Modafinil rescues repeated morphine‐induced synaptic and behavioural impairments via activation of D1R–ERK–CREB pathway in medial prefrontal cortex

Long‐term opioid abuse causes a variety of long‐lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake‐promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid‐induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine‐induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH‐23390 reverses the morphine‐induced synaptic abnormalities and activation of the D1R–ERK–CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse. Systemic modafinil treatment at low dose efficiently ameliorated morphine‐induced attention dysfunction and improved motivation and working memory in mice. High modafinil dose had adverse effects on impulsive action and attention. By inhibiting dopamine uptake transporters, modafinil increased the dopamine levels in the synaptic cleft and enhanced the D1R–ERK–CREB signalling activity.