Metabotropic glutamate receptor 5 in the anterior cingulate cortex predicts individual differences in motor impulsivity but not in risky decision-making

Abstract Impulsivity is a multidimensional construct implicated in various psychiatric disorders, yet its neurobiological underpinnings are insufficiently understood. The metabotropic glutamate receptor type 5 (mGluR5) has emerged as a promising target for modulating impulsive behavior, but whether impulsivity is associated with alterations in mGluR5 availability is unknown. Here, we investigated mGluR5 availability in relation to different impulsivity constructs in male Roman high- (RHA) and low-avoidance (RLA) rat lines, which exhibit divergent impulsive profiles. Motor impulsivity and risky decision-making were assessed using the rat gambling task prior to positron emission tomography measurement of brain mGluR5 availability. Compared to low-impulsive RLA rats, high-impulsive RHA rats showed reduced mGluR5 availability across multiple brain regions. Voxel-wise analysis localized these deficits primarily in the motor cortex, anterior cingulate cortex (ACC), and mediodorsal thalamus. Voxel-wise analyses further highlighted a strong inverse relationship between mGluR5 availability in the ACC and premature responding, but not risky-decision making. Region-of-interest analysis showed that the ACC exhibited a robust within-line association between mGluR5 deficits and premature responses in low-impulsive RLA rats, along with a near-significant relationship in high-impulsive RHA rats. No other brain region demonstrated such consistent within-line correlations across both phenotypes. These findings provide the first evidence that localized mGluR5 reductions predict individual differences in motor impulsivity, with the ACC emerging as the region most consistently associated with this relationship. Collectively, our results offer novel insights into the neurobiological mechanisms underlying impulsivity and support the therapeutic potential of regionally targeted mGluR5 modulation for disorders characterized by dysregulated motor impulsivity.