Atg5- and Atg7-dependent autophagy in dopaminergic neurons regulates cellular and behavioral responses to morphine

Abstract

The molecular basis of chronic morphine exposure remains unknown. In this study, we hypothesized that macroautophagy/autophagy of dopaminergic neurons would mediate the alterations of neuronal dendritic morphology and behavioral responses induced by morphine. Chronic morphine exposure caused Atg5 (autophagy-related 5)- and Atg7 (autophagy-related 7)-dependent and dopaminergic neuron-specific autophagy resulting in decreased neuron dendritic spines and the onset of addictive behaviors. In cultured primary midbrain neurons, morphine treatment significantly reduced total dendritic length and complexity, and this effect could be reversed by knockdown of Atg5 or Atg7. Mice deficient for Atg5 or Atg7 specifically in the dopaminergic neurons were less sensitive to developing a morphine reward response, behavioral sensitization, analgesic tolerance and physical dependence compared to wild-type mice. Taken together, our findings suggested that the Atg5- and Atg7-dependent autophagy of dopaminergic neurons contributed to cellular and behavioral responses to morphine and may have implications for the future treatment of drug addiction.

Sodium butyrate inhibits migration and induces AMPK‐mTOR pathway‐dependent autophagy and ROS‐mediated apoptosis via the miR‐139‐5p/Bmi‐1 axis in human bladder cancer cells

“…Overwhelming evidence has elucidated the intricate relationship between apoptosis and autophagy . ATG7 has been reported to be a vital regulator in autophagy . To confirm the interplay between these biological processes, we used 3‐MA (3‐methyladenine) and ATG7 siRNA to pharmacologically and genetically block autophagy.…”

“…Furthermore, emerging studies have demonstrated a link between autophagy and apoptosis . Atg7, an essential autophagy regulator, plays important roles in disease development and progression . In this study, we used ATG7 siRNA and 3‐MA to inhibit autophagy and explore the potential role of autophagy in NaB‐induced apoptosis.…”

“…[39][40][41][42] Atg7, an essential autophagy regulator, plays important roles in disease development and progression. 31,33 In this study, we used ATG7 siRNA and 3-MA to inhibit autophagy and explore the potential role of autophagy in NaB-induced apoptosis. Pharmacological and genetic inhibition of autophagy rescued cell death, which indicated that autophagy played a pro-cell death role in NaB treatment of human bladder cancer cells.…”

“…41,42 ATG7 has been reported to be a vital regulator in autophagy. [31][32][33] To confirm the interplay between these biological processes, we used 3-MA (3-methyladenine) and ATG7 siRNA to pharmacologically and genetically block autophagy. As shown in Figure 6A, blocking autophagy significantly rescued cell viability following NaB treatment in both cell lines.…”

“…30 ATG7 has been reported to be a vital regulator of autophagy and plays an irreplaceable role in regular biological processes. [31][32][33] Autophagy can be monitored by the conversion of MAP1LC3B-I to LC3B-II and the degradation of SQSTM1/ p62. 34,35 Mammalian target of rapamycin (mTOR), a serine/ threonine kinase, is of great importance in cell proliferation and growth and is widely known to negatively regulate autophagy.…”