title: Role of serotonin transporter function in rat orbitofrontal cortex in impulsive choice.
abstract: Impulsivity is a multi-faceted personality construct that plays a prominent role in drug abuse vulnerability. Dysregulation of 5-hydroxytryptamine (serotonin, 5-HT) systems in subregions of the prefrontal cortex has been implicated in impulsivity. Extracellular 5-HT concentrations are regulated by 5-HT transporters (SERTs), indicating that these transporters may be important molecular targets underlying individual differences in impulsivity and drug abuse vulnerability. The present study evaluated the role of SERT in mediating individual differences in impulsivity. Rats were tested for both impulsive action using the cued go/no-go task and for impulsive choice using a delay discounting task in a counterbalanced design. Following behavioral evaluation, Km and Vmax were obtained from kinetic analysis of [(3)H]5-HT uptake by SERT using synaptosomes prepared from both orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) obtained from each individual rat. Vmax for SERT in OFC, but not mPFC, was negatively correlated with mean adjusted delay scores in the delay discounting task. In contrast, Vmax for SERT in OFC and mPFC was not correlated with performance in the cued go/no-go task. To further evaluate the relationship between SERT function and impulsive choice, a selective SERT inhibitor, fluoxetine (0, 15, 50 and 150pmol/side) was microinjected bilaterally into OFC and effects on the delay discounting task determined. Following stabilization of behavior, fluoxetine increased mean adjusted delay scores (decreased impulsivity) in high impulsive rats compared to saline microinjection, but had no effect in low impulsive rats. These ex vivo and in vivo results suggest that enhanced SERT function in OFC underlies high impulsive choice behavior.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Darna
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Chow
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY 40536, USA; Department of Psychological Science, Northern Kentucky University, Highland Heights, KY 41099, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA; Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Charnigo
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Department of Psychology, University of Kentucky, Lexington, KY 40536, USA; Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Drug Abuse Research Translation, University of Kentucky, Lexington, KY 40536, USA. Electronic address: ldwoskin@email.uky.edu.
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D007839:Functional Laterality; D007175:Impulsive Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D014316:Tritium; D012701:Serotonin
keywords: Cued go/no-go; Delay discounting; Impulsivity; Serotonin transporter