Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT 2A Receptor System

Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT 2A R receptor (5-HT 2A R) promote and 5-HT 2A R antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT 2A R, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT 2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT 2A R antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT 2A R binding density in frontal cortex ([ 3 H]-ketanserin radioligand binding). Elevated mPFC 5-HT 2A R protein expression concomitant with augmented association of the 5-HT 2A R with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT 2A R ligands and associated distinct 5-HT 2A R protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT 2A R system.