mPFC DUSP1 mediates adolescent cocaine exposure-induced higher sensitivity to drug in adulthood

Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity, and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neuron activity and blocks sdC-induced CPP in ACE mice during adulthood. On the contrary, depleting DUSP1 in CaMKII-positive neurons activates more neurons and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use. Overall design: Adolescent cocaine-exposed (ACE) male mice models were established by administrating cocaine during adolescent period.

青少年时期可卡因滥用会增加成年后成瘾的风险，但其潜在分子机制仍未明确。本研究构建了青少年可卡因暴露（Adolescent Cocaine-Exposed, ACE）雄性小鼠模型。给予阈下剂量可卡因（subthreshold dose of cocaine, sdC）处理——该剂量无法使青少年小鼠产生条件性位置偏爱（conditioned place preference, CPP）——却可诱导成年期ACE小鼠出现CPP，同时其内侧前额叶皮层（medial prefrontal cortex, mPFC）内CaMKII阳性神经元（CaMKII-positive neurons）激活水平显著升高、双特异性蛋白激酶磷酸酶-1（dual specificity protein kinase phosphatase-1, Dusp1）的mRNA表达量上调、DUSP1活性与蛋白表达量均下调。在CaMKII阳性神经元中过表达DUSP1可抑制神经元活性，并阻断成年期ACE小鼠中sdC诱导的CPP。反之，在CaMKII阳性神经元中敲除DUSP1则可激活更多神经元，并进一步增强成年期ACE小鼠中sdC诱导的行为反应。此外，ERK1/2可能是该过程中DUSP1的下游信号分子。本研究结果揭示了内侧前额叶皮层DUSP1在ACE模型成年小鼠药物敏感性升高过程中的关键作用。DUSP1或可作为潜在药理学靶点，用于预测或干预青少年时期物质使用所致的成瘾药物易感性。实验整体设计：通过在青少年时期给予可卡因，构建青少年可卡因暴露（ACE）雄性小鼠模型。