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

26 Citations (Scopus)

Abstract

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
Volume6
Issue number7
DOIs
StatePublished - Jul 15 2015

Fingerprint

Receptor, Serotonin, 5-HT2A
Impulsive Behavior
Prefrontal Cortex
Serotonin
Proteins
Rats
Serotonin 5-HT2 Receptor Antagonists
Individuality

Keywords

  • 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

Cite this

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

In: ACS Chemical Neuroscience, Vol. 6, No. 7, 15.07.2015, p. 1248-1258.

Research output: Contribution to journalArticle

Anastasio, Noelle ; Stutz, Sonja J. ; Fink, Latham H L ; Swinford-Jackson, Sarah E. ; Sears, Robert M. ; Dileone, Ralph J. ; Rice, Kenner C. ; Moeller, F. Gerard ; Cunningham, Kathryn. / 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. In: ACS Chemical Neuroscience. 2015 ; Vol. 6, No. 7. pp. 1248-1258.
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abstract = "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.",
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