Volume 13, Number 5 (February, 1999)
Cocaine Activates Different Brain Regions for Rush Versus Craving
By Steven Stocker, NIDA NOTES Contributing Writer
Using a brain imaging technology called functional magnetic resonance imaging (fMRI), NIDA-funded scientists have shown that different parts of the human brain are activated during cocaine "rush" versus cocaine craving. This technology is also being used to identify the parts of the brain that become active when a cocaine addict sees or hears environmental stimuli that trigger a craving for cocaine. These studies may be useful in the development of medications for treating cocaine addiction, because they help scientists pinpoint specific brain regions that need to be targeted by medications for countering cocaine's multiple effects.
Developed in the early 1990s, fMRI can visualize areas of the brain that many researchers believe are regions with increased nerve cell activity. Images can be produced quickly, enabling volunteers to describe their sensations at the same time that the images are being produced. As a result, fMRI allows researchers to closely associate regions of brain activity with specific emotions.
Dr. Hans Breiter, left, Dr. David Kennedy, center, and Dr. Randy Gollub will use images produced by this magnetic resonance imaging scanner to identify areas of the brains of cocaine-addicted volunteers that become activated during cocaine rush and craving.
Using fMRI, Dr. Hans Breiter and his colleagues at the Massachusetts General Hospital in Boston administered cocaine to cocaine-addicted volunteers whom they had trained to continuously rate their feelings of rush, high, low, and craving. The rush experience involved elevated heart rate and sweating, along with feelings of "speeding" or "being out of control." The high experience was generally associated with feelings of euphoria, self-confidence, well-being, and sociability. The low experience involved negative emotions, such as anxiety, paranoia, and the loss of any feelings of pleasure. Craving was defined as the desire to use more cocaine.
Rush and high both peaked within 3 minutes after the volunteers received cocaine. While the rush dissipated quickly, the high decreased more gradually. The low slowly increased, peaking 11 minutes after receiving cocaine, and craving peaked 12 minutes after receiving cocaine.
The researchers determined that certain areas of brain activity were associated more with feelings of rush, and other areas were associated more with feelings of craving. "We only looked at brain regions associated with rush and craving because these were the two ratings that were the most distinct from each other," says Dr. Breiter. "The rush scores were coming down at the same time that the craving scores were going up."
Rush was associated with activity in many areas of the brain, including the ventral tegmentum in the midbrain and the basal forebrain, or base of the forebrain. This activity peaked shortly before the volunteers reported that they had reached peak rush, and then the activity began to dissipate, much like the reported rush.
No areas of brain activity directly paralleled the ratings for craving. What did seem to be associated with craving was the fact that activity in a few regions continued after all others had stopped. These regions included the nucleus accumbens and the right parahippocampal gyrus, both in the forebrain.
"Craving may not be mediated by one or two distinct brain regions," says Dr. Breiter. "Rather, the craving that occurs shortly after taking cocaine may be due to a change in the pattern of brain activity over time. Many brain regions are active when the volunteers report feelings of rush. Over time, however, only a few brain regions remain activated. This change in activation pattern may be what causes the subjective experience of craving."
These results bear out similar findings in animals. Some of the regions of activity that were associated with rush or craving have been implicated in animal studies as being important in producing the pleasurable feelings associated with cocaine use. The regions include the ventral tegmentum, nucleus accumbens, and basal forebrain. "This study provides a bridge between the animal studies and the human studies," says Dr. Breiter.
Instead of investigating the craving that occurs after cocaine is injected, Luis Maas, Dr. Scott Lukas, Dr. Perry Renshaw, and their colleagues at McLean Hospital in Belmont, Massachusetts, used fMRI to investigate brain activation during what is known as cue-induced craving. In this type of craving, cocaine-related stimuli or cues from the environment, such as seeing someone cook crack cocaine or smoke a crack pipe, trigger memories of the drug-taking experience, which elicit craving. "What we think is happening is not unlike what happened in the Pavlov's dog experiment," says Dr. Lukas. In this experiment, Russian physiologist Dr. Ivan Pavlov rang a bell shortly before he presented food to hungry dogs. After many pairings of the bell with food, Dr. Pavlov found that merely ringing the bell caused the dogs to salivate.
In the McLean Hospital experiment, the researchers showed crack cocaine abusers a 10-minute videotape that consisted of segments with crack cocaine-related images and sounds alternating with segments that involved neutral stimuli, such as images of butterflies. When the volunteers saw the cocaine-related segments, two brain regions in particular became activated - the anterior cingulate and the left dorsolateral prefrontal cortex, both in the forebrain. However, when the volunteers saw the neutral segments, these regions remained inactive. "The brain regions that became active during the cocaine-related portions of the videotape are associated with changes in mood state and with positive reinforcement. They are also in an area of the brain where memories are stored," says Dr. Lukas. "Conse-quently, we think that we are seeing the 'turning on' of cocaine-related memories."
Dr. Scott Lukas, left, and Dr. Perry Renshaw discuss the brain scan of a cocaine-addicted volunteer that shows which brain regions were activated when the volunteer watched a videotape of cocaine-related images. Two regions that became activated are circled on the brain scan shown at right.
These results are consistent with a previous study conducted by Dr. Steven Grant, Dr. Edythe London, and their colleagues in NIDA's Division of Intramural Research. This study utilized a different imaging technology called positron emission tomography (PET) that, like fMRI, produces images of brain regions with increased nerve cell activity but takes longer to produce these images.
In that study, as in the McLean Hospital study, the researchers exposed cocaine abusers to cocaine-related stimuli, such as equipment used for snorting cocaine powder, plus a videotape showing people snorting cocaine and smoking crack. After the volunteers reported that they felt cocaine craving, the PET images showed increased nerve cell activity in certain brain regions, including the two identified in the McLean Hospital study (see "NIDA Brain Imaging Research Links Cue-Induced Craving to Structures Involved in Memory," NIDA NOTES, November/December 1996).
The fact that brain imaging techniques can visualize brain regions associated with the subjective effects of cocaine could be particularly useful to scientists developing medications for treating cocaine addiction, according to Dr. Joseph Frascella, chief of NIDA's Etiology and Clinical Neurobiology Branch. Earlier studies with animals have provided good indication of which regions are affected by cocaine, he says. "However, it is difficult to assess craving or the subjective feelings of rush or euphoria in animals," he says. "You can't exactly ask an animal, ‘How much are you craving at this point?'" The value of fMRI in particular is that human volunteers can tell researchers what they are feeling and at the same instant the researchers can see increased activity in brain regions that are associated with that subjective state, says Dr. Frascella. "This type of work is helping scientists identify the brain systems that need to be targeted by medications that counter cocaine's subjective effects," he says.
Breiter, H.C.; et al. Acute effects of cocaine on human brain activity
and emotion. Neuron 19(3):591-611, 1997.
Grant, S.; et al. Activation of memory circuits during cue-elicited cocaine craving. Proceedings of the National Academy of Sciences USA 93:12040-12045, 1996.
Maas, L.C.; et al. Functional magnetic resonance imaging of human brain activation during cue-induced cocaine craving. American Journal
of Psychiatry 155(1):124-126, 1998.
NIDA NOTES - Volume 13, Number 5
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