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The Neurobiology of Free Will and Drug Addiction
- By Misc Author
- Published 04/18/2008
- Understanding Addiction
- Unrated
Colby Stong, Neuropsychiatry Reviews
SAN DIEGO —Advances in brain-imaging technology have shown what many researchers have long suspected—that drug addiction is a disease of the brain, and not simply a failure of free will.
One of the most instrumental leaders in that effort has been Nora Volkow, MD. The sometimes controversial work of Dr. Volkow and others during the past 15 years has provided a better understanding of how neurobiological changes in the brain can lead a person to lose control over his or her behavior and become addicted to drugs.
That research and understanding may soon yield more effective medications and better overall treatment for patients with addiction, said Dr. Volkow at the 2007 Annual Meeting of the American Psychiatric Association.
A primary focus of addiction research has been the dopaminergic system, as drugs of abuse increase dopamine in limbic areas of the brain, which can then trigger a sensation of pleasure.
“But what has become clear is that dopamine is not just about pleasure,” said Dr. Volkow, Director of the National Institute on Drug Abuse in Rockville, Maryland. Imaging studies have shown that multiple systems in the brain are affected by long-term substance abuse, including those relating to motivation, drive, memory, inhibitory control, and what we perceive as salient.
Drug use can lead to plastic changes in the brain that “ultimately underlie the compulsive drug intake and loss of control that causes drug addiction,” said Dr. Volkow.
In an early study that challenged the reward theory of drug addiction, Dr. Volkow used positron emission tomography to observe the effects of IV methylphenidate in persons addicted to cocaine and in healthy controls.
She found that the subjects addicted to cocaine had a reduced amount of dopamine released in the striatum when given IV methylphenidate and a reduced “high” relative to that of controls. Persons addicted to cocaine also had an increased thalamic response associated with craving—a finding not observed in controls.
“What we documented was that the controls and the cocaine addicts differed not just in terms of the qualitative response to the drug, but they actually had a quantitatively different response,” said Dr. Volkow. “So contrary to what we hypothesized—that cocaine abusers would report a more intense high than controls—we saw exactly the opposite.”
In a recently completed, but as yet unpublished, study comparing 20 alcoholics and 20 healthy controls, Dr. Volkow found that the amount of dopamine released in alcoholics was 70% lower than in controls, “indicating, indeed, that decreases in reward circuitry are not just specific for cocaine,” she noted.
MEMORY, CRAVING, ADDICTION
An addicted person is likely to form a memory when a particular stimulus provides a boost in dopamine, which will then affect his or her behavior.
For example, dogs will salivate when they see a light after the same light had been previously associated with the reward of food.
Research has also shown that dopamine can be increased in the nucleus accumbens of animals by the presence of an auditory cue by itself, after the cue has been repeatedly paired with the administration of cocaine.
“This is actually what is considered to be at the essence of conditioned responses,” said Dr. Volkow. An example involving addicted persons is that they will frequently relapse after reentering an environment where they have previously taken drugs, even if they have just spent time in a rehabilitation program.
“This is one of these conditioned responses, which makes the treatment of addictions a challenge,” said Dr. Volkow. “It also makes the treatment of other compulsive behaviors very challenging, because [persons become addicted] to stimuli that increase dopamine, which are not just drugs. Food, for example, can do exactly the same thing.”
In a study published in 2006, Dr. Volkow and colleagues examined 18 persons who were addicted to cocaine. The researchers measured changes in dopamine by comparing the specific binding of 11Craclopride when the subjects watched videos of either nature scenes or of individuals preparing to use cocaine. The specific binding of 11Craclopride in the dorsal striatum—but not in the ventral striatum—was significantly reduced when the participants watched the cocaine videos, indicating an increase in dopamine binding.
Furthermore, the magnitude of the reduction correlated with self-reports of craving among the addicted persons. “In the drug-addicted person, not only is there decreased sensitivity to the drug itself, but what we are starting to observe is that there has been a transfer of the ability to increase dopamine to a wide variety of stimuli that are linked to the experience of taking the drug,” said Dr. Volkow.
“Drug addiction is not as simple as we thought, [ie], a disease of the limbic brain of reward,” she said. “It also involves memory systems that are extraordinarily important in motivating our behavior, and they are not conscious. It’s not that we control when we are going to get that conditioned response. It’s not that I control when I salivate when I see a Starbucks coffee cup. I immediately want it…. Or if I see someone eating chocolate, immediately, I have the craving of chocolate. This is a universal response that is accentuated in the brain of a person who is addicted.”
Imaging technology has also allowed researchers to look inside the brains of addicted people when they are exposed to natural reinforcers. “Whether it is food, sex, or a universal reinforcer [like] money, regardless, the magnitude of the activation of the limbic areas is significantly blunted in people who are addicted,” said Dr. Volkow.
“The same reward that you have with no dopamine is likely to be much less pleasurable and much less reinforcing than if you have it with dopamine. So the question is, Why would they take drugs?… In the person who is addicted, the drug will be able to increase dopamine to such an extent and for such a long period of time that even though [the reward] may be blunted overall, [the drug] still has sufficient potency to exert a response. Persons who are addicted start to seek the drug of abuse, because it can activate that system. At the same time, they learn that natural reinforcers are no longer stimulating and no longer motivating that behavior. This, in turn, leads them, and puts them at greater risk, to take the drugs, because the drugs will be powerful enough to activate that system.”
THE ROLE OF D2 RECEPTORS
Cocaine-addicted people, in general, have significantly lower levels of dopamine D2 receptors, Dr. Volkow has found. However, “this is not a biomarker of addiction,” she said. “You are not addicted because you have low levels of dopamine D2 receptors…. These reductions may make these people at greater risk for taking drugs. It is not making them addicted.” Reductions in dopamine D2 receptors are not limited to cocaine users, as similar decreases have been observed in methamphetamine abusers and alcoholics. “This appears to be a common finding across a wide variety of addictions,” commented Dr. Volkow.
Potentially, a therapeutic intervention that would increase dopamine D2 receptors could help patients stop taking drugs, because it would make them more sensitive to other reinforcers, Dr. Volkow reasoned. “They would have a wider variety of stimuli that motivates their behavior,” she explained.
Gene therapy has shown promise in increasing dopamine D2 receptors in animals. In rats that were taught to self-administer alcohol, Thanos and colleagues directly injected an adenovirus that contained a D2 receptor gene into the nucleus accumbens. When the levels of dopamine D2 receptors were increased, the rats consumed less alcohol.
“These data clearly show that overexpressing D2 receptors profoundly depresses the consumption of alcohol in these animals,” said Dr. Volkow. “It does not stop them from drinking alcohol; it interferes with the consumption of high doses.”
Thanos’ group has also shown that gene therapy reduced drinking in rats that had been bred to have a genetic predisposition to prefer alcohol. “This is fascinating from many perspectives, because if we can develop strategies to increase dopamine D2 receptors, we may [develop] interventions that protect people from taking drugs,” commented Dr. Volkow.
“You might say that is science fiction,” she said. “It is not science fiction. The dopamine system in our brain is there in order for us to be responsive to external stimuli. As a psychotherapeutic community, it behooves us to do interventions that can actually lead to an increased sensitivity for these dopaminergic signals.”
ADDICTION AND OTHER BRAIN REGIONS
Changes in the orbital frontal cortex and cingulate gyrus have also been observed in addicted persons. Animals with a damaged orbital frontal cortex can still learn to press a lever to receive food, for example. However, when food was no longer made available, these animals continued to press the lever. “In other words, the orbital frontal cortex allows you to change your behavior as a function of the reinforcer,” commented Dr. Volkow.
“If you lose that ability, then your behavior becomes fixated and cannot be modified as a function of the circumstances. This is the essence of what we see with obsessive-compulsive disorder [and] with a person who is addicted. It is extraordinarily difficult to shift their behavior when they are taking drugs, even though they know it has devastating consequences, even though they know cognitively they should not be doing that.”
In a study of persons at high risk for alcohol addiction, including those who had a family history of alcoholism, Dr. Volkow found abnormalities in the orbital frontal cortex, “and these abnormalities were indeed related to changes in dopamine D2 receptors,” noted Dr. Volkow. “But the dopamine D2 receptors were not actually decreased.” These results, she said, demonstrated the importance of the orbital frontal cortex in regulating behaviors that are driven initially by the pleasure response, but then by conditioned responses.
CLINICAL IMPLICATIONS
Recognizing addiction as a disease that involves disruption of multiple systems in the brain opens up new avenues of research to try and treat patients, according to Dr. Volkow. She urged clinicians and researchers to find ways to help addicted persons overcome their compulsive patterns.
“We’ve come to recognize the different systems that are involved,” she said. “We can target therapeutic interventions. We know that they are less sensitive to natural reinforcers. Natural reinforcers can be social reinforcers; those are some of the most powerful that we have as human beings. Can we strengthen the effects of nondrug reinforcers? We can do that with psychotherapeutic interventions and with medications. Can we strengthen inhibitory control? We can do that with psychotherapeutic interventions.”
A number of medications are currently being investigated regarding their ability to improve executive function in addicted individuals. “We know, for example, that modafinil can improve executive function,” said Dr. Volkow. “So would that help our patients who are addicted exert better control over their actions? Can this lead to a strengthening of the prefrontal-striatal communication, such that even though you may have this ability, you can strengthen it?...
"Can you interfere with conditioned memories [associated with] craving—by medications or, again, with therapeutic intervention? Finally, we’ve come to realize that stress is extraordinarily important in the patterns of drug taking. Not only does it increase the likelihood of experimenting with drugs, of taking high doses of drugs, but it also leads to relapse. So can we develop strategies to [reduce] the stressful responses? With that search, of course, we can help our patients stop taking drugs.”
—Colby Stong
Suggested Reading
Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403-1413.
Thanos PK, Taintor NB, Rivera SN, et al. DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking. Alcohol Clin Exp Res. 2004;28(5):720-728.
Volkow ND, Wang GJ, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386(6627):830-833.
Volkow ND, Wang GJ, Telang F, et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583-6588.
Source: Neuropsychiatry Reviews July 2007
SAN DIEGO —Advances in brain-imaging technology have shown what many researchers have long suspected—that drug addiction is a disease of the brain, and not simply a failure of free will.
One of the most instrumental leaders in that effort has been Nora Volkow, MD. The sometimes controversial work of Dr. Volkow and others during the past 15 years has provided a better understanding of how neurobiological changes in the brain can lead a person to lose control over his or her behavior and become addicted to drugs.
That research and understanding may soon yield more effective medications and better overall treatment for patients with addiction, said Dr. Volkow at the 2007 Annual Meeting of the American Psychiatric Association.
A primary focus of addiction research has been the dopaminergic system, as drugs of abuse increase dopamine in limbic areas of the brain, which can then trigger a sensation of pleasure.
“But what has become clear is that dopamine is not just about pleasure,” said Dr. Volkow, Director of the National Institute on Drug Abuse in Rockville, Maryland. Imaging studies have shown that multiple systems in the brain are affected by long-term substance abuse, including those relating to motivation, drive, memory, inhibitory control, and what we perceive as salient.
Drug use can lead to plastic changes in the brain that “ultimately underlie the compulsive drug intake and loss of control that causes drug addiction,” said Dr. Volkow.
In an early study that challenged the reward theory of drug addiction, Dr. Volkow used positron emission tomography to observe the effects of IV methylphenidate in persons addicted to cocaine and in healthy controls.
She found that the subjects addicted to cocaine had a reduced amount of dopamine released in the striatum when given IV methylphenidate and a reduced “high” relative to that of controls. Persons addicted to cocaine also had an increased thalamic response associated with craving—a finding not observed in controls.
“What we documented was that the controls and the cocaine addicts differed not just in terms of the qualitative response to the drug, but they actually had a quantitatively different response,” said Dr. Volkow. “So contrary to what we hypothesized—that cocaine abusers would report a more intense high than controls—we saw exactly the opposite.”
In a recently completed, but as yet unpublished, study comparing 20 alcoholics and 20 healthy controls, Dr. Volkow found that the amount of dopamine released in alcoholics was 70% lower than in controls, “indicating, indeed, that decreases in reward circuitry are not just specific for cocaine,” she noted.
MEMORY, CRAVING, ADDICTION
An addicted person is likely to form a memory when a particular stimulus provides a boost in dopamine, which will then affect his or her behavior. For example, dogs will salivate when they see a light after the same light had been previously associated with the reward of food.
Research has also shown that dopamine can be increased in the nucleus accumbens of animals by the presence of an auditory cue by itself, after the cue has been repeatedly paired with the administration of cocaine.
“This is actually what is considered to be at the essence of conditioned responses,” said Dr. Volkow. An example involving addicted persons is that they will frequently relapse after reentering an environment where they have previously taken drugs, even if they have just spent time in a rehabilitation program.
“This is one of these conditioned responses, which makes the treatment of addictions a challenge,” said Dr. Volkow. “It also makes the treatment of other compulsive behaviors very challenging, because [persons become addicted] to stimuli that increase dopamine, which are not just drugs. Food, for example, can do exactly the same thing.”
In a study published in 2006, Dr. Volkow and colleagues examined 18 persons who were addicted to cocaine. The researchers measured changes in dopamine by comparing the specific binding of 11Craclopride when the subjects watched videos of either nature scenes or of individuals preparing to use cocaine. The specific binding of 11Craclopride in the dorsal striatum—but not in the ventral striatum—was significantly reduced when the participants watched the cocaine videos, indicating an increase in dopamine binding.
Furthermore, the magnitude of the reduction correlated with self-reports of craving among the addicted persons. “In the drug-addicted person, not only is there decreased sensitivity to the drug itself, but what we are starting to observe is that there has been a transfer of the ability to increase dopamine to a wide variety of stimuli that are linked to the experience of taking the drug,” said Dr. Volkow.
“Drug addiction is not as simple as we thought, [ie], a disease of the limbic brain of reward,” she said. “It also involves memory systems that are extraordinarily important in motivating our behavior, and they are not conscious. It’s not that we control when we are going to get that conditioned response. It’s not that I control when I salivate when I see a Starbucks coffee cup. I immediately want it…. Or if I see someone eating chocolate, immediately, I have the craving of chocolate. This is a universal response that is accentuated in the brain of a person who is addicted.”
Imaging technology has also allowed researchers to look inside the brains of addicted people when they are exposed to natural reinforcers. “Whether it is food, sex, or a universal reinforcer [like] money, regardless, the magnitude of the activation of the limbic areas is significantly blunted in people who are addicted,” said Dr. Volkow.
“The same reward that you have with no dopamine is likely to be much less pleasurable and much less reinforcing than if you have it with dopamine. So the question is, Why would they take drugs?… In the person who is addicted, the drug will be able to increase dopamine to such an extent and for such a long period of time that even though [the reward] may be blunted overall, [the drug] still has sufficient potency to exert a response. Persons who are addicted start to seek the drug of abuse, because it can activate that system. At the same time, they learn that natural reinforcers are no longer stimulating and no longer motivating that behavior. This, in turn, leads them, and puts them at greater risk, to take the drugs, because the drugs will be powerful enough to activate that system.”
THE ROLE OF D2 RECEPTORS
Cocaine-addicted people, in general, have significantly lower levels of dopamine D2 receptors, Dr. Volkow has found. However, “this is not a biomarker of addiction,” she said. “You are not addicted because you have low levels of dopamine D2 receptors…. These reductions may make these people at greater risk for taking drugs. It is not making them addicted.” Reductions in dopamine D2 receptors are not limited to cocaine users, as similar decreases have been observed in methamphetamine abusers and alcoholics. “This appears to be a common finding across a wide variety of addictions,” commented Dr. Volkow.
Potentially, a therapeutic intervention that would increase dopamine D2 receptors could help patients stop taking drugs, because it would make them more sensitive to other reinforcers, Dr. Volkow reasoned. “They would have a wider variety of stimuli that motivates their behavior,” she explained.
Gene therapy has shown promise in increasing dopamine D2 receptors in animals. In rats that were taught to self-administer alcohol, Thanos and colleagues directly injected an adenovirus that contained a D2 receptor gene into the nucleus accumbens. When the levels of dopamine D2 receptors were increased, the rats consumed less alcohol.
“These data clearly show that overexpressing D2 receptors profoundly depresses the consumption of alcohol in these animals,” said Dr. Volkow. “It does not stop them from drinking alcohol; it interferes with the consumption of high doses.”
Thanos’ group has also shown that gene therapy reduced drinking in rats that had been bred to have a genetic predisposition to prefer alcohol. “This is fascinating from many perspectives, because if we can develop strategies to increase dopamine D2 receptors, we may [develop] interventions that protect people from taking drugs,” commented Dr. Volkow.
“You might say that is science fiction,” she said. “It is not science fiction. The dopamine system in our brain is there in order for us to be responsive to external stimuli. As a psychotherapeutic community, it behooves us to do interventions that can actually lead to an increased sensitivity for these dopaminergic signals.”
ADDICTION AND OTHER BRAIN REGIONS
Changes in the orbital frontal cortex and cingulate gyrus have also been observed in addicted persons. Animals with a damaged orbital frontal cortex can still learn to press a lever to receive food, for example. However, when food was no longer made available, these animals continued to press the lever. “In other words, the orbital frontal cortex allows you to change your behavior as a function of the reinforcer,” commented Dr. Volkow.
“If you lose that ability, then your behavior becomes fixated and cannot be modified as a function of the circumstances. This is the essence of what we see with obsessive-compulsive disorder [and] with a person who is addicted. It is extraordinarily difficult to shift their behavior when they are taking drugs, even though they know it has devastating consequences, even though they know cognitively they should not be doing that.”
In a study of persons at high risk for alcohol addiction, including those who had a family history of alcoholism, Dr. Volkow found abnormalities in the orbital frontal cortex, “and these abnormalities were indeed related to changes in dopamine D2 receptors,” noted Dr. Volkow. “But the dopamine D2 receptors were not actually decreased.” These results, she said, demonstrated the importance of the orbital frontal cortex in regulating behaviors that are driven initially by the pleasure response, but then by conditioned responses.
CLINICAL IMPLICATIONS
Recognizing addiction as a disease that involves disruption of multiple systems in the brain opens up new avenues of research to try and treat patients, according to Dr. Volkow. She urged clinicians and researchers to find ways to help addicted persons overcome their compulsive patterns.
“We’ve come to recognize the different systems that are involved,” she said. “We can target therapeutic interventions. We know that they are less sensitive to natural reinforcers. Natural reinforcers can be social reinforcers; those are some of the most powerful that we have as human beings. Can we strengthen the effects of nondrug reinforcers? We can do that with psychotherapeutic interventions and with medications. Can we strengthen inhibitory control? We can do that with psychotherapeutic interventions.”
A number of medications are currently being investigated regarding their ability to improve executive function in addicted individuals. “We know, for example, that modafinil can improve executive function,” said Dr. Volkow. “So would that help our patients who are addicted exert better control over their actions? Can this lead to a strengthening of the prefrontal-striatal communication, such that even though you may have this ability, you can strengthen it?...
"Can you interfere with conditioned memories [associated with] craving—by medications or, again, with therapeutic intervention? Finally, we’ve come to realize that stress is extraordinarily important in the patterns of drug taking. Not only does it increase the likelihood of experimenting with drugs, of taking high doses of drugs, but it also leads to relapse. So can we develop strategies to [reduce] the stressful responses? With that search, of course, we can help our patients stop taking drugs.”
—Colby Stong
Suggested Reading
Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005;162(8):1403-1413.
Thanos PK, Taintor NB, Rivera SN, et al. DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking. Alcohol Clin Exp Res. 2004;28(5):720-728.
Volkow ND, Wang GJ, Fowler JS, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386(6627):830-833.
Volkow ND, Wang GJ, Telang F, et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26(24):6583-6588.
Source: Neuropsychiatry Reviews July 2007
