It’s no secret that doing drugs can be dangerous for the Brain. But just how dangerous? Cocaine in particular poses a threat because of its means of ingestion. The nostrils connect directly to the brain using the olfactory nerve - the first cranial nerve - which allows us to have a sense of smell by delivering vital sensory information to the brain. Because the most popular method of ingesting cocaine is through the nostrils, and occasionally the mouth, there is a more or less direct connection between the substance and its target for effect.

Cocaine inhibits the reuptake of serotonin, norepinephrine, and dopamine, resulting in greater concentrations of these three neurotransmitters in the brain. This results in the infamous “high” feeling, which can ultimately be addictive. But the extent of the effects of cocaine on our brains may be more severe than we previously realized. A recent study conducted on mice revealed that high doses of cocaine can actually cause brain cells to digest their own insides. This is done by sending a natural clearing process called Autophagy into overdrive.

Can Cocaine Cause Cell Suicide?

Interestingly, our cells have three built-in mechanisms that they can use to destroy themselves. Usually, these come into play when the cell begins malfunctioning or gets “worn out.” One of these mechanisms is known as autophagy and it’s primary role is to digest and recycle waste materials. However, autophagy can also potentially be initiated as a suicide program if it is triggered to eat essential cell components.

Soon to be published in the Proceedings of the Natural Academy of Sciences, new research from Johns Hopkins University shows that high doses of cocaine in mice can cause autophagy to kick into overdrive in their brains. Postdoctoral student, Dr. Prasun Guha explains: “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.”

Is There an Antidote?

The authors of the study tested a potential antidote for the effect in the form of an experimental drug. Known as CGP3466B, the drug is known to be safe for humans due to it formerly being tested (unsuccessfully) in phase 2 trials for its effect on Parkinson’s and ALS. Describing the application of the drug in the more recent experiment, Solomon Snyder, professor of neuroscience  at Johns Hopkins states: “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.”

Previously, in their earlier work, the team had established that nitric oxide, released by cells, was involved in cocaine-induced cell-death due to an interaction with an enzyme known as GADPH. This new research, however, reveals how the cells actually die. Autophagy, the process in question, clears out cell waste by collecting it within membrane-enclosed vacuoles. These sacs inside the cell fuse with each other as well as with other sacs which contain digesting acids which degrade the contents. Professor Snyder claims that cell death occurs when this process gets out of control.

To get a closer look, the researchers measured changes in the protein levels that are already known to trigger cell-death and watched what happened in brain cells or neurons as these protein levels changed in response to the introduction of the cocaine. They observed clearly that high doses of cocaine caused neuronal death due to overactive autophagy. This finding confirms those of other studies which found that cocaine triggers autophagy in two other types of cell which are found in the brain: astrocytes and microglia. The researchers then showed that CGP3466B, which is known to disrupt the interactions of nitric oxide/GAPDH, halted the cocaine-induced autophagy. They tested other compounds which were known to stop the two other forms of cell-suicide, but only CGP3466B successfully protected the neurons in the mouse brains from death caused by the cocaine.

Further Research is Needed

The fact is that cocaine appeared to act exclusively via autophagy as opposed to other cell-death programs. This finding offers a good chance of developing new drugs which target it’s toxic effect. More research is needed to eventually develop treatments which may protect both adults and infants from the devastating effects cocaine can have on the brain. Moreover, further studies can help determine whether or not cocaine can also damage or kill any other cells outside of the brain.

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