The Addicted Brain: Why Such Poor Decisions?

One central puzzle haunts any consideration of drug addiction, for research scientists as well as for the rest of the population: Why do men and women who have developed addiction obsessively seek and use drugs, even after the drugs no longer produce pleasure? Why do individuals who are addicted to drugs persist in behavior that damages their health and corrodes the quality of their lives? How can they make such poor decisions?

We are far from having complete answers to these questions, but NIDA-sponsored research has begun to provide clues that might lead to answers. We are beginning to understand that drugs exert persistent neurobiological effects that extend beyond the midbrain centers of pleasure and reward to disrupt the function of the brain's frontal cortex--the thinking region of the brain, where risks and benefits are weighed and decisions made.

The exploration of drugs' effects on decision making is a logical extension of NIDA's decades-long scientific inquiry into the neurobiology of drug abuse and addiction, which was the focus of a 2-day symposium held in May to honor the accomplishments of the late Dr. Roger Brown, associate director for neuroscience in NIDA's Division of Neuroscience and Behavioral Research (see "Dr. Roger M. Brown: Drug Abuse Neuroscience Pioneer"). Many of the presentations given at that meeting summarized research that has led to our detailed understanding of crucial midbrain dopamine pathways in the ventral tegmental area and nucleus accumbens, where drugs trigger pleasure and establish reinforcement--the desire to repeat the behavior that produces the pleasure.

Other presentations described changes in distribution and density of dopamine receptors in the frontal cortex in animals and humans after drug use. Still other presentations depicted the network of neural circuits that use dopamine and other neurotransmitters to maintain finely tuned two-way communication among brain regions. These networks allow the midbrain regions, where drugs act as reinforcers, to influence and be influenced by the frontal cortical regions, the site of control over motivation, behavior, and inhibition. Taken together, these presentations sketch a rough outline of addiction as an integrated process that may explain how exposure to a drug triggers changes throughout the brain, leading from initial intoxication and reinforcement through craving to compulsive, continued drug use despite destructive consequences.

NIDA-supported research has established that the brain's frontal regions, in particular the orbitofrontal cortex, play a role in all stages of the development of addiction. For example, imaging studies conducted within NIDA's Intramural Research Program (IRP) and at Harvard Medical School show changes in cortical blood flow during initial drug exposure (see "Cocaine's Effects on Cerebral Blood Flow Differ Between Men and Women"). Research described in this issue (see "New Avenues of Research Explore Addiction's Disrupted and Destructive Decision Making") shows that drug addiction is associated with altered cortical activity and decision making that appears to overvalue reward, undervalue risk, and fail to learn from repeated errors.

These recent studies illustrate the similarity of addiction to some disorders that are not associated with drugs. For example, compulsive behavior and poor choices are hallmarks of obsessive-compulsive disorder and pathological gambling. These disorders, too, are characterized by disruption of the frontal brain's capacity for reason and control. NIDA and the National Institute of Mental Health are collaborating to investigate such commonalities by developing new chemical "labels" that will allow us to use brain imaging techniques to study in more detail the structure and activity of frontal brain regions in patients suffering addiction or other decision-making disorders.

The emerging picture of addiction as a disease of compulsion and disrupted control (the frontal brain) and not merely pursuit of pleasure (the midbrain) suggests new possibilities for treatment. The neural networks that link brain regions--particularly the interwoven connections between the ventral tegmental area, nucleus accumbens, and prefrontal cortex--may offer targets for pharmacological therapies to modulate signaling that results in compulsive behavior or destructive choice.

Studying the role of frontal brain function also will contribute to development of new behavioral therapies, which help patients recognize conditions that trigger drug craving and alter their behavior to resist the compulsion. Investigators can test these cognitive-behavioral therapies in the same way, and with the same patients, that they have employed to study craving and decision making--through imaging that provides real-time images of the functioning brain.

How do drugs lead to such destructive decisions? Answering this question will not answer all questions about drug abuse and addiction. It will not tell us what role genetics or environment plays in the progression from initial pleasure to crippling compulsion. It will not explain whether a dysfunction in decision making predisposes one person to drug use, while in another person drug use triggers such a dysfunction. But looking for the answer will bring us closer to developing a comprehensive understanding of addiction and, more important, closer to more effective treatment for men and women whose lives are diminished by decisions that bring only harm.