Autophagic Degradation of the Dopamine Transporter Regulates Behavioural Effects of Cocaine

Post by Amanda McFarlan

What's the science?

Cocaine blocks dopamine reuptake and causes prolonged dopamine signaling in the brain by directly binding to the dopamine transporter. Researchers, however, have speculated that this might not be cocaine’s only mechanism of action, since other drugs that block dopamine reuptake, such as sibutramine or bupropion, fail to induce the stimulant effects of cocaine. Recent findings have shown that cocaine may be associated with autophagy, a lysosomal process that involves the degradation and recycling of cellular components to maintain cellular homeostasis. This week in Molecular Psychiatry, Harraz and colleagues examine the role of autophagy in regulating the molecular and behavioural effects of cocaine.

How did they do it?

The authors explored whether cocaine administration in cortical and ventral midbrain neuronal cultures induced autophagy. They used confocal microscopy and transmission electron microscopy to quantify levels of LC3-II, a microtubule-associated protein that tags the autophagosomal membranes. Then, the authors investigated the role of autophagy in the behavioural stimulant effects associated with cocaine. To do this, they treated mice with either one of three autophagy inhibitors (HCQ, vacuolin-1, or SBI-0206965) or saline 45 minutes prior to being placed in an open field test. After measuring baseline locomotor activity, they delivered intraperitoneal injections of either cocaine or saline and placed the mice back in the open field test to monitor locomotor behaviour. Next, the authors performed synaptosome fractions (separation of molecules in the synapse based on size or density) to explore the role of cocaine-induced autophagy on the degradation of the dopamine transporter. Finally, to examine the effect of autophagy on the rewarding actions of cocaine, the authors treated mice with either HCQ (an autophagy inhibitor) or saline prior to administering cocaine in the conditioned place preference paradigm.

What did they find?

The authors determined that cocaine induces autophagy with high potency in neurons. They showed that cocaine-induced locomotor stimulation was greatly reduced in mice that were treated with an autophagy inhibitor compared to mice that were treated with saline. Next, synaptosomal fractions from the nucleus accumbens (an area of the brain associated with reward) revealed that the dopamine transporter was largely depleted in mice that had been treated with cocaine compared to mice treated with saline. The cocaine-induced depletion of the dopamine transporter could be rescued with the administration of an autophagy inhibitor 90 minutes prior to cocaine administration. Notably, cocaine’s effects were selective for the dopamine transporter since levels of the serotonin transporter or tyrosine hydroxylase (an enzyme involved in the synthesis of dopamine) were unchanged. Finally, the authors found that cocaine-induced conditioned place preference was impaired in mice treated with HCQ compared to saline, suggesting that autophagy is involved in regulating the rewarding effects of cocaine.

What’s the impact?

This study is the first to show that cocaine induces autophagic degradation of the dopamine transporter with high potency. The authors found that this cocaine-induced autophagy was important for regulating behavioural characteristics associated with cocaine, including locomotion and reward. These findings provide new insights into the mechanisms by which cocaine acts in the brain.

Harraz et al. Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter. Molecular Psychiatry (2021). Access the original scientific publication here.