title: The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.
abstract: Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK. Electronic address: de102@cam.ac.uk.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Eagle
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Cristie
authors.initials: C
authors.lastname: Noschang
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Laure-Sophie Camilla
authors.initials: LS
authors.lastname: d'Angelo
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Christie A
authors.initials: CA
authors.lastname: Noble
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Jacob O
authors.initials: JO
authors.lastname: Day
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Dongelmans
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Theobald
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Mar
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Gonzalo P
authors.initials: GP
authors.lastname: Urcelay
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Morein-Zamir
authors.affiliation: Department of Psychology and Behavioural and Clinical Neuroscience Institute, University of Cambridge, Downing Site, Cambridge, CB2 3EB, UK.
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Robbins
mesh_terms: D000818:Animals; D001007:Anxiety / Q000175:diagnosis / Q000209:etiology; D003192:Compulsive Behavior / Q000139:chemically induced* / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning; D019370:Observation; D011597:Psychomotor Performance; D019257:Quinpirole / Q000633:toxicity*; D051381:Rats; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D018709:Statistics, Nonparametric; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D019257:Quinpirole; D013469:Sulpiride
keywords: Checking; Dopamine; Obsessive-compulsive disorder; Rat