The scientists have found that the neurotransmitter dopamine, which earlier was linked to mammals' internal reward system and to drug abuse, increased significantly in the brain moments before laboratory rats decided to get more cocaine by pressing on a special bar.
That chemical signal, triggered by an outside cue, appears to cause the rodents to seek the drug and may parallel what happens moments before humans seek out substances to which they are addicted.
"Our findings reveal for the first time that rapid dopamine transmission occurs during key components of cocaine-seeking behavior and during presentation of cocaine-associated stimuli," said Dr. Regina M. Carelli, associate professor of psychology at UNC. "Rather than just having a pharmacological effect, dopamine increases in response to cues that have a learned association to cocaine. "Our work indicates that just the anticipation of receiving cocaine may cause significant increases in dopamine levels that may control drug-taking behaviors."
A report on the findings appears in the April 10 issue of Nature, a scientific journal. Besides Carelli, authors, all at UNC, are Dr. Paul E.M. Phillips, research assistant professor of psychology; Garret D. Stuber and Michael L.A.V. Heien, graduate students in neurobiology and chemistry, respectively; and Dr. R. Mark Wightman, Kenan professor of chemistry.
The experiments involved surgically inserting a delicate carbon fiber electrode into an area of the rats' brains called the nucleus accumbens that has been associated with drug use to measure changes in dopamine concentrations in relation to rats' behavior, Phillips said. Previous studies used a technique known as microdialysis that could only measure dopamine relatively slowly in animals trained to self- administer cocaine rather than 10 times a second.
"This represents the fastest chemical measurements ever made in an active animal and is an enormously valuable research tool," he said.
Self-administration too is the best animal model of drug addiction since scientists do not give cocaine to the rat, Carelli added. Instead, rats learn to press a bar for intravenous infusion of the drug and thus have the option of self-administering it when they wish.
"Dopamine not only increases when animals press a bar for intravenous cocaine, but also during experimenter-controlled presentations of stimuli such as tones and light that lets the animals know cocaine is available," she said. "We also showed that artificially stimulating the brain dopamine system by electrically stimulating dopamine neurons that project into the nucleus accumbens increased the probability that rats would press the bar again for cocaine."
Animals not trained to get cocaine when they wanted to showed no comparable increase in brain dopamine levels, Phillips said. Dopamine levels jumped in trained rats in response to the sound cue even when researchers turned the intravenous drug pump off so that cocaine was withheld.
"All that was known before was that dopamine would increase in rats' brains a few minutes after they got cocaine but there were no specifics to be able to relate this to any particular behavior," he said.
The findings may be relevant to human cocaine addiction where drug-associated cues such as drug paraphernalia or surroundings associated with prior drug use often result in intense craving, Carelli said. It is this nearly instantaneous craving for cocaine that is one of the leading causes of relapse of drug use following periods of drug abstinence.
"Ideally, one approach to treating cocaine addiction in humans would be a pharmacological intervention targeted at reducing 'cue-evoked craving' for the drug," she said. "Our results indicate that real time increases in dopamine may play a critical role in this process and should be considered in any drug therapy for cocaine addicts."
More than 20 years ago, chemist Wightman pioneered an electrochemistry technique called fast scan cyclic voltammetry technique that now allows the team to measure dopamine levels in the rats instantaneously – some 200 times faster than has ever been done before.
"We were among the first groups to fabricate the carbon-fiber electrodes, the first really small chemical sensors," Wightman said. "Over the years we have developed its sensitivity for detecting molecules like dopamine and developed ways to distinguish signals due to dopamine from signals from the many other molecules present in the environment around neurons."
The research on cocaine administration was a perfect collaboration, he said.
"On the one hand, Regina Carelli's laboratory understood the behavioral aspects involved in cocaine self-administration in rats," the scientist said. "On the other hand, we had the analytical chemistry techniques to measure dopamine during these behaviors. This combined approach led to the new insights about drug abuse revealed in this manuscript."
Note: Phillips, Carelli and Wightman can re reached, respectively, at (919) 962-0419, 962-8775 and 962-1472.
Contact: David Williamson, (919) 962-8596
By DAVID WILLIAMSON
UNC News Services
Journal
Nature