Cocaine is notorious for producing a rapid high and for being extremely addicting. Now positron emission scanning technology (PET) is revealing the nuances of how this drug induces such intense craving so rapidly.
PET is a noninvasive way to observe the functions of biochemicals in the living human brain, including observations of normal physiology, disease states and the effects of drugs. The technology is based on positron emitters for natural elements of life, such as carbon, oxygen and nitrogen.
"It allows us to label compounds without changing their structure or function," says Nora Volkow, director of the Nuclear Medicine Program at Brookhaven National Laboratory in Upton, N.Y., and associate professor in the Department of Psychiatry and Behavioral Sciences at the Stony Brook campus of the State University of New York (SUNY). "A second beauty of PET is that it is extremely sensitive, so we can do not just functional, but neurochemical imaging," she adds.
Volkow described her research at "Current and Emerging Techniques for Monitoring Brain Structure and Function," held at the National Library of Medicine in Bethesda, Md., March 28 and 29.
Quick on the uptake
A drugís effects stem not only from its presence and location in the brain, but from how quickly it gets there and how fast it is metabolized. Cocaine comes and goes relatively quickly. "Its fast uptake and clearance are what promote repeated self-administration," Dr. Volkow hypothesizes. After only 30 minutes, an addict feels the urge for another dose.
Cocaine exerts its effects at the synapses that separate nerve cells, specifically at transporter proteins that normally ferry the neurotransmitter dopamine from a neuron sending an electrochemical signal to the neuron receiving it. In the PET studies, volunteers received cocaine radioactively labeled with 11C (carbon).
As expected, images revealed the drug in the basal ganglia, the part of the brain with the highest concentration of dopamine transporters. More telling was the glimpse of cocaine action over time. "PET measures moment-to-moment changes in a drugís concentration in the human brain," says Dr. Volkow. "It reveals that cocaineís uptake in the brain takes only four to six minutes. There is also fast clearance. It loses half of its activity 20 minutes after administration.
Cocaineís fast action had previously been demonstrated in blood plasma, and by observing users, but the PET experiment documents it at the site of action. In addition, the volunteers were asked to describe their feelings as the PET scans progressed, and their mounting and ebbing euphoria, and growing craving paralleled the brain activity.
Volkow suggests that chronic drug use may disable dopamine function in the orbital frontal cortex, a part of the brain which, when damaged in laboratory animals, causes them to exhibit obsessive-compulsive characteristics, such as eating until they deplete a huge food supply or grooming themselves until they bleed.
"This could lead to the emergence of compulsive aspects of addiction," she explains. "The pleasurable aspect is not the whole story. Disrupting the dopamine circuits could lead to addiction."
Support for Volkowís idea that uptake and clearance rate affect how addictive a drug is comes from 11C PET studies on another well-known drug, methylphenidate. More commonly known as Ritalin, this drug is the most frequently prescribed medication for children, and it is used to control symptoms of attention deficit disorder. Curiously, Ritalin has similar pharmacological properties to cocaine and resembles it chemically. Although cocaine users claim that Ritalin gives them a high, this drug is apparently not addicting.
PET scans for the two drugs are remarkably similar. "There was no significant difference in the distribution in the brain. We were puzzled. Were there other subtle differences between the drugs?" Volkow wondered.
On to nicotine
Further studies revealed that both cocaine and Ritalin bind the dopamine transporter, which is a large molecule. The evidence for this is that giving one drug inhibits binding of the otherñthey therefore must both go to the same place in the brain. The only difference between the two drugs identified so far is the time course of their action. Unlike the fast intake and dissipation of cocaine, Ritalin enters the brain slowly, remains for awhile, then is slowly cleared. And this, Volkow suggests, is why one drug is addictive and abused, and the other is nonaddictive and therapeutic.
At the Brookhaven Laboratory, Volkow and her colleagues are excited about PET because it is "opening up new ways to look at drug addiction." Their next target? Nicotine. Stay tuned.
By Dr. Ricki Lewis
Contributing Editor
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