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.

Role of Mitochondrial Dynamics in Cocaine’s Neurotoxicity

“…Meanwhile, coordinating with mitochondria, ER stress induced by cocaine exposure via disrupting intracellular calcium homeostasis may also simultaneously induce apoptosis [ 57 , 58 ]. In addition, studies have suggested that autophagic cell death participates in the neurotoxicity of cocaine [ 59 , 60 ]. However, the role of cocaine-induced autophagy in neurotoxicity remains to be elucidated.…”

Autophagy-Based Hypothesis on the Role of Brain Catecholamine Response During Stress

“…In fact, autophagy grants the survival of both DA-and NE-containing neurons during a variety of stressful conditions (49,51,52,68,70). Autophagy alterations are associated with the effects of abused substances (amphetamine, methamphetamine, cocaine, ethanol) on brain catecholamine neurons concerning their morphology, neuroplasticity, as well as neurotoxic and behavioral effects (51,52,56,61). This is evident by a variety of behavioral effects produced by psychostimulants based on autophagy-dependent alterations (56,61).…”

“…Autophagy alterations are associated with the effects of abused substances (amphetamine, methamphetamine, cocaine, ethanol) on brain catecholamine neurons concerning their morphology, neuroplasticity, as well as neurotoxic and behavioral effects (51,52,56,61). This is evident by a variety of behavioral effects produced by psychostimulants based on autophagy-dependent alterations (56,61). Psychostimulants alter neuroplasticity of DA and NE neurons through receptor sensitization/desensitization while affecting their activity and metabolism (7,49).…”

“…In the latter decades, substantial attention has been paid to the role of the autophagy machinery in the physiology of catecholamine brain systems when insulted by pharmacological and neurotoxic agents ( 51 – 54 ). Autophagy has been recently connected with stress- and substance abuse-related disorders such as depression and addiction ( 51 , 53 , 55 , 56 ). In keeping with this, the beneficial effects of several antidepressants and mood stabilizers are bound to autophagy activation ( 57 – 60 ) and autophagy inducers counteract behavioral sensitization induced by abused drugs ( 51 , 56 , 61 ).…”

“…Autophagy has been recently connected with stress- and substance abuse-related disorders such as depression and addiction ( 51 , 53 , 55 , 56 ). In keeping with this, the beneficial effects of several antidepressants and mood stabilizers are bound to autophagy activation ( 57 – 60 ) and autophagy inducers counteract behavioral sensitization induced by abused drugs ( 51 , 56 , 61 ). This wide and prolific research produced results that strongly suggest a crucial role of autophagy in response and adaptation of LC-NE and VTA-DA systems to stress.…”