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According to the Global Drug Survey, cocaine is one of the top ten drugs in terms of usage. Between November 7 and December 30, 2019, 31% of respondents had reported using it in the last 12 months. The US has the highest prevalence of cocaine use in people aged 15-64 at 2.7%, according to the United Nations Office on Drugs and Crime (UNODC).
Cocaine works by inhibiting the reuptake of dopamine via dopamine transporters, causing it to build up in the synapse. This leads to a stronger dopamine signal, causing effects such as euphoria. However, research published in Molecular Psychiatry shows evidence that cocaine has another way of working: making your neural cells eat themselves.
In the paper, the researchers write “Cocaine induces autophagy with very great potency … both in vitro and in vivo.” Autophagy is a process where components of cells are degraded and recycled, almost as if the cell is eating itself for sustenance. The name “autophagy” literally translates to “self-eating.”
The researchers focused on the effect of cocaine on the autophagy of dopamine transporters in the nucleus accumbens, a brain region that mediates reward and has a role in addiction. When mice were injected with cocaine, signs of autophagy were seen at the axon terminals – which is the region that makes synaptic connections. In neural cell cultures, markers of autophagy were seen with doses of cocaine as low as 0.1 nanomolar (nM).
The researchers then gave mice one of three autophagy inhibitors before dosing them with cocaine. Without inhibitors, dopamine levels outside the neural cells peaked by 424% 20 minutes after cocaine dosing, slowly decreasing after 20 minutes. With two of the inhibitors, dopamine had lower peaks of around 292 and 337%, with a much swifter decline afterward. All of the inhibitors reduced locomotor stimulation caused by cocaine.
In nucleus accumbens samples from mice given cocaine, the researchers observed a “substantial” depletion of the dopamine transporter. However, giving the mice autophagy inhibitors 90 minutes before giving them cocaine prevented this. Lysosomes are small parts of the cells containing digestive enzymes, essential for autophagy. The researchers observed that six hours after cocaine injection, dopamine transporter levels were increased in lysosomes.
“Based on our findings, we propose that at lower cocaine concentrations that do not inhibit the [dopamine] transport activity, autophagic degradation of [dopamine transporter] is the main driver of [dopamine] reuptake inhibition,” write the authors in the paper, “while at higher cocaine concentrations both autophagic degradation of [dopamine transporter] and direct transport inhibition by cocaine binding to the transporter might underlie [dopamine] reuptake inhibition.”
Although autophagy can cause cells to die, it can also have a protective effect on cells, with some researchers saying enhancing it could help with some diseases. The Michael J. Fox Foundation has even funded studies to develop drugs that promote autophagy to treat Parkinson’s disease. The authors of this study state that extremely low doses of cocaine “may exert beneficial effects that warrant exploration for therapeutic application.”
