title: Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity.
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.
authors.forename: Noelle C
authors.initials: NC
authors.lastname: Anastasio
authors.forename: Sonja J
authors.initials: SJ
authors.lastname: Stutz
authors.forename: Latham H L
authors.initials: LH
authors.lastname: Fink
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Swinford-Jackson
authors.affiliation: §Department of Psychiatry, Yale University, New Haven, Connecticut 06520, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sears
authors.affiliation: §Department of Psychiatry, Yale University, New Haven, Connecticut 06520, United States.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.affiliation: ∥Chemical Biology Research Branch, National Institute on Drug Abuse, DHHS/NIH/NIDA, Bethesda, Maryland 20892, United States.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: ⊥Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, United States.
authors.forename: F Gerard
authors.initials: FG
authors.lastname: Moeller
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D005464:Fluorobenzenes / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009483:Neuropsychological Tests; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D005464:Fluorobenzenes; D008562:Membrane Glycoproteins; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017472:Receptors, Interleukin-1; D012702:Serotonin Antagonists; C434984:TIRAP protein, human; C079049:volinanserin
keywords: 1-Choice serial reaction time task; 5-HT2A receptor; 5-HT2C receptor; medial prefrontal cortex; motor impulsivity; serotonin