Drug addicts might soon find it easier to kick their habits, thanks to a groundbreaking new study by Yale professors. Focusing on how cocaine interacts with the brain, the study may lead to the development of new drugs that will help addicts to avoid relapsing.
Cocaine hooks people through its effect on the neurotransmitter dopamine, one of the chemicals which enable nerve cells to communicate. The study targeted two dopamine receptors called D1 and D2 and showed that they act in surprising ways when dopamine binds to them. Psychiatry Professor Erik Nestler, JE' 76, MED '82, GRD '83, said that they discovered that the two receptors react in virtually opposite ways, and they now have a much better understanding of cocaine addiction.
"The first step was to develop an animal model for cocaine-seeking behavior," Nestler said."We then studied drugs that stimulate and inhibit craving." The way cocaine works on the brain is very similar in rats and in humans, so they put the rats in a box with a lever which allowed them to inject themselves with cocaine when they pressed it. Like their human counterparts, the addicted rats did this enthusiastically, but they would stop when the researchers switched the cocaine with a placebo; after a few times, the rats could tell within one lever press that they were no longer getting high and would stop trying.
The rats also behaved like humans in another key way. A small dose of cocaine or environmental cues associated with drug use can make recovering addicts crave a fix. In the same way, a minute dose of cocaine sent the rats running back to the lever for more. They continued to press it wildly, although they were just receiving the placebo. This powerful reaction is one of the main hurdles in overcoming cocaine addiction-someone can be clean for years and try a small dose once, and an almost irresistible craving for it will be triggered. "Cocaine craving has been described as resembling the positive or 'high'-like qualities of the drug itself," the paper, published in the March 15 issue of Science, said. This pattern of addiction differs from the craving for other drugs like heroin or alcohol, which the addict longs for in order to alleviate the negative symptoms associated with drug withdrawal.
Once the rats adequately imitated humans in their drug-addicted behavior, the team, which included David Self, William Barnhart, TC '93, David Lehman, DC '95, and Nestler, ran tests with drugs to determine exactly how D1 and D2 receptors work. They found that when the D2 receptor was stimulated by a drug that acts like dopamine, but only binds to the one specific receptor, the rats desperately craved cocaine. When the D1 agonist was used, however, the rats stopped trying to get themselves high, even when they were given a small priming dose of cocaine. "It seems that the D2 receptors tell the rat, 'It was good to do it, do it more,' while the D1 receptor is telling it, 'It was good to do it, now stop,'" Nestler said. Since the D1 receptor seems to suppress the craving for cocaine, it is very possible that the drug that targeted the D1 receptor could be used in humans to treat cocaine addicts, much the way methadone helps heroin users.
Researchers have tested other drugs that attempt to inhibit the effects of cocaine, but this research points to the first one that might be effective without having too many negative side effects. Nestler said that some studies have been done using drugs that activate the D2 receptor in the hope that they will lessen the addiction to cocaine, but that the new study shows that this could actually worsen the effects of cocaine. "It seems that cocaine activates D1 and D2, one stimulating the craving and the other lessening it, so that if one used a D2 agonist by itself, it could actually make the craving worse."
Those drugs that inhibit dopamine release, which is what cocaine activates, have been somewhat successful, but patients have experienced side effects that resemble those of Parkinson's disease, which a lack of dopamine in the brain causes. Actually, the drugs used as agonists were developed to treat Parkinson's disease, and Nestler said that the next step would be to begin clinical trials to see if the D1 agonist was indeed effective in treating cocaine addiction.
Although the research, funded by the National Institute for Drug Addiction, is very promising, Nestler said that there have been some unwanted delays. "Drug companies aren't forthcoming when it comes to looking at drug addiction," he said. They might be reluctant to use medication that is used for other diseases for drug treatment, because it might give the drug a bad name."For instance, Parkinson's patients might not want to use certain medications if they become known as treatments for coke addicts."
Cocaine itself affects the brain by blocking the re-uptake of dopamine by the cell that originally released it. Neurons communicate when an electrical impulse causes one cell to release dopamine, which then activates another cell by binding to the receptors on its surface. The first cell will continue to release dopamine until it is switched off by a molecule called dopamine transporter, which is the key to cocaine's activity. It is to this molecule that cocaine binds, blocking its signal and causing cells to flood receptors with their continual release of dopamine. This causes permanent changes in cell function, leading to the high that addicts feel, and their weird behavior.
Graphic by Alan Tseng.
Copyright 1996, The Yale Herald, Inc. All rights reserved.
This article may be freely distributed electronically, provided it is distributed in its entirety and includes this notice, but may not be reprinted without the express written permission of The Yale Herald, Inc. Write to herald@yale.edu for additional details.