title: Pharmacological inactivation of the prelimbic cortex emulates compulsive reward seeking in rats.
abstract: Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug use. Contemporary addiction theories state that loss of control over drug use is mediated by a combination of several processes, including a transition from goal-directed to habitual forms of drug seeking and taking, and a breakdown of the prefrontally-mediated cognitive control over drug intake. In recent years, substantial progress has been made in the modelling of loss of control over drug use in animal models, but the neural substrates of compulsive drug use remain largely unknown. On the basis of their involvement in goal-directed behaviour, value-based decision making, impulse control and drug seeking behaviour, we identified the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) as candidate regions to be involved in compulsive drug seeking. Using a conditioned suppression model, we have previously shown that prolonged cocaine self-administration reduces the ability of a conditioned aversive stimulus to reduce drug seeking, which may reflect the unflagging pursuit of drugs in human addicts. Therefore, we tested the hypothesis that dysfunction of the PrL and OFC underlies loss of control over drug seeking behaviour, apparent as reduced conditioned suppression. Pharmacological inactivation of the PrL, using the GABA receptor agonists baclofen and muscimol, reduced conditioned suppression of cocaine and sucrose seeking in animals with limited self-administration experience. Inactivation of the OFC did not influence conditioned suppression, however. These data indicate that reduced neural activity in the PrL promotes persistent seeking behaviour, which may underlie compulsive aspects of drug use in addiction.
authors.affiliation: Brain Center Rudolf Magnus, Dept. of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jules H W
authors.initials: JH
authors.lastname: Limpens
authors.affiliation: Brain Center Rudolf Magnus, Dept. of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ruth
authors.initials: R
authors.lastname: Damsteegt
authors.affiliation: Brain Center Rudolf Magnus, Dept. of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Broekhoven
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Voorn
authors.affiliation: Brain Center Rudolf Magnus, Dept. of Translational Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands; Dept. of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands. Electronic address: l.j.m.j.vanderschuren@uu.nl.
authors.forename: Louk J M J
authors.initials: LJ
authors.lastname: Vanderschuren
mesh_terms: D000818:Animals; D001418:Baclofen / Q000633:toxicity; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D003657:Decision Making / Q000502:physiology*; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D058999:Drug-Seeking Behavior / Q000502:physiology*; D056344:Executive Function / Q000502:physiology*; D018755:GABA Agonists / Q000633:toxicity; D006040:Goals; D007175:Impulsive Behavior / Q000502:physiology*; D008297:Male; D009118:Muscimol / Q000633:toxicity; D017208:Rats, Wistar; D012201:Reward
chemical_list: D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; D018755:GABA Agonists; D009118:Muscimol; D001418:Baclofen; D003042:Cocaine
keywords: Cocaine; Conditioned suppression; Drug addiction; Orbitofrontal cortex; Prelimbic cortex; Sucrose