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In several studies, including the current one, they've used postmortem samples of brain tissue from known cocaine users who were using the drug at the time of their deaths, and from well-matched control subjects. They focused in on the striatum, an area of the brain with the highest concentration of dopamine neurons.
With approval from the U-M Institutional Review Board and appropriate consent, they interviewed relatives and friends of the subjects, and asked about the subjects' alcohol use, mental illness and other characteristics.
The team previously showed that cocaine users have higher numbers of dopamine transporters, suggesting that the cells tried to make more return gateways to compensate for blocked ones. Recently, they showed in cell cultures that cocaine causes more dopamine transporters to travel from the interior of a cell to the membrane, increasing the overall dopamine uptake level.
The data provide support for the idea that chronic cocaine abuse leads to a phenomenon seen in animals, called allostasis of reward. With extended use of cocaine, the brain's response to the drug is "reset", and drug-taking once pursued for the pleasure it caused becomes drug-taking to avoid the negative feelings associated with the absence of cocaine.
The new data suggest this same phenomenon occurs in human cocaine users, and is quite pronounced at the neurochemical level. The experiment sheds light on the molecular mechanisms involved as dopamine-producing brain cells try to adapt to a cocaine-drenched environment.
VMAT2 protein levels, measured through the use of specific antibodies that bind to the protein, are not as affected by other factors as dopamine transporters are. VMAT2 binding availability, measured through an unique radioactive tracer developed by U-M nuclear medicine specialists, is another assessment of VMAT2 presence and activity. And the overall dopamine level, measured through liquid chromatography, shows how much of the chemical was available at the time of death.
On the whole, all three were significantly lower in cocaine users than in non-drug users. A history of alcohol abuse in cocaine users or controls did not affect the difference significantly.
Levels of VMAT2 protein were lowest in the seven cocaine users with mood disorders that may have been caused by cocaine use. Researchers have found that depressed cocaine users have more severe addiction and mental health problems than non-depressed users. Little hypothesizes that the decreased dopamine vesicles and increased transporters may contribute to cocaine-induced depression and other depressive disorders. This may explain why depressed cocaine users are less likely to respond to some depression treatments.
In all, Little says, "We could be seeing the result of the brain's attempt to regulate the dopamine system in response to cocaine use, to try to reduce the amount of dopamine that's released by reducing the ability to collect it in vesicles. But we could also be seeing real damage or death to dopamine neurons. Either way, this highlights the fragility of these neurons and shows the vicious cycle that cocaine use can create." New treatments will have to break that cycle, he adds, and the new findings may help steer clinical researchers.
He also emphasizes that the vulnerable nature of dopamine neurons is important in understanding the moods and actions of normal adults as they age and lose dopamine neurons naturally. Considerable evidence suggests that uncontained dopamine may be mildly toxic over time.
In future research, Little and his colleagues hope to look for differences in the number of dopamine neurons in the subjects' brain samples, and to study gene activity in the cells of cocaine users and control subjects. They also hope their results will help other researchers study living cocaine users and look for signs of decreased VMAT2 levels.
In addition to Little, the study's authors are David Krolewski, M.S.; Lian Zhang, Ph.D.; and Bader Cassin, M.D. U-M nuclear medicine researcher Kirk Frey, M.D., led the team that developed the radioactive tracer used to measure VMAT2 binding levels. The study was funded by the National Institute on Drug Abuse of the National Institutes of Health, and by a VA Merit Award.
Reference: American Journal of Psychiatry 160:1-9, January 2003.
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