Serotonin (5-HT) 5-HT_2A Receptor (5-HT_2AR):5-HT_2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

A feature of multiple neuropsychiatric disorders is motor impulsivity. Recent studies have implicated serotonin (5-HT) systems in medial prefrontal cortex (mPFC) in mediating individual differences in motor impulsivity, notably the 5-HT_2AR receptor (5-HT_2AR) and 5-HT_2CR. We investigated the hypothesis that differences in the ratio of 5-HT_2AR:5-HT_2CR protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT_2CR would result in high motor impulsivity concomitant with elevated 5-HT_2AR expression and pharmacological sensitivity to the selective 5-HT_2AR antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT_2AR and the 5-HT_2CR predicted the intensity of motor impulsivity and the 5-HT_2AR:5-HT_2CR ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT_2AR and 5-HT_2CR act in concert to control motor impulsivity is supported by the observation that high phenotypic motor impulsivity associated with a diminished mPFC synaptosomal 5-HT_2AR:5-HT_2CR protein:protein interaction. Knockdown of mPFC 5-HT_2CR resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT_2AR:5-HT_2CR balance as evidenced by a compensatory upregulation of 5-HT_2AR protein expression and a leftward shift in the potency of M100907 to suppress impulsive behavior. We infer that there is an interactive relationship between the mPFC 5-HT_2AR and 5-HT_2CR, and that a 5-HT_2AR:5-HT_2CR imbalance may be a functionally relevant mechanism underlying motor impulsivity.