title: The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study.
abstract: BACKGROUND
  Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved.
  
  
  OBJECTIVE
  The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms.
  
  
  METHODS
  In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 μg/side) on performance in this task.
  
  
  RESULTS
  In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4).
  
  
  CONCLUSIONS
  Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK. ja476@cam.ac.uk.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK. ja476@cam.ac.uk.|Department of Neuroscience, Unit of Functional Neurobiology, University of Uppsala, Uppsala, SE-75124, Sweden. ja476@cam.ac.uk.
authors.forename: J
authors.initials: J
authors.lastname: Alsiö
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: S R O
authors.initials: SR
authors.lastname: Nilsson
authors.affiliation: Lilly Centre for Cognitive Neuroscience, Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, GU20 6PH, UK.
authors.forename: F
authors.initials: F
authors.lastname: Gastambide
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: R A H
authors.initials: RA
authors.lastname: Wang
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Dam
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Mar
authors.affiliation: Lilly Centre for Cognitive Neuroscience, Eli Lilly & Co. Ltd., Erl Wood Manor, Windlesham, GU20 6PH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Tricklebank
authors.affiliation: Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.|Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EB, UK.
authors.forename: T W
authors.initials: TW
authors.lastname: Robbins
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001418:Baclofen / Q000494:pharmacology; D002755:Choice Behavior / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012193:Reversal Learning / Q000187:drug effects*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D009118:Muscimol; D001418:Baclofen
keywords: 5-HT2C receptor; Orbitofrontal cortex; Rat; Reversal learning; SB 242084