title: Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments.
abstract: Humans with drug addiction exhibit compulsive drug-seeking associated with impairment of prefrontal cortex cognitive function. Whether prefrontal cortex dysfunction is a consequence of chronic drug exposure, or mediates the transition from drug use to drug dependence, is unknown. The current study investigates whether a history of escalated vs controlled cocaine intake is associated with specific working memory impairments, and long-lasting alterations of the dorsomedial prefrontal cortex and orbitofrontal cortex in rats. Working memory was assessed in rats with a history of extended (6 h per session) or limited (1 h per session) access to cocaine (0.5 mg/kg per injection), 3-17 days after the last self-administration session, using a delayed nonmatching-to-sample task. The density of neurons, oligodendrocytes, and astrocytes was quantified in the dorsomedial prefrontal cortex and orbitofrontal prefrontal cortex 2 months after the last self-administration session. Working memory impairments were observed after a history of chronic and escalated cocaine intake, but not after repeated limited access to cocaine. Moreover, working memory impairments were correlated with a decreased density of neurons and oligodendrocytes but not astrocytes in the dorsomedial prefrontal cortex, and with a decreased density of oligodendrocytes in the orbitofrontal cortex. Considering the role of the prefrontal cortex in goal-directed behavior, the prefrontal cortex dysfunctions observed here may exacerbate the loss of control associated with increased drug use and facilitate the progression to drug addiction.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA. ogeorge@scripps.edu
authors.forename: Olivier
authors.initials: O
authors.lastname: George
authors.forename: Chitra D
authors.initials: CD
authors.lastname: Mandyam
authors.forename: Sunmee
authors.initials: S
authors.lastname: Wee
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002908:Chronic Disease; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects; D004334:Drug Administration Schedule; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000009:adverse effects; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013995:Time
chemical_list: D018765:Dopamine Uptake Inhibitors; D009498:Neurotoxins; D003042:Cocaine