Activation of the mPFC-NAc Pathway Reduces Motor Impulsivity but Does Not Affect Risk-Related Decision-Making in...

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD) are characterized by exacerbated motor and risk-related impulsivities, which are associated with decreased cortical activity. In rodents, the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been separately implicated in impulsive behaviors, but studies on the specific role of the mPFC-NAc pathway in these behaviors are limited. Here, we investigated whether heightened impulsive behaviors are associated with reduced mPFC activity in rodents and determined the involvement of the mPFC-NAc pathway in motor and risk-related impulsivities. We used the Roman High- (RHA) and Low-Avoidance (RLA) rat lines, which display divergent phenotypes in impulsivity. To investigate alterations in cortical activity in relation to impulsivity, regional brain glucose metabolism was measured using positron emission tomography and [¹⁸F]-fluorodeoxyglucose ([¹⁸F]FDG). Using chemogenetics, the activity of the mPFC-NAc pathway was either selectively activated in high-impulsive RHA rats or inhibited in low-impulsive RLA rats, and the effects of these manipulations on motor and risk-related impulsivity were concurrently assessed using the rat gambling task. We showed that basal [¹⁸F]FDG uptake was lower in the mPFC and NAc of RHA compared to RLA rats. Activation of the mPFC-NAc pathway in RHA rats reduced motor impulsivity, without affecting risk-related decision-making. Conversely, inhibition of the mPFC-NAc pathway had no effect in RLA rats. Our results suggest that the mPFC-NAc pathway controls motor impulsivity, but has limited involvement in risk-related decision-making in our current model. Our findings suggest that reducing fronto-striatal activity may help attenuate motor impulsivity in patients with impulse control dysregulation.