NEW YORK CITY—“I have never encountered a single patient who wants to be addicted. They are addicted at enormous personal and social cost, but something fundamental has changed in their brains so that the drives that normally motivate others are disrupted by the drugs,” said Nora D. Volkow, MD, Director of the National Institute on Drug Abuse.

Addiction is not caused by bad behavior or acting out, but by pathologic changes in brain mechanisms, Dr. Volkow reported at the American Psychiatric Association’s 157th Annual Meeting. The user’s brain chemistry plays a crucial role in the addictive qualities of a drug, she added. “The effects of a drug are not just a function of its pharmacologic properties but of the interaction between the drug and the unique biochemical characteristics of the subject’s brain,” she explained.

Using imaging techniques such as positron emission tomography (PET) and fMRI to study the brains of people with addictions, Dr. Volkow and her colleagues have made significant strides toward piecing together the complex puzzle of addiction. The dopamine system “is one of the main targets for drug abuse,” and dopamine appears to “play a role in the transition from being able to experience a drug like any other event in your life to experiencing it as one of extreme saliency, setting the stage for the process that leads to addiction,” she said.

WHAT IS THE DOPAMINE CONNECTION?

Dr. Volkow described her study of 20 hospitalized cocaine abusers who showed markedly decreased reductions in dopamine D2 receptors, compared with 23 controls. The diminution of receptors was even apparent four months after cocaine discontinuation. These findings extended the results of other studies showing dopamine D2 receptor reductions in current cocaine abusers as well as studies showing reductions in D2 receptors in other addictions such as alcoholism, heroin, and methamphetamine. “This study documented for the first time the biochemical changes in the brain of addicted people, and showed that the reductions [in dopamine D2 receptors] are long-lasting,” she said.

Addicts have fewer dopamine D2 receptors in several regions of their brains than do controls. Through dopamine receptors, which include D2 but also D1, D3, D4, and D5 receptors, dopamine regulates the function of several circuits that are known to be involved in addiction including rewarding, motivation, memory, and inhibitory control circuits. Of particular relevance in the reward, motivation, and control circuits is the role of dopamine in regulating activity in the orbitofrontal cortex and in the anterior cingulate gyrus.

The orbitofrontal cortex is responsible, among other things, for determining saliency and attributing importance (valence)—both pleasant and aversive—to events and experiences. The experienced saliency will then motivate the behaviors that result from these events. Saliency is determined, in part, by the amount of “liberated” or available dopamine to interact with the dopamine receptors. When dopamine is liberated, it interacts, among others, with D2 receptors, signaling that an event, experience, or object is salient, deserves attention, and should be consigned to memory for future attention.

There is a very narrow window of time—less than 50 milliseconds—for a given DA molecule to communicate this message, Dr. Volkow noted. Upon release, dopamine is almost immediately removed from the synapse by the dopamine transporter, and thus has a very limited opportunity to reach the receptor. Fewer receptors for the same amount of released dopamine means less “received” dopamine and consequently less dopamine signaling. “We postulate that this makes the person less sensitive to day-to-day salient events, such as natural reinforcers,” Dr. Volkow pointed out. Drug abusers are therefore more prone to boredom, which Dr. Volkow called “the motivational thirst of the brain,” which drives the person to “engage in a reinforcing activity, such as reading a book, listening to music, calling a friend, going jogging, as a means to break the uncomfortable feeling of boredom.”

Drugs such as cocaine, methamphetamine, and amphetamine all block the transporter responsible for removing dopamine from the synapse, so dopamine remains accessible to the receptor for a longer period of time. This leads to increased dopamine signaling, despite diminished receptors. “The drug abuser learns that natural reinforcers are no longer salient, but the drug of abuse is salient and very reinforcing,” Dr. Volkow explained.

DOPAMINE D2 RECEPTORS AND PREVENTION

Having more dopamine D2 receptors in the brain may confer protective benefit against vulnerability to addiction, Dr. Volkow noted. She and her colleagues have measured the number of dopamine D2 receptors in a group of nonaddicted subjects, then administered intravenous methylphenidate. The subjects who described their experience as pleasurable had significantly fewer dopamine D2 receptors than those who described it as nonpleasurable. Liberating more dopamine triggered an aversive experience because it boosted dopamine levels “over the threshold of what would be considered reinforcing.” The experience was too intense and so unpleasant that these subjects refused to return for a follow-up study, Dr. Volkow reported.

This finding has relevance for understanding predisposition to drugs of abuse, she said. A person who experiences a positive reaction to a drug is more likely to use it again than one who reacts negatively—the difference in reactions might lie in the number of dopamine D2 receptors in their brains. In this respect, having high receptor levels could favor aversive responses to drugs of abuse thus decreasing the likelihood that the person will take the drug when exposed to it again. Indeed, in animal studies, increasing the levels of dopamine D2 receptors markedly decreases the administration of, and preference for, alcohol.

BRAIN-BASED COMPULSION

Once individuals have had an initially pleasurable experience with a drug, Dr. Volkow explained, they seek to replicate it, and, if vulnerable, with repeated drug administration will become addicted. In the transition from recreational use to addiction the initial motivation of taking the drug for its pleasurable experience is shifted to taking it to overcome the intense urge to have the drug. This urge drives the drug use in the addicted person even when the drug is no longer perceived as being pleasurable. Dr. Volkow postulated that the urge and compulsion to take the drug in the addicted person share some similarities to the urge of engaging in the compulsive behavior in patients with obsessive compulsive disorder who, like drug-addicted subjects, also display abnormalities in the orbitofrontal cortex and anterior cingulate gyrus.

“What these two diseases have in common is a compulsive quality of behavior and an obsessiveness regarding the target,” she observed. A person with obsessive compulsive disorder who engages in excessive handwashing may recognize cognitively that the hands are clean but feels driven to continue washing them. Addicts are similarly driven. “They say, ‘I don’t know why I take the drug, it’s not even pleasurable any more, I just can’t control it,’” Dr. Volkow said.

The orbitofrontal cortex and the anterior cingulate gyrus are involved in decision-making and in inhibitory control, so their disruption could lead to the inability to recognize that something is harmful and to stop doing it. This is shown in animal studies. For example, a group of primates were trained to press a lever in order to obtain a food reward. When the lever stopped producing the reward, most animals eventually stopped pressing it. Animals with a damaged orbitofrontal cortex continued to press the lever. “The animal lost its ability to realize that this reinforcer was no longer salient,” Dr. Volkow commented.

SOCIAL IMPLICATIONS

Abnormal brain circuitry and/or neurochemistry does not necessarily determine that a person must become addicted, or cannot recover from addiction. “Predisposition is not the same as predetermination,” Dr. Volkow emphasized.

Although there are genetic factors that play a role in determining brain structure and function, environmental factors are equally important, Dr. Volkow said. She cited studies demonstrating that stress reduces the number of dopamine D2 receptors in the brain. Primate studies showed greater numbers of receptors in dominant versus subordinate monkeys. One study looked at monkeys raised in isolation, all with relatively low levels of dopamine D2 receptors. However, once they were socialized and a hierarchical order was established, the dominant monkeys increased the levels of dopamine D2 receptors, while the subordinate monkeys remained unchanged. Interestingly, the dominant animals in whom the group housing led to increases in D2 receptors when exposed to cocaine did not administer it to any significant extent whereas the subordinate animals who remained with low receptor levels readily administered cocaine.

Epidemiologic studies have shown that poverty, lack of parental support, and other environmental stressors are associated with a higher risk for addiction. The neurobiologic mechanism underlying the environmental factors associated with addiction are not properly understood, but the primate study cited above suggests that one of the mechanisms may relate to the effects of chronic stressor on dopamine activity (ie, D2 receptor down-regulation), Dr. Volkow suggested. She advocated the development of therapeutic intervention to counteract the detrimental effects that social stressors may have on the brain as a means to protect against drug abuse.

Regarding those who are already addicted, Dr. Volkow encouraged multipronged approaches that include medications as well as psychotherapeutic approaches to strengthen the saliency of day-to-day events while interfering with the conditioned responses and enhancing motivational value of drugs in the addicted person. As for future research in drug addiction, she encouraged transdisciplinary approaches to investigate the interactions between genes and environment as well as system approaches that integrate information on genetics, molecular biology, brain circuitry, and individual and social behavior.

—Batya Swift Yasgur

Suggested Reading
Volkow ND, Fowler JS, Wang GJ, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004;9:557-569.
Volkow ND, Fowler JS, Wang GJ. The addicted human brain: insights from imaging studies. J Clin Invest. 2003;111:1444-1451.
Volkow ND, Fowler JS, Wang GJ. Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol. 2002;13:355-366.
Volkow ND, Fowler JS. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb Cortex. 2000;10:318-325.
White NM. Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction. 1996;91:921-949.

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