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
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
Nora Volkow, M.D.: "When the pathology [of addiction] erodes the
various [involved brain] systems, you disrupt the ability to compensate, and
the addictive disease erodes and destroys the life of the
Credit: David Hathcox
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
"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
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
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
"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
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
"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
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
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 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>.▪