(L) Volkow May Have Uncovered Answer to Addiction Riddle (2004)

Comments: Nora Volkow is the head of NIDA. This covers the role of dopamine (D2) receptors and desensitization in addiction.

Volkow May Have Uncovered Answer to Addiction Riddle

Psychiatric News June 4, 2004

Volume 39 Number 11 Page 32

Jim Rosack

Addictive disorders may be a “shift in the salience meter” in which normal stimuli are no longer recognized as salient, yet the effects of drugs of abuse on the brain’s dopamine system are highly salient, NIDA’s director believes.

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 City.

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 addicted.”

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 again.

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?”

Imaging Fills In Some Blanks

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.

Resetting the Salience Meter

“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 crowd’s delight.

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 attention!”

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 addiction?

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 feel.

“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 self controlled 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.”