Drug blunts cocaine addiction in mice
JOHNS HOPKINS (US) — Neuroscientists trying to explain cocaine’s effects on the brain have stumbled onto a chemical compound that blocks cravings for the drug in addicted mice.
The compound is already known to be safe for people to take, though it was ineffective as a medicine years ago in tests against Parkinson’s disease and amyotrophic lateral sclerosis.
It will now undergo further animal testing in preparation for possible clinical trials in human cocaine addicts, the researchers say.
“It was remarkably serendipitous that when we learned which brain pathway cocaine acts on, we already knew of a compound . . . that blocks that specific pathway,” says Solomon Snyder, a professor of neuroscience at the Johns Hopkins University School of Medicine. “Not only did CGP3466B help confirm the details of cocaine’s action, but it also may become the first drug approved to treat cocaine addiction.”
Details of the research appear May 22 on the website of the journal Neuron.
Snyder has been studying the brain for decades. Twenty years ago, he and his team discovered that the gas nitric oxide (NO) is a major player in the complex signaling network that allows neurons to coordinate with one another. They have since studied many of the proteins in that network, including one called GAPDH.
A few years ago, Snyder’s team and other researchers found that if NO reacts with GAPDH in a brain cell, GAPDH can then bind to another protein that whisks GAPDH into the nucleus, the cell’s control center.
There, depending on what other chemical signals are present, the GAPDH can either stimulate the neuron’s growth or activate a self-destruct program—called apoptosis—that will kill the neuron.
In his research on GAPDH, Snyder came across a paper published in 1998 by scientists at Novartis. They had found interactions in the brain between GAPDH and a failed Parkinson’s/ALS candidate drug, CGP3466B. When Snyder saw the old paper, he connected it to his team’s findings, realizing that CGP3466B might prevent GAPDH from entering the cell nucleus to trigger cell death.
In a study published in 2006, he and other Johns Hopkins researchers tested two compounds similar to CGP3466B to see if they would block GAPDH under conditions that would normally cause apoptosis.
The protective drugs worked, the team found, by disrupting the reaction between NO and GAPDH, ultimately keeping GAPDH out of the nucleus and keeping the cell alive.
In the new study, graduate student Risheng Xu worked with other members of Snyder’s team to investigate whether cocaine works through the NO signaling network and, if so, how. Using mice, they found that cocaine induces NO to react with GAPDH so that GAPDH does move into the nucleus.
At low doses of cocaine, the GAPDH in the nucleus will stimulate the neuron, but at higher doses it activates the cell’s self-destruct pathway.
“This explains why cocaine can have very different effects depending on the dosage,” Xu says.
The team then tested whether CGP3466B would block cocaine’s effects as it blocks the reaction between NO and GAPDH. In one experiment, they placed mice in a cage with two rooms, and trained them to expect occasional doses of cocaine in one.
When the mice began spending most of their time in that room, it showed they had become addicted to cocaine. But when treated with CGP3466B, the mice went back to spending roughly equal amounts of time in both rooms: their cocaine cravings had abated, Xu says.
“What’s exciting is that this drug works at very low doses, and it also appears only to affect this specific pathway, making it unlikely to have unwanted side effects,” Xu notes. “We also know from Novartis’ early stage clinical trials that the drug exhibits few documented side effects in people.”
CGP3466B is now owned by a different company. Snyder has brokered a deal allowing the National Institute on Drug Abuse to test CGP3466B as a treatment for cocaine addiction. NIDA will first conduct more animal trials, and then, if all goes well, move on to clinical trials in addicts.
Another member of the research team, Nilkanta Sen, cautions that more research is needed to see whether CGP3466B will fulfill its apparent promise. But, says Sen, now an assistant professor at Georgia Regents University, “what we cannot deny is that this study provides a new hope in the field of addiction research.”
The National Institute on Drug Abuse funded the study.
Source: Johns Hopkins University
You are free to share this article under the Creative Commons Attribution-NoDerivs 3.0 Unported license.