Nora Volkow, M.D., has studied the human brain's response to addictive
substances for nearly 25 years. Now, after all those years of clinical
observation and research, she is using her position as the director of the
National Institute on Drug Abuse (NIDA) to find the answer to a fundamental
question: why does the human brain become addicted?
Indeed, after a quarter of a century pondering that deceptively simple
question, Volkow—using her own research and that of other addiction
researchers—now believes the field is well on its way to an answer.
Under her direction, NIDA-funded researchers are in hot pursuit of the
answer. Last month, Volkow shared her thoughts with an overflow crowd during a
distinguished psychiatrist lecture at APA's annual meeting in New York
An extensive body of research has shown that all drugs of addiction
increase dopamine activity in the human brain's limbic system. But, Volkow
stressed, "while this increase in dopamine is essential to create
addiction, it does not actually explain addiction. If you give a drug of abuse
to anyone, their dopamine levels increase. Yet the majority do not become
Over the past decade, brain-imaging studies have indicated that the
increase in dopamine associated with drugs of abuse is less in those who are
addicted than in those who are not addicted. Yet in those vulnerable to
addiction, this comparatively smaller increase in dopamine levels leads to a
subjectively intense desire to seek out the drug of abuse again and
Nora Volkow, M.D.: "What we need to know is what effects and
changes are common to all drugs of abuse."
"Is dopamine playing a role in this transition?" Volkow asked."
What actually leads to the compulsion to take the drug of abuse? What
fuels the addict's loss of control?"
Advances in brain-imaging techniques have allowed researchers to use
different biochemical markers to look at the components of the dopamine
system—the dopamine transporter and the dopamine receptors (at least
four different subtypes of dopamine receptors have been identified to date).
In addition, researchers are now able to watch changes in the brain's
metabolism over time, using biochemical markers for glucose, to see how drugs
of abuse affect that metabolism.
"These advances have allowed us to look at the different drugs of
abuse and what specific effects and changes [in the dopamine system] are
associated with each of them," Volkow explained. "What we need to
know is what effects and changes are common to all drugs of abuse."
It became apparent early on that some drugs of abuse appeared to affect the
dopamine transporter, yet others did not. Research then focused on dopamine
receptors and metabolism to find common effects, Volkow explained. One of her
studies in the 1980s showed consistent decreases in dopamine receptor
concentration, particularly in the ventral striatum, of patients addicted to
cocaine, compared with control subjects. Volkow was intrigued to find that
these decreases were long-lasting, well beyond the resolution of acute
withdrawal from the cocaine.
"The reduction in dopamine type-2 receptors is not specific to
cocaine addiction alone," Volkow continued. Other research found similar
results in patients addicted to alcohol, heroin, and methamphetamine.
"So, what does it mean, this common reduction in D2
receptors in addiction?" Volkow asked.
"I always start with the simpler answers, and if they don't work,
then I allow my brain to become convoluted," Volkow noted, to the
The dopamine system, she said, responds to salient stimuli—to
something that is either pleasurable, important, or worth paying attention to.
Other things can be salient as well, such as novel or unexpected stimuli or
aversive stimuli when they are threatening in nature.
"So dopamine is really saying, `Look, pay attention to this—it
is important,'" Volkow said. "Dopamine signals salience."
But, she continued, dopamine generally stays within the synapse for only a
short time—less than 50 microseconds—before it is recycled by the
dopamine transporter. So under normal circumstances, dopamine receptors should
be plentiful and sensitive if they are going to pay attention to a short burst
of dopamine that is intended to carry the message, "Pay
With the decrease in D2 receptors associated with addiction, the
individual has a decreased sensitivity to salient stimuli acting as natural
reinforcers for behaviors.
"Most drugs of abuse, however," Volkow said, "block the
dopamine transporter in the brain's reward circuits, allowing the
neurotransmitter to remain in the synapse for a comparative eternity. This
results in a large and lasting reward, even though the individual has reduced
numbers of receptors.
"Over time, addicts learn that natural stimuli are no longer
salient," Volkow stressed. "But the drug of abuse is."
So, she asked, "How do we know which is the chicken and which is the
egg?" Does the continued use of a drug of abuse lead to decreases in
D2 receptors, or does an innately lower number of receptors lead to
Research is now addressing that question, Volkow confirmed. And it appears
that the latter may be the answer. In nonaddicted individuals who have not
been exposed to drugs of abuse, there is a widely varying range of
D2 receptor concentrations. Some normal control subjects have
D2 levels as low as some cocaine-addicted subjects.
In one study, Volkow said, researchers gave intravenous methylphenidate to
non-addicted individuals and asked them to rate how the drug made them
"Those with high levels of D2 receptors said it was awful,
and those with lower levels of D2 receptors were more likely to say
it made them feel good," Volkow reported.
"Now," she continued, "this does not necessarily mean
that those individuals with low levels of D2 receptors are
vulnerable to addiction. But it may mean that individuals who have high levels
of D2 receptors end up having too intense a response to the large
increase in dopamine seen in drugs of abuse. The experience is inherently
aversive, potentially protecting them from addiction."
In theory, she suggested, if addiction treatment researchers could find a
way to cause an increase in D2 receptors in the brain, "you
might be able to transform those individuals with lower D2 levels
and create aversive behavior in response to drugs of abuse."
Recent findings from one of Volkow's postdoctoral research fellows showed
that it is possible in mice to introduce into the brain an adenovirus with the
gene for D2 receptor production, causing an increase in
D2 receptor concentration. In response, the mice correspondingly
reduce their selfcontrolled intake of alcohol. Other researchers recently
replicated the findings with cocaine as well.
"But," Volkow cautioned, "you need more than just a low
level of D2 receptors." Imaging studies of glucose metabolism
have indicated that metabolism decreases significantly in the orbital frontal
cortex (OFC) and cingulate gyrus (CG) in response to cocaine, alcohol,
methamphetamine, and marijuana in those addicted, compared with control
subjects. And, she added, this decrease in metabolism is strongly correlated
with decreased levels of D2 receptors.
Volkow postulated that dysfunction in the OFC and CG "causes
individuals to no longer be able to judge the salience of the drug—they
take the drug of abuse compulsively, yet it does not give them pleasure and,
in most instances, has negative consequences." Yet still, they cannot
stop using the drug.
Other research is showing that inhibitory control; reward, motivation, and
drive; and learning and memory circuits are all abnormal in individuals with
an addictive disorder, she noted. As a result, treatment of addiction requires
an integrated, systems approach.
"No one chooses to become addicted," Volkow concluded."
They simply are cognitively unable to choose not to be addicted."▪