Serotonin (5-HT) 5-HT<inf>2A</inf> Receptor (5-HT<inf>2A</inf>R): 5-HT<inf>2C</inf>R Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

Noelle Anastasio, Sonja J. Stutz, Latham H L Fink, Sarah E. Swinford-Jackson, Robert M. Sears, Ralph J. Dileone, Kenner C. Rice, F. Gerard Moeller, Kathryn Cunningham

Research output: Contribution to journalArticle

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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<inf>2A</inf>R receptor (5-HT<inf>2A</inf>R) and 5-HT<inf>2C</inf>R. We investigated the hypothesis that differences in the ratio of 5-HT<inf>2A</inf>R:5-HT<inf>2C</inf>R protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT<inf>2C</inf>R would result in high motor impulsivity concomitant with elevated 5-HT<inf>2A</inf>R expression and pharmacological sensitivity to the selective 5-HT<inf>2A</inf>R antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT<inf>2A</inf>R and the 5-HT<inf>2C</inf>R predicted the intensity of motor impulsivity and the 5-HT<inf>2A</inf>R:5-HT<inf>2C</inf>R ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT<inf>2A</inf>R and 5-HT<inf>2C</inf>R 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<inf>2A</inf>R:5-HT<inf>2C</inf>R protein:protein interaction. Knockdown of mPFC 5-HT<inf>2C</inf>R resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT<inf>2A</inf>R:5-HT<inf>2C</inf>R balance as evidenced by a compensatory upregulation of 5-HT<inf>2A</inf>R 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<inf>2A</inf>R and 5-HT<inf>2C</inf>R, and that a 5-HT<inf>2A</inf>R:5-HT<inf>2C</inf>R imbalance may be a functionally relevant mechanism underlying motor impulsivity.

Original languageEnglish (US)
Pages (from-to)1248-1258
Number of pages11
JournalACS Chemical Neuroscience
Issue number7
StatePublished - Jul 15 2015



  • 1-Choice serial reaction time task
  • 5-HT<inf>2A</inf> receptor
  • 5-HT<inf>2C</inf> receptor
  • medial prefrontal cortex
  • motor impulsivity
  • serotonin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

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