title: Individual Differences in Impulsive Action Reflect Variation in the Cortical Serotonin 5-HT2A Receptor System.
abstract: Impulsivity is an important feature of multiple neuropsychiatric disorders, and individual variation in the degree of inherent impulsivity could play a role in the generation or exacerbation of problematic behaviors. Serotonin (5-HT) actions at the 5-HT2AR receptor (5-HT2AR) promote and 5-HT2AR antagonists suppress impulsive action (the inability to withhold premature responses; motor impulsivity) upon systemic administration or microinfusion directly into the medial prefrontal cortex (mPFC), a node in the corticostriatal circuit that is thought to play a role in the regulation of impulsive action. We hypothesized that the functional capacity of the 5-HT2AR, which is governed by its expression, localization, and protein/protein interactions (eg, postsynaptic density 95 (PSD95)), may drive the predisposition to inherent impulsive action. Stable high-impulsive (HI) and low-impulsive (LI) phenotypes were identified from an outbred rodent population with the 1-choice serial reaction time (1-CSRT) task. HI rats exhibited a greater head-twitch response following administration of the preferential 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and were more sensitive to the effects of the selective 5-HT2AR antagonist M100907 to suppress impulsive action relative to LI rats. A positive correlation was observed between levels of premature responses and 5-HT2AR binding density in frontal cortex ([(3)H]-ketanserin radioligand binding). Elevated mPFC 5-HT2AR protein expression concomitant with augmented association of the 5-HT2AR with PSD95 differentiated HI from LI rats. The observed differential sensitivity of HI and LI rats to 5-HT2AR ligands and associated distinct 5-HT2AR protein profiles provide evidence that spontaneously occurring individual differences in impulsive action reflect variation in the cortical 5-HT2AR system.
authors: 1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors: Latham H L
authors: LH
authors: Fink
authors: 1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors: Noelle C
authors: NC
authors: Anastasio
authors: 1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors: Robert G
authors: RG
authors: Fox
authors: Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors: Kenner C
authors: KC
authors: Rice
authors: Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors: F Gerard
authors: FG
authors: Moeller
authors: 1] Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors: Kathryn A
authors: KA
authors: Cunningham
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000502:physiology; D004118:Dimethoxyphenylethylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects; D047468:Immunoprecipitation; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D007206:Individuality; D007650:Ketanserin / Q000493:pharmacokinetics; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D004118:Dimethoxyphenylethylamine; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D014316:Tritium; D007650:Ketanserin; C079049:volinanserin; C521995:4-iodo-2,5-dimethoxy-beta-phenethylamine