specific functions. Drugs can alter important brain areas that are necessary for life-sustaining functions and can drive the compulsive drug abuse that marks addiction. Brain areas affected by drug abuse -

- The brain stem controls basic functions critical to life, such as heart rate, breathing, and sleeping.

- The limbic system contains the brain's reward circuit - it links together a number of brain structures that control and regulate our ability to feel pleasure. Feeling pleasure motivates us to repeat behaviors such as eating - actions that are critical to our existence. The limbic system is activated when we perform these activities - and also by drugs of abuse. In addition, the limbic system is responsible for our perception of other emotions, both positive and negative, which explains the mood-altering properties of many drugs.

- The cerebral cortex is divided into areas that control specific functions. Different areas process information from our senses, enabling us to see, feel, hear, and taste. The front part of the cortex, the frontal cortex or forebrain, is the thinking center of the brain; it powers our ability to think, plan, solve problems, and make decisions.


How does the brain communicate?

The brain is a communications center consisting of billions of neurons, or nerve cells. Networks of neurons pass messages back and forth to different structures within the brain, the spinal column, and the peripheral nervous system. These nerve networks coordinate and regulate everything we feel, think, and do.


- Neuron to Neuron
Each nerve cell in the brain sends and receives messages in the form of electrical impulses. Once a cell receives and processes a message, it sends it on to other neurons.

- Neurotransmitters - The Brain's Chemical Messengers
The messages are carried between neurons by chemicals called neurotransmitters. (They transmit messages between neurons.)

- Receptors - The Brain's Chemical Receivers
The neurotransmitter attaches to a specialized site on the receiving cell called a receptor. A neurotransmitter and its receptor operate like a "key and lock," an exquisitely specific mechanism that ensures that each receptor will forward the appropriate message only after interacting with the right kind of neurotransmitter.

- Transporters - The Brain's Chemical Recyclers
Located on the cell that releases the neurotransmitter, transporters recycle these neurotransmitters (i.e., bringing them back into the cell that released them), thereby shutting off the signal between neurons.