Featured Paper of the Month – January 2022
Published in Translational Psychiatry by Juan Gomez and Michael Michaelides of the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit.
Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc also binds to the DAT, but the in vivo relevance of this interaction is unknown. We examined this interaction by altering zinc availability and measuring behavior and physiology associated with cocaine exposure. To alter zinc levels, we manipulated dietary zinc or used a mouse model that lacked the zinc transporter ZnT3. The body has no storage system for zinc and one must consistently replenish this essential element via zinc-rich food sources. Of the 24 transporters dedicated to moving zinc around the body, ZnT3 is necessary to shuttle zinc around the brain. By putting mice on a zinc deficient diet or by genetically deleting ZnT3, we show that mice are less sensitive to cocaine and find it less rewarding. We also show that low brain zinc decreases cocaine’s effects on DA neurotransmission and that repeated cocaine use in humans lowers zinc levels in the brain. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that zinc may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.