The study shows that cocaine triggers death of neurons in the brains of mice by sending a cell waste-disposal process called autophagy into overdrive.
Cells have three built-in mechanisms for destroying themselves - for instance, if they start malfunctioning or get worn out. One of these is autophagy, where waste materials are digested and recycled. But autophagy can also be used as a suicide program - by triggering it to eat essential cell components.
In a new study about to be published in the Proceedings of the National Academy of Sciences, researchers from Johns Hopkins University in Baltimore, MD, describe how they found high doses of cocaine can cause autophagy in mouse brains to become hyperactive.
Even mice born to mothers who had been given cocaine when they were pregnant showed signs of hyperactive autophagy in their brain cells.
Dr. Prasun Guha, postdoctoral student at Johns Hopkins, says:
"Autophagy is the housekeeper that takes out the trash - it's usually a good thing. But cocaine makes the housekeeper throw away really important things, like mitochondria, which produce energy for the cell."
The authors also describe how they tested a potential antidote to the effect in the form of the experimental drug CGP3466B. The drug is already known to be safe in humans because it has been tested in phase 2 trials of its (unsuccessful) effect on Parkinson's disease and ALS.
Solomon Snyder, professor of neuroscience at Johns Hopkins, explains:
"We performed 'autopsies' to find out how cells die from high doses of cocaine. That information gave us immediate insight into how we might use a known compound to interfere with that process and prevent the damage."
Cocaine triggers death of neurons by sending autophagy into overdrive
In previous work, the team had already established that nitric oxide released by cells is involved in cocaine-induced cell death by interaction with an enzyme called GAPDH. But the new study sheds light on how the cells actually die.
Autophagy clears out cell waste by collecting it in membrane-enclosed vacuoles, or sacs inside the cell. The vacuoles fuse with each other and other sacs containing digesting acids that degrade the contents. Cell death is triggered when this process spins out of control, says Prof. Snyder.
To get a closer look at what is happening in this process, the team measured changes in protein levels that are known to trigger the cell-death program and watched what happened in brain cells or neurons as the protein levels changed in response to cocaine.
They could clearly see that high doses of cocaine triggered the death of neurons by sending autophagy into overdrive. The finding confirms that of other studies that have shown cocaine triggers autophagy in two other types of cell found in the brain: astrocytes and microglia.
The team then showed that CGP3466B - known to disrupt nitric oxide/GAPDH interactions - halted cocaine-induced autophagy. They also tested other compounds that are known to stop the other two forms of cell suicide, but only CGP3466B protected neurons in the mouse brain from death by cocaine.
Team hopes findings will lead to treatments
The fact that cocaine appears to act exclusively via autophagy - and not via the other cell-death programs - offers a good chance of developing new drugs that target its toxic effect, suggest the researchers.
While many more years of studies in mice and then humans lie ahead, the team hopes the findings will eventually lead to treatments that protect adults and babies from the devastating effects that cocaine can cause in the brain.
They also want to find out if cocaine kills any other cells outside the brain.
In an earlier mouse study that Medical News Today reported in 2013, another team also found that cocaine triggers rapid growth in brain structures for memory and learning - but only in a way that encourages more drug-seeking behavior. That finding suggests a novel way in which cocaine users select environments linked to the drug, the researchers noted.