Cocaine Appears to Damage Brain’s Dopamine Neurons

Analysis of postmortem brain tissue has provided the most comprehensive evidence that chronic cocaine use reduces striatal levels of vesicular monoamine transporter protein (VMAT2) and results in dopamine neuronal changes related to disordered mood.

“This is the clearest evidence to date that cocaine dependency results in deleterious changes in dopamine neurons,” Karley Little, M.D., chief of the Ann Arbor VA Medical Center’s Affective Neuropharmacology Laboratory and an associate professor of psychiatry at the University of Michigan Medical School, told Psychiatric News.

The study, revealing differences in dopamine neurons between postmortem brain tissue from cocaine users and controls, appeared in the January issue of the American Journal of Psychiatry. Little and colleagues David Krolewski, M.S., Lian Zhang, Ph.D., and Bader Cassin, M.D., assessed the integrity of the dopamine system in brain tissue from 35 known cocaine users and 35 nonusers matched for age, sex, race, and cause of death. Using tissue from the striatum, an area of the brain with the highest concentration of dopamine neurons, they measured the level of VMAT2, a protein that pumps dopamine molecules into storage vesicles; VMAT2’s binding availability to a selective radiotracer molecule, another assessment of VMAT2 presence and activity; and the overall dopamine level to find how much was available at the time of death. They found that all three levels were lower in cocaine users than in nonusers. And levels tended to be lowest in cocaine users who were diagnosed as having cocaine-induced mood disorders at the time of their deaths.

It has long been known that immediately after cocaine exposure, synaptic dopamine increases, an event believed to be critical in causing the pleasurable experience associated with cocaine intake. The present study illuminates the molecular mechanisms responsible for the withdrawal symptoms and sustained depression that some cocaine users experience after chronic use. Other researchers have found that those individuals who not only experience pleasure from cocaine use, but also are “punished” by its withdrawal, by dysthymic and suicidal feelings, as well as persistent depression, are those who are hard to treat and whose addiction is most disruptive.

Traditionally, cocaine use has not been associated with the intense physical dependence that is seen with alcohol and narcotics. But the clinical literature does indicate that cocaine users have withdrawal symptoms—which vary a lot between individuals, from mild to intense. About a third feel markedly depressed, listless, anxious, and uncomfortable. It has become clear that people who have those symptoms are likely to become more dependent on the drug and find it harder to quit.

“Our data provide a very good biochemical basis for cocaine withdrawal symptoms. The existing literature shows that a depressed cocaine user is going to have more problems maintaining family and work, have a harder time quitting, is more likely to drop out of treatment, and is more likely to commit suicide,” Little said.

Vesicular monoamine transporter (VMAT) collects the neurotransmitter into the vesicle after it is synthesized or been returned to the cell from the synapse. Variations in its level are a measure of vesicular stores of neurotransmitter, but also of total number of neuronal axons.

“Thus the present finding may mean that the neuron is trying to adapt and down-regulate how much dopamine it releases, or it may mean that there is some damage or loss of neurons,” Little said. “Our findings are somewhat controversial because no one has been able to show that the VMAT is down-regulated by drugs, but neither has anyone found that cocaine kills nerve cells. At this point we don’t quite know how to interpret this decrease in VMAT function.

“What we need to do now is to count the dopamine neurons and axons in our remaining samples, which is a big undertaking. If we find they are not decreased, then it will mean we are dealing with an unprecedented down-regulation of the VMAT . . . . And if they are diminished, then we are dealing with unprecedented neuronal loss. Either way, it is going to be an interesting outcome. If the change is permanent, it is quite a problem, and if it is reversible, then we must find out the mechanism by which it can be reversed.”

This is the latest in a series of experiments begun in 1993 by Little and colleagues, who initially found that chronic cocaine use increases the synaptic dopamine transporter (DAT), the actual molecule to which cocaine binds and inhibits. The reuptake activity of this molecule represents the other half of the equation that controls how much dopamine exists in the synapse. After releasing neurotransmitter, neurons quickly suck it back into the cell that released it, thus sharpening the communicative process and conserving neurotransmitter for continued use.

By helping lessen synaptic levels of dopamine, up-regulation of synaptic dopamine transporter may be helpful in some individuals by helping lessen synaptic levels of dopamine when cocaine is present. But when cocaine disappears, the increase in uptake means there will be even less dopamine in the synapse. In conjunction with diminished dopamine release from vesicles, this may lead to decreased response to normal rewards. Thus, normal rewards become less significant, and cocaine less effective, so the dosage must be increased. Thus, a classic cycle of tolerance—dose escalation—and resetting of reward levels may develop, a process sometimes called allostasis, in contrast to homeostasis.

The drug amantadine is mildly helpful in reducing cocaine withdrawal symptoms and keeping cocaine addicts in treatment. It is especially useful for depressed cocaine users, in contrast to the SSRIs, which don’t seem very effective. This fact has suggested that cocaine-induced mood disorders have a more dopaminergic than serotoninergic basis. Little has developed a cell culture model of the up-regulation of DAT by cocaine (Molecular Pharmacology61:436-445, 2002). In this model, he has found that amantadine has a reverse effect compared with cocaine, suggesting how it might mitigate the effects of chronic cocaine exposure on dopamine transport. Using this model system, it may become possible to develop drugs that are better than amantadine.

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.

These studies were funded by NIDA and a VA Merit Award.

The study, “Loss of Striatal Vesicular Monoamine Transporter Protein (VMAT2) in Human Cocaine Users,” is posted on the Web at http://ajp.psychiatryonline.org/cgi/content/full/160/1/47?. ▪

Am J Psychiatry 2003 160 47