Activation of AMPK‐dependent autophagy in the nucleus accumbens opposes cocaine‐induced behaviors of mice

Abstract Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine‐induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D 1 receptor ‐CaMKII‐AMPK‐FoxO3a signaling pathway was involved in acute cocaine application‐induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo . Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine‐induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.