Cocaine might give users a buzz, but it could also be making brain cells eat themselves, according to new research. While normally an important survival mechanism for the cell, at high enough doses the drug seems to make this process go into overdrive, causing cells to digest their innards to such an extent that they die.
More than just contributing to our knowledge of how this drug leads to its notable toxic effects, the work could potentially offer scientists a new treatment avenue to explore. Inhibiting this pathway with a different drug was found to protect neurons against cocaine-triggered death, raising the possibility that the same agent or something related may represent a viable therapy for cocaine abuse. The study has been published in Proceedings of the National Academy of Sciences.
“When we talk about cocaine, we mostly discuss its addiction,” lead researcher Prasun Guha told IFLScience. “But it’s been shown that long-term cocaine exposure causes memory problems and brain function abnormalities. That tells you that eventually, when you’re an addict, you’re killing some of your neurons. We wanted to see the basic mechanism of this neurotoxicity.”
The work centers on a molecule called nitric oxide (NO), a gas that nerve cells can use to communicate. A few years ago, the same team from Johns Hopkins University School of Medicine found that part of cocaine’s stimulant effects are the result of the activation of a signaling pathway involving NO and an enzyme called GAPDH, which NO can modify and subsequently alter the activity of. Interestingly, they also found that these two molecules seem have an involvement in cocaine-triggered cell death, although their precise role was hazy.
To find out, the team administered a range of doses of cocaine to brain cells in a dish, which revealed a series of markers for a cell-death pathway called autophagy. Literally meaning “eating oneself,” autophagy involves packaging bits of the cell, such as debris, into membrane-bound sacs and then fusing these with acid-filled compartments that degrade the contents.
The team then gave live mice clinically relevant doses of cocaine and observed subsequently removed slices of their brains under the microscope. Once again, they saw signs of overactive autophagy across the brain, including in a region called the lateral habenula, an area targeted by cocaine. But what was perhaps most interesting was that the brains of mouse pups whose mothers had been given cocaine during pregnancy also showed overactive autophagy, even to a greater extent than the mothers themselves.
This mechanism of cocaine toxicity was also present in pups whose pregnant mothers were given cocaine. gorken demir/Shutterstock
So how does this all tie together? “We previously showed that cocaine activates the production of NO in the brain, and other studies have shown that NO can play a role in the induction of autophagy,” said Guha. “We have now shown that NO plays a big role in the modification of an enzyme called GAPDH, a key event in controlling cocaine-induced autophagy.”
This modification, called nitrosylation, abolishes GAPDH’s enzymatic activity while also triggering its translocation to the nucleus, where it leads to changes in gene expression, Guha says. Ultimately, this triggers the autophagy pathway to go into overdrive. But promisingly, using a well-established NO inhibitor prevented cocaine-treated neurons from dying, raising the possibility that this drug, or similar substances, could be used as a novel cocaine therapy, providing the findings are translatable to humans of course.