The DUSP1 on CaMKII-positive neurons in mPFC mediates adolescent cocaine exposure-induced higher sensitivity to cocaine during adulthood

Abstract

Cocaine abuse during adolescence increases the risk for developing drug addiction in later life, but the underlying molecular mechanism remains unclear. Here, adolescent cocaine-exposed (ACE) male mice models were established by giving once-daily intraperitoneal injections of 15 mg/kg cocaine to mice during adolescence (P28-P42). We found that ACE mice exhibited a higher sensitivity to subthreshold dose of cocaine (1 mg/kg) in adulthood, accompanied with triggered activities and dendritic spine density of pyramidal neuron, increased Dusp1 gene, as well as reduced protein levels and activity of dual specificity phosphatase 1 (DUSP1) in mPFC. Specific overexpression of DUSP1 on mPFC glutamatergic neurons efficiently blocked cocaine-preferred behaviors and reduced mPFC activity, while knockdown of DUSP1 maintained cocaine-preferred behaviors and increased mPFC activity in ACE mice. MAPK-related signals, especially ERK1/2, might underlie the mediating effects of DUSP1. Collectively, these findings suggested that targeting mPFC DUSP1 may represent a promising therapeutic strategy for the treatment and attenuation of addiction susceptibility, particularly in addicts with a history of adolescent drugs exposure.