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Researchers report most direct evidence to date that cocaine harms brain's "pleasure center"

Drug attacks the very cells that allow users to feel its effects fFinding may aid understanding of addiction, depression, normal aging

ANN ARBOR, MI - New research results strongly suggest that cocaine bites the hand that feeds it, in essence, by harming or even killing the very brain cells that trigger the "high" that cocaine users feel.

This most comprehensive description yet of cocaine-induced damage to key cells in the human brain's dopamine "pleasure center" may help explain many aspects of cocaine addiction, and perhaps aid the development of anti-addiction drugs. It also could help scientists understand other disorders involving the same brain cells, including depression.

The results are the latest from research involving postmortem brain tissue samples from cocaine abusers and control subjects, performed at the University of Michigan Health System and the VA Ann Arbor Healthcare System. The paper will appear in the January issue of the American Journal of Psychiatry.

"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," says Karley Little, M.D., associate professor of psychiatry at the U-M Medical School and chief of the VAHS Affective Neuropharmacology Laboratory. "The questions we now face are: Are the cells dormant or damaged, is the effect reversible or permanent, and is it preventable?"

Little and his colleagues report results from 35 known cocaine abusers and 35 non-drug users of about the same age, sex, race and causes of death. Using brain samples normally removed during autopsy, the researchers measured several indicators of the health of the subjects' dopamine brain cells, which release a pleasure-signaling chemical called dopamine. The cells interact directly with cocaine.

The team looked at levels of a protein called VMAT2, as well as VMAT2's binding to a selective radiotracer molecule, and overall dopamine level.

In all three, cocaine users' levels were significantly lower than control subjects. Levels tended to be lowest in cocaine users with depression.

The paper gives the most conclusive evidence yet that dopamine neurons are harmed by cocaine use, because it uses three molecular measures that provide a trustworthy assessment of dopamine neuron health.

Dopamine, Little explains, triggers the actions required to repeat previous pleasures. It's not only involved in drug users' "high" – it helps drive us to eat, work, feel emotions, and reproduce. Normally, when something pleasurable happens, dopamine neurons pump the chemical into the gaps between themselves and related brain cells. Dopamine finds its way to receptors on neighboring cells, triggering signals that help set off pathways to different feelings or sensations.

Then, the dopamine is normally brought back into its home cell, entering through a gateway in the membrane called a transporter. While our brain waits for another pleasurable stimulus – a good meal, a smile from a friend, a kiss – dopamine lies waiting inside the neuron, sequestered in tiny packets called vesicles. VMAT2 acts as a pump to pull returning dopamine into vesicles.

When it comes time for another dopamine release, the vesicles merge with the cell membrane, dumping their contents into the gap, or synapse, and the pleasure signaling process begins again.

Dopamine neurons in the brain's pleasure center die off at a steady rate over a person's lifetime. Severe damage is a hallmark of Parkinson's disease, causing its loss of movement control. "As the words themselves suggest, there's an intimate connection between motion and emotion," says Little. "Emotion puts you in motion — they're pre-activity preparations. It's not surprising that the basal ganglia, where these dopamine neurons are, is very active in ‘emotional states.'"

When first taken, cocaine has a disruptive effect on the brain's dopamine system: It blocks the transporters that return dopamine to its home cell once its signaling job is done. With nowhere to go, dopamine builds up in the synapse and keeps binding with other cells' receptors, sending pleasure signals over and over again. This helps cause the intense "high" cocaine users feel.

Since the dopamine system helps us recognize pleasurable experiences and seek to repeat them, cocaine's long-term dopamine effects likely contribute to the craving addicts feel, and the decreased motivation, stunted emotion and uncomfortable withdrawal they face.

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, and in the genetic instructions needed to make those molecules. Little and his colleagues are studying the effects of long-term cocaine use on the brain at a molecular level, in an attempt to explain the effects seen in cocaine users and addicts.

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 Michael Kilbourn, Ph.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.