The American team reported results from 35 known cocaine abusers and 35 non-drug users of about the same age, sex, race, and causes of death. With use of brain samples normally removed during autopsy, the researchers measured several indicators of the health of the subjects' dopaminergic neurons. Specifically, they evaluated overall level of dopamine, as well as levels of a protein called VMAT2 and its binding to a selective radiotracer molecule. VMAT2 was chosen because it is the protein pump that recycles free dopamine in the synapse to axonal vesicles.

In all three molecular measures, cocaine users' levels were significantly lower than those for control subjects, indicating poor neuronal health. Levels tended to be lowest in cocaine users who also had depression.

"This is the clearest evidence to date that the specific neurons cocaine interacts with don't like it and are disturbed by the drug's effects," said Karley Little, M.D., lead author of the study. "The questions we now face are: Are the cells dormant or damaged, is the effect reversible or permanent, and is it preventable?"

When cocaine is first used, it blocks transporters such as VMAT2. The continued high level of dopamine in the synapses contributes to intense psychological euphoria. Because the dopamine system helps recognize pleasurable experiences and seek to repeat them, cocaine's long-term dopamine effects likely contribute to the craving associated with addiction and the decreased motivation, stunted emotion, and uncomfortable symptoms associated with withdrawal.

In recent years, many researchers have come to suspect that chronic cocaine use causes the brain to adapt to the drug's presence by altering the molecules involved in dopamine release and reuptake. In several studies, including the current one, researchers use postmortem samples taken from the striatum of known cocaine users who were using the drug at the time of their deaths and from well-matched control subjects.

The data provide support for the idea that chronic cocaine abuse leads to a phenomenon called allostasis of reward in animals. With extended use, 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.

Little said "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.