Addiction and the progressive loss of control over behavior that seems to accompany the addictive process are the result of changes in multiple regions of the brain.

That's what Nora Volkow, M.D., director of the National Institute on Drug Abuse, described in a lecture titled "The Neurobiology of Free Will" at APA's 2007 annual meeting in San Diego in May.

Changes occur initially as a result of the abnormal increase in dopamine that results from use of all drugs of addiction and eventually affect memory and attention, the regulation of impulsivity, and executive function.

What Volkow described is an emerging understanding of addiction and the underlying neurobiology of free will and choice that is vastly more sophisticated than theories that were dominant 15 years ago, when addiction was hypothesized as an overactivation of reward systems in the brain by dopamine.

Instead, what has evolved is a picture of multiple regions of the brain being progressively compromised—the anterior cingulate gyrus, which governs attention and regulation of impulsivity; the orbital prefrontal cortex, which mediates the assignment of value to stimuli in the environment; and the dorsal lateral prefrontal cortex, which governs executive function and decision making.FIG1

It is a picture of the destruction of complex, interacting systems corresponding remarkably with the clinical picture of progressive alcoholism and drug addiction: each of these interacting regions of the brain compensate for each other, so that in the early stages, when damage to the brain caused by the pathological increase in dopamine is still relatively minor, the addict may yet assert some control over choices.

But as the addiction progresses with continual administration of the abused drug, all of these brain systems are progressively destroyed, so that in the later stages the individual may seem to lack all power of choice and free will.

"We have come to see addiction as a disease that involves the destruction of multiple systems in the brain that more or less are able to compensate for one another," Volkow said. "When the pathology erodes the various systems, you disrupt the ability to compensate, and the addictive disease erodes and destroys the life of the individual."

Dopamine has been recognized for some time as a key in addiction, the neurochemical that alcohol and all drugs of abuse are known to increase dramatically in the brain. But until recently, it was believed that dopamine acted principally on limbic areas of the brain, associated with reward and pleasure.

Volkow explained that it is not just pleasure, but" saliency"—the brain's perception of stimuli in the environment as vital or important to pay attention to—that dopamine signals. So, natural stimuli, such as food, sex, or money, or aversive stimuli, such as the perception of danger or fear, also increase dopamine in the brain.

But drugs and alcohol are known to be much more potent stimulators, flooding the brain with dopamine at levels that are" supraphysiological" and ultimately destructive to multiple brain regions.

"What drugs are doing is exactly the same thing that nature has generated for us to respond to stimuli in the environment, but the drugs do it in a much more potent way," Volkow said. "It is believed that this large increase in signaling leads to plastic changes in the brain that underlie compulsive drug intake."

Under the earlier conception of dopamine as working primarily on reward centers of the brain, it was believed that addicts were experiencing a greater sense of reward or pleasure. But Volkow described studies from the early 1990s showing that in fact cocaine abusers who were given intravenous methylphenidate—a proxy for cocaine—experienced a less-intense high while also experiencing greater drug craving than control subjects.

Moreover, several studies have documented the surprising fact that cocaine addicts actually have lower levels of dopamine D₂ receptors than control subjects, she said. This in turn has led to a new insight—not that addicts are experiencing greater pleasure from drugs of abuse, but that they are actually less sensitive to the effects of dopamine.

And so they seek out drugs because of the very potency with which they can increase dopamine in the brain, often at the expense of other pleasurable natural stimulants that do not increase dopamine so dramatically. And it is the neurobiological reflection of the phenomenon of "diminishing effects" that addicts typically report clinically: they require more and more of the drug to get a similar effect.

"Cocaine-addicted people are not taking the drug because it is more pleasurable," Volkow said. "If anything, it is documented that the sensitivity of the reward system in the brain is in fact decreased. They have a hypofunctional dopaminergic system.

"The person who is addicted starts to seek the drug of abuse because it is powerful enough to activate the system," she said.

Underscoring that insight is research described by Volkow showing that when rats trained to press a lever for alcohol are injected with an adenovirus carrying a D₂ receptor, their alcohol consumption is markedly diminished.

"An overexpression of D₂ receptors profoundly depresses the consumption of alcohol," Volkow said. "This is fascinating because if we can develop strategies to increase D₂ receptors, we may be able to do interventions that prevent people from doing drugs.

"The dopamine system is in our brains in order for us to be responsive to external stimuli, so it behooves us as a therapeutic community to do interventions that can lead to an increase in D₂ receptors," she said.

Also corresponding to the clinical picture of addiction is the discovery that dopamine can be released into the brain as a conditioned response to stimuli associated with the drug of abuse. Volkow reported results of a study by her and colleagues published in the June 2006 Journal of Neuroscience in which increases in dopamine in striatal regions of the brain were measured in 18 cocaine users while watching neutral video images of nature, and again when watching video images of people preparing and administering cocaine.

When watching the cocaine cue videos, subjects experienced an increase in dopamine. Moreover, the magnitude of the increase was significantly associated with subjects' self-report of craving.

"They are not taking cocaine—only observing someone taking cocaine," she said. "That by itself is able to increase dopamine in the striatal regions.

"This is ver y important clinically because we know that when patients go into an environment where there are people taking the drug, they react," Volkow added. "This is the essence of the conditioned response, and it makes the treatment of addiction a very tough challenge."

The carnage in the brain wrought by addiction extends as well to the prefrontal cortex, areas of the brain that govern executive function and the ability to change behavior in response to changing circumstances.

In a January 1999 report in the American Journal of Psychiatry, Volkow and colleagues showed that cocaine abusers had diminished glucose metabolism compared with healthy controls; other research by Volkow and colleagues established a correlation between glucose metabolism in the brains of cocaine and methamphetamine abusers and the number of D₂ receptors in striatal regions of the brain.

And a September 2006 report in the Archives of General Psychiatry showed that in nonalcoholic subjects with a family history of alcoholism, the level of D₂ receptors was higher than in nonalcoholic subjects with no family history, and was associated with glucose metabolism in the orbitofrontal cortex, the cingulate gyrus, and the dorsolateral prefrontal cortex. According to the report, the finding suggests that the presence of D₂ receptors may be protective.

"This highlights the importance of the orbital frontal cortex in our ability to regulate behaviors that are driven initially by the plastic response to drugs, but then by conditioned responses," Volkow said.

When that ability is lost over time due to the effects of addiction, behavior cannot be modified as a function of circumstances, making it extraordinarily difficult for addicts to change their behavior even when they know cognitively it has bad consequences for them."

She concluded by suggesting that potential clinical applications of these findings lay in psychotherapeutic and pharmacologic interventions designed to strengthen the systems of all those areas of the brain affected by dopamine.

"Dopamine is involved not only with reward and prediction of reward, and with more than learning and memory, but also with motivation and executive function via regulation of frontal activity," Volkow said.

An abstract of "Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction" is posted online at<www.jneurosci.org/cgi/content/abstract/26/24/6583>.▪