Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity

ACS Chem Neurosci. 2015 Jul 15;6(7):1248-58. doi: 10.1021/acschemneuro.5b00094. Epub 2015 Jul 7.


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-HT2AR receptor (5-HT2AR) and 5-HT2CR. We investigated the hypothesis that differences in the ratio of 5-HT2AR:5-HT2CR protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT2CR would result in high motor impulsivity concomitant with elevated 5-HT2AR expression and pharmacological sensitivity to the selective 5-HT2AR antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT2AR and the 5-HT2CR predicted the intensity of motor impulsivity and the 5-HT2AR:5-HT2CR ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT2AR and 5-HT2CR act in concert to control motor impulsivity is supported by the observation that high phenotypic motor impulsivity associated with a diminished mPFC synaptosomal 5-HT2AR:5-HT2CR protein:protein interaction. Knockdown of mPFC 5-HT2CR resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT2AR:5-HT2CR balance as evidenced by a compensatory upregulation of 5-HT2AR 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-HT2AR and 5-HT2CR, and that a 5-HT2AR:5-HT2CR imbalance may be a functionally relevant mechanism underlying motor impulsivity.

Keywords: 1-Choice serial reaction time task; 5-HT2A receptor; 5-HT2C receptor; medial prefrontal cortex; motor impulsivity; serotonin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Outbred Strains
  • Choice Behavior / drug effects
  • Choice Behavior / physiology
  • Executive Function / drug effects
  • Executive Function / physiology
  • Fluorobenzenes / pharmacology
  • Gene Knockdown Techniques
  • Impulsive Behavior / drug effects
  • Impulsive Behavior / physiology*
  • Male
  • Membrane Glycoproteins
  • Motor Activity / drug effects
  • Motor Activity / physiology*
  • Neuropsychological Tests
  • Phenotype
  • Piperidines / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Receptors, Interleukin-1
  • Serotonin Antagonists / pharmacology
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism


  • Fluorobenzenes
  • Membrane Glycoproteins
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Interleukin-1
  • Serotonin Antagonists
  • TIRAP protein, human
  • volinanserin