Finding May Help Cocaine Addicts
Researchers reported a discovery Friday that could eventually lead to a drug to help cocaine addicts break free from their dependence, much in the way methadone currently helps heroin addicts.
By partially mimicking one of the brain’s natural chemical transmitters, scientists have shown--at least in rats--that it is possible to stave off the cocaine craving that trips up many recovering addicts. The mechanism should work the same way in the human brain, the researchers said.
Unlike methadone, it appears that a drug triggering this mechanism would not itself be addictive, the researchers said.
“This is looking pretty promising,” said Yale University psychiatry professor David Self, the lead author of the article that appears in Friday’s issue of the journal Science.
The research focuses on dopamine, one of the chemicals called neurotransmitters that act as message-carrying keys in the brain. Like a key turning a lock, dopamine hooks into one of two types of receiving locations, called D1 and D2, on the surface of about 1% of brain cells.
This binding of the dopamine to the cell activates certain normal functions within the cell.
Cocaine stimulates the brain to overproduce dopamine and then blocks it from returning normally to the sending cells. The dopamine flood at the receiving end is thought to produce the euphoria associated with the drug.
In their experiments, Self and the other Yale researchers found that although dopamine binds equally to D1 and D2, the two receptors have opposite effects on cocaine addiction.
The researchers trained rats to press a lever to inject a cocaine solution into their bloodstreams. After a couple of hours, a salt solution replaced the cocaine. The rats gradually stopped pressing the lever as their bodies sensed they were no longer receiving the addictive drug.
Cocaine, even when it is too diluted to have a direct effect, can reignite an intense craving for the substance. In the rats, this meant that injecting a tiny bit of cocaine caused them to futilely press the lever even though it dispensed just the harmless salt solution.
The researchers found that a chemical that mimicked dopamine’s stimulation of the D1 receptors--but not the D2 ones--completely blocked this cocaine-seeking behavior. By contrast, a second chemical that turned on the D2 receptors caused the rats to press the lever much more often.
The D1 receptor, Self hypothesized, triggers a feeling of satisfaction similar to having eaten a full meal. By contrast, Self suggested, the D2 receptor sends a message of craving, something like the effect of chocolate on some people. “They may continue eating even though they’re full,” he said.
Cocaine, Self said, “has both of these actions built into it,” causing simultaneous satisfaction and craving. However, he added, “this [research] is very preliminary, and it is in animals. We really don’t know what the rats are experiencing.”
The hope, Self said, is to eventually create a D1-activating drug that will be able to banish cocaine craving among recovering addicts and thus avoid many relapses. Earlier efforts to develop an anti-cocaine drug had focused on those that totally shut off dopamine’s effect--essentially jamming the keyhole between the dopamine and the receptors--but these proved mostly ineffective and often had severe, Parkinson’s disease-like side effects.
“What this study does is tell us things that stimulate the D1 receptor may be an ideal target for medication development,” said Alan Leshner, director of the National Institute on Drug Abuse in Rockville, Md., which funded the research. “This is a perfect example of basic science being usable in real-life applications.”
However, no D1-activating drugs--including the one used in the rats--have been approved for use in humans. “We have at least one in early clinical trials in humans,” Leshner said. The institute is pursuing several different possible drugs with pharmaceutical companies, he said.
Other companies, such as Interneuron of Lexington, Mass., are developing drugs with similar actions to battle Parkinson’s disease, which results from the death of dopamine-producing brain cells. Those drugs could potentially be used for cocaine addiction as well, but approval is at best still years away.
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Suppressing the Urge
Cocaine stimulates the overproduction of a chemical messenger molecule known as dopamine, which then floods locations on certain brain cells called D1 and D2 receptors. Many recovering cocaine addicts still suffer intense cravings for the drug, but researchers have shown that, in rats, a drug that activates the D1 dopamine receptors--but not the D2 ones--can eliminate this craving.
