Some neuroscientists are experiencing what amounts to a natural high. For the first time, they have captured images of the brains of addicts in the throes of craving for a drug, revealing the neural basis for addiction.
The finding caps a decade or more of intensive brain research seeking the grail of substance abuse, the neurological circuitry that compels addicts to pursue the next fix. And the discovery confirms a number of emerging scientific hunches about the neurology of addiction.
For instance, no matter what the addictive substance is -- amphetamines, heroin, alcohol or nicotine -- all seem to activate a single circuit for pleasure deep in the most ancient part of the brain. This circuit, for the neurotransmitter dopamine, is the site of the high that addictive drugs bring.
And fine-grained studies of brain cells reveal that repeatedly dosing the brain with addictive drugs is akin to a chemical assault that alters the very structure of the neurons in the circuitry for pleasure. These changes starve brain cells of dopamine, triggering a craving for the addictive drugs that will once again swamp the brain with it.
A drumbeat of findings from dozens of scientific laboratories, several within the last few months and as yet not published, herald these conclusions, which "offer an extraordinary insight into the brain basis of drug addiction," said Dr. Alan I. Leshner, director of the National Institute on Drug Abuse. He added, "There have been a tremendous number of major advances in the last year."
The identity of this brain circuit for addiction is a scientific flashback of sorts, if not a hallucinatory deja vu: the same brain area was the focus of intense study as long ago as the 1950s, when psychologists routinely implanted electrodes into rats' brains in the region they then called the brain's "reward center." After the rats were trained to push a lever to stimulate this center, they would do nothing else, even forsaking food and water to dose themselves with dollops of rodent bliss -- an animal model of addiction. But the specific neural circuitry involved was, at the time, a scientific mystery.
Today that mystery seems to have been solved by using positron emission tomography scans of the brains of patients being treated for cocaine addiction. Reports from three different laboratories using PET scans show that when addicts feel a craving for a drug, there is a high level of activation in a strip of areas ranging from the amygdala and the anterior cingulate to the tip of both temporal lobes.
This mesolimbic dopamine system, as it is called, shows heightened metabolic activity "when people are in a profound state of craving for cocaine, primed to seek it out and take it," said Dr. Annarose Childress, a neuroscientist at the University of Pennsylvania who did one of the PET studies. The work has been reported at scientific meetings but has not yet been published. The same system seems to be ordinarily in play to provide a sense of pleasure in whatever people find rewarding, like sex or chocolate or a job well done. Dopamine may also be part of a reward system in creatures as different from humans as bees, other researchers have shown.
In Dr. Childress's study, PET scans were done on patients under treatment for cocaine addiction while the patients were being exposed to cues that had made them crave cocaine in the past -- like seeing a videotape of people taking cocaine or handling crack pipes or other drug paraphernalia. Drug treatment programs routinely caution patients to avoid such Pavlovian cues, which addicts have learned to associate with the drug high itself, because the cues have long been known to trigger the craving for the drug.
The PET scans showed activation in the mesolimbic dopamine system as the addicts described feeling intense cravings for cocaine.
The mesolimbic dopamine system connects structures high in the brain, especially the orbitofrontal cortex, in the prefrontal area behind the forehead, with the amygdala in the brain's center, and with the nucleus accumbens, a structure that in animal research has proved to be a major site of activity in addiction, although in humans it is about the size of a squished pea, too small to register in PET images. The ultimate source of this dopamine system is the same brain region where psychologists stuck electrodes decades earlier to make rats endlessly stimulate themselves for pleasure, a location called the ventral tegmental area.
These brain areas have emerged in the last several years as hot spots in research on every addictive substance studied, and some that create dependency, if not strict addiction. Last month, for instance, Italian researchers reported in the journal Nature that the mesolimbic dopamine system was active in nicotine addiction, adding tobacco to a roster that includes heroin, morphine, cocaine, amphetamines, marijuana and alcohol.
In addiction studies with lab animals, a main site of activity is the outer layer of the nucleus accumbens. In humans, a nearby interconnected structure, the amygdala, "is more important in craving," said Dr. George F. Koob, a neuroscientist at the Scripps Institute in San Diego. "If people have a lesion in a section of the amygdala, they no longer link pleasure to its causes -- they wouldn't experience a favorite food as enjoyable," he said.
What ties years of brain research on addiction together in a "final bow," Koob said, is the new finding by Dr. Childress and others that "what lights up during craving is the temporal lobe, particularly the amygdala, where all these pathways converge." Koob reviewed earlier findings on the dopamine system in the May issue of the journal Neuron.
The various brain pathways he is referring to all have a particular kind of cell that has the D2 dopamine receptor, which is distinct from other dopamine receptors, like those involved in Parkinson's disease. PET images of cocaine patients taken over several weeks after they stop using the drug show a drop in those neuronal activity levels that is consistent with a lessened ability to receive dopamine. Although the degree of this reduction lessens over time, it is evident "even a year and a half after withdrawal," said Dr. Nora Volkow, director of the Division of Nuclear Medicine at Brookhaven National Laboratory on Long Island. She has also done some of the other recent PET studies.
This pattern of reduced brain activity directly reflects the course of the craving. "The highest risk of relapse for cocaine addicts is during the third and fourth week after they've stopped taking the drug," said Dr. Joseph C. Wu, a psychiatrist at the University of California at Irvine who has made PET images of cocaine addicts that verify the other reports. "You see the lowest levels of activity in the mesolimbic dopamine system during that time." This work has also been reported at meetings but is still unpublished.
The brains of addicts are almost back to normal after a year without the drug, though not completely, he said. "If you can stay abstinent for about a year," Wu said, "you've weathered the periods of greatest vulnerability." Scientists are still debating whether the dopamine cells ever fully return to normal.
The gross patterns of brain activity detected in PET scans represent changes at the microscopic level that are so dramatic that they are akin to the kinds of changes that result from a brain injury, in the view of Dr. Eric J. Nestler, a neuroscientist at the Laboratory of Molecular Psychiatry at Yale University School of Medicine. In an anatomical study of dopamine cells in rats who had become addicted to morphine, Nestler's team found that the neurons with D2 dopamine receptors had become 25 percent smaller and had lost much of their ability to receive dollops of dopamine from nearby neurons. Their report will be published later this year in The Proceedings of the National Academy of Sciences.
The afflicted neurons also underwent a drastic change in their internal dynamics, altering the workings of the so-called second messengers, proteins like cyclic AMP. After a molecule like dopamine latches on to a receptor on the cell surface, the second messenger acts within the cell to coordinate its response, like the release of neurotransmitters to signal other neurons.
"When you take a drug like cocaine, it floods the neurons with levels of dopamine never seen in nature," Nestler said. "The addictive drugs have an impact on the dopamine circuitry like a sledgehammer, storming through this pathway with an intensity that never occurs ordinarily. Taking drugs over and over perturbs these systems, and they try to adapt by making the dopamine less effective."
Once the cells adapt this defensive maneuver and become less responsive, the cells are left bereft of normal levels of the neurotransmitter if a person stops taking a substance that floods the mesolimbic systems with dopamine. These changes seem to be the neural engine driving the craving for more of any drug.
"You find the same changes not just with cocaine," Dr. Volkow said, "but also with other addictions, such as to heroin and to alcohol," although each drug affects the dopamine system through distinctive neural routes.
The shift to addiction seems to occur as dopamine deprivation produces chronic unpleasant feelings, depression and a loss of motivation, which leads to the need to take the drug to feel better. "Once these cellular changes occur," Nestler said, "addicts will take a drug just to feel right, not for a high."
What does all this portend for the treatment of drug addiction? "The research suggests a common biological essence to all addictions," Leshner, of the National Institute on Drug Abuse, said, "though I don't think we'll ever have a single magic bullet. We might instead one day have neurochemical cocktails that are specific to each addictive drug that would break the cycle of craving."
In the meantime, Leshner sees a continued role for behavioral treatments of addiction. Approaches that count on people's ability to resist craving, like that of Alcoholics Anonymous, are still the most successful, many studies have found. "If addiction means the brain has changed, then the task is to change the brain back to normal," Leshner said. "But that doesn't mean treatments have to be biological. Behavioral treatments can change the brain, too."
The finding caps a decade or more of intensive brain research seeking the grail of substance abuse, the neurological circuitry that compels addicts to pursue the next fix. And the discovery confirms a number of emerging scientific hunches about the neurology of addiction.
For instance, no matter what the addictive substance is -- amphetamines, heroin, alcohol or nicotine -- all seem to activate a single circuit for pleasure deep in the most ancient part of the brain. This circuit, for the neurotransmitter dopamine, is the site of the high that addictive drugs bring.
And fine-grained studies of brain cells reveal that repeatedly dosing the brain with addictive drugs is akin to a chemical assault that alters the very structure of the neurons in the circuitry for pleasure. These changes starve brain cells of dopamine, triggering a craving for the addictive drugs that will once again swamp the brain with it.
A drumbeat of findings from dozens of scientific laboratories, several within the last few months and as yet not published, herald these conclusions, which "offer an extraordinary insight into the brain basis of drug addiction," said Dr. Alan I. Leshner, director of the National Institute on Drug Abuse. He added, "There have been a tremendous number of major advances in the last year."
The identity of this brain circuit for addiction is a scientific flashback of sorts, if not a hallucinatory deja vu: the same brain area was the focus of intense study as long ago as the 1950s, when psychologists routinely implanted electrodes into rats' brains in the region they then called the brain's "reward center." After the rats were trained to push a lever to stimulate this center, they would do nothing else, even forsaking food and water to dose themselves with dollops of rodent bliss -- an animal model of addiction. But the specific neural circuitry involved was, at the time, a scientific mystery.
Today that mystery seems to have been solved by using positron emission tomography scans of the brains of patients being treated for cocaine addiction. Reports from three different laboratories using PET scans show that when addicts feel a craving for a drug, there is a high level of activation in a strip of areas ranging from the amygdala and the anterior cingulate to the tip of both temporal lobes.
This mesolimbic dopamine system, as it is called, shows heightened metabolic activity "when people are in a profound state of craving for cocaine, primed to seek it out and take it," said Dr. Annarose Childress, a neuroscientist at the University of Pennsylvania who did one of the PET studies. The work has been reported at scientific meetings but has not yet been published. The same system seems to be ordinarily in play to provide a sense of pleasure in whatever people find rewarding, like sex or chocolate or a job well done. Dopamine may also be part of a reward system in creatures as different from humans as bees, other researchers have shown.
In Dr. Childress's study, PET scans were done on patients under treatment for cocaine addiction while the patients were being exposed to cues that had made them crave cocaine in the past -- like seeing a videotape of people taking cocaine or handling crack pipes or other drug paraphernalia. Drug treatment programs routinely caution patients to avoid such Pavlovian cues, which addicts have learned to associate with the drug high itself, because the cues have long been known to trigger the craving for the drug.
The PET scans showed activation in the mesolimbic dopamine system as the addicts described feeling intense cravings for cocaine.
The mesolimbic dopamine system connects structures high in the brain, especially the orbitofrontal cortex, in the prefrontal area behind the forehead, with the amygdala in the brain's center, and with the nucleus accumbens, a structure that in animal research has proved to be a major site of activity in addiction, although in humans it is about the size of a squished pea, too small to register in PET images. The ultimate source of this dopamine system is the same brain region where psychologists stuck electrodes decades earlier to make rats endlessly stimulate themselves for pleasure, a location called the ventral tegmental area.
These brain areas have emerged in the last several years as hot spots in research on every addictive substance studied, and some that create dependency, if not strict addiction. Last month, for instance, Italian researchers reported in the journal Nature that the mesolimbic dopamine system was active in nicotine addiction, adding tobacco to a roster that includes heroin, morphine, cocaine, amphetamines, marijuana and alcohol.
In addiction studies with lab animals, a main site of activity is the outer layer of the nucleus accumbens. In humans, a nearby interconnected structure, the amygdala, "is more important in craving," said Dr. George F. Koob, a neuroscientist at the Scripps Institute in San Diego. "If people have a lesion in a section of the amygdala, they no longer link pleasure to its causes -- they wouldn't experience a favorite food as enjoyable," he said.
What ties years of brain research on addiction together in a "final bow," Koob said, is the new finding by Dr. Childress and others that "what lights up during craving is the temporal lobe, particularly the amygdala, where all these pathways converge." Koob reviewed earlier findings on the dopamine system in the May issue of the journal Neuron.
The various brain pathways he is referring to all have a particular kind of cell that has the D2 dopamine receptor, which is distinct from other dopamine receptors, like those involved in Parkinson's disease. PET images of cocaine patients taken over several weeks after they stop using the drug show a drop in those neuronal activity levels that is consistent with a lessened ability to receive dopamine. Although the degree of this reduction lessens over time, it is evident "even a year and a half after withdrawal," said Dr. Nora Volkow, director of the Division of Nuclear Medicine at Brookhaven National Laboratory on Long Island. She has also done some of the other recent PET studies.
This pattern of reduced brain activity directly reflects the course of the craving. "The highest risk of relapse for cocaine addicts is during the third and fourth week after they've stopped taking the drug," said Dr. Joseph C. Wu, a psychiatrist at the University of California at Irvine who has made PET images of cocaine addicts that verify the other reports. "You see the lowest levels of activity in the mesolimbic dopamine system during that time." This work has also been reported at meetings but is still unpublished.
The brains of addicts are almost back to normal after a year without the drug, though not completely, he said. "If you can stay abstinent for about a year," Wu said, "you've weathered the periods of greatest vulnerability." Scientists are still debating whether the dopamine cells ever fully return to normal.
The gross patterns of brain activity detected in PET scans represent changes at the microscopic level that are so dramatic that they are akin to the kinds of changes that result from a brain injury, in the view of Dr. Eric J. Nestler, a neuroscientist at the Laboratory of Molecular Psychiatry at Yale University School of Medicine. In an anatomical study of dopamine cells in rats who had become addicted to morphine, Nestler's team found that the neurons with D2 dopamine receptors had become 25 percent smaller and had lost much of their ability to receive dollops of dopamine from nearby neurons. Their report will be published later this year in The Proceedings of the National Academy of Sciences.
The afflicted neurons also underwent a drastic change in their internal dynamics, altering the workings of the so-called second messengers, proteins like cyclic AMP. After a molecule like dopamine latches on to a receptor on the cell surface, the second messenger acts within the cell to coordinate its response, like the release of neurotransmitters to signal other neurons.
"When you take a drug like cocaine, it floods the neurons with levels of dopamine never seen in nature," Nestler said. "The addictive drugs have an impact on the dopamine circuitry like a sledgehammer, storming through this pathway with an intensity that never occurs ordinarily. Taking drugs over and over perturbs these systems, and they try to adapt by making the dopamine less effective."
Once the cells adapt this defensive maneuver and become less responsive, the cells are left bereft of normal levels of the neurotransmitter if a person stops taking a substance that floods the mesolimbic systems with dopamine. These changes seem to be the neural engine driving the craving for more of any drug.
"You find the same changes not just with cocaine," Dr. Volkow said, "but also with other addictions, such as to heroin and to alcohol," although each drug affects the dopamine system through distinctive neural routes.
The shift to addiction seems to occur as dopamine deprivation produces chronic unpleasant feelings, depression and a loss of motivation, which leads to the need to take the drug to feel better. "Once these cellular changes occur," Nestler said, "addicts will take a drug just to feel right, not for a high."
What does all this portend for the treatment of drug addiction? "The research suggests a common biological essence to all addictions," Leshner, of the National Institute on Drug Abuse, said, "though I don't think we'll ever have a single magic bullet. We might instead one day have neurochemical cocktails that are specific to each addictive drug that would break the cycle of craving."
In the meantime, Leshner sees a continued role for behavioral treatments of addiction. Approaches that count on people's ability to resist craving, like that of Alcoholics Anonymous, are still the most successful, many studies have found. "If addiction means the brain has changed, then the task is to change the brain back to normal," Leshner said. "But that doesn't mean treatments have to be biological. Behavioral treatments can change the brain, too."