NIH Press Release

National Institute on Drug Abuse

Thursday, Apr. 24, 1997

Mona W. Brown
Sheryl Massaro
(301) 443-6245

Scientists Identify Brain Mechanisms of Cocaine's Euphoric Effects

For the first time, researchers have observed in human cocaine abusers some of the ways by which cocaine produces its pleasurable effects as they are occurring. Researchers at the Brookhaven National Laboratory in Upton, NY, State University of New York at Stony Brook, and Columbia University have found a significant relationship between the intensity and duration of the "high" induced by cocaine and the degree to which the drug blocks one of the major mechanisms to control the amount of dopamine in the brain. There is a clear relationship between the degree to by which cocaine blocks the dopamine transporter and the cocaine abuser's experience of euphoric feelings. The results of this study using the brain imaging techniques of positron emission tomography (PET) will appear in the April 24, issue of Nature.

Until now, scientists have relied heavily on animal models to determine how cocaine produces its effects and to identify which sites in the brain are primarily involved. Those studies have suggested that cocaine works in large part by occupying or blocking dopamine transporter (DAT) sites, thereby preventing reuptake of dopamine by the brain cells that release it, which then allows higher concentrations of dopamine to remain available in the brain longer than normal. It is this abnormally long presence of dopamine in the brain that is believed to cause the high and other effects associated with cocaine use.

To study the relationship between subjective effects of cocaine and its activity in the brain of humans, Dr. Nora Volkow and colleagues gave injections of cocaine to 17 volunteers who were current cocaine users. Using PET scans, they produced images of the volunteers' brains showing the concentrations of cocaine occupying DAT sites. They found that doses of cocaine commonly abused by humans blocked about 60 to 77 percent of the cocaine users' DAT sites. The researchers also asked the volunteers to describe the effects they felt from the drug as it was being administered and their brain activity monitored.

By analyzing the PET images together with the volunteers' subjective reports on the drug's effects, the researchers were able to document a significant relationship between the intensity and duration of the high induced by the cocaine and the concentration of the drug at DAT sites seen in the PET scans. In order for the subjects to perceive cocaine's effects, at least 47 percent of the DAT sites had to be blocked by cocaine.

"To our knowledge, this is the first demonstration in humans that the doses often used by cocaine abusers lead to the significant blockade of DAT sites and that this blockade is actually associated with the subjective effects of cocaine," said Dr. Nora D. Volkow, Chair of the Medical Department and Director of Nuclear Medicine at the Brookhaven National Laboratory. "These results clarify the role of the DAT blockade as a crucial mechanism in the reinforcing properties of cocaine in humans," she concluded.

Dr. Alan I. Leshner, Director of the National Institute on Drug Abuse ( NIDA), which funded this study in conjunction with the Department of Energy, said, "This study demonstrates the potential of human neuroscience research as it allows us to look into the brains of people experiencing various aspects of cocaine addiction. Researchers can now see specifically where cocaine acts in the brain and can then target efforts to block those effects and treat their addiction."

In another study published in the same issue of Nature, Dr. Volkow and colleagues compared the functioning of the dopamine system in the brains of chronic cocaine users with that in non-users. Methylphenidate, a stimulant similar to cocaine that increases dopamine responsiveness in the brain, was administered to both the users and non-users. Using the PET technology, researchers obtained brain images that contrasted how the dopamine systems in the two groups responded to the methylphenidate.

They found that, compared to the non-users, the cocaine-dependent group showed reduced dopamine responses to the drug in the striatum, a region of the brain linked to motivation control and reward. At the same time, they found an abnormal increase in the level of dopamine response in the thalamus, a region of the brain that communicates sensory information. This enhanced response in the thalamus, which also was associated with experiences of intense cocaine cravings among those who were addicted to cocaine, was not observed in the control group.

In explaining the significance of this study, Dr. Volkow said, "This research suggests that dopamine pathways in the thalamus as well as in the striatum are critically involved in cocaine addiction. More research is needed to determine just how drug-related changes in these areas of the brain may affect drug cravings and compulsive drug use by cocaine addicts."

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