Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments

Neuropsychopharmacology. 2008 Sep;33(10):2474-82. doi: 10.1038/sj.npp.1301626. Epub 2007 Nov 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Chronic Disease
  • Cocaine / adverse effects*
  • Cocaine-Related Disorders / pathology
  • Cocaine-Related Disorders / physiopathology*
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / adverse effects
  • Drug Administration Schedule
  • Male
  • Memory Disorders / chemically induced*
  • Memory Disorders / pathology
  • Memory Disorders / physiopathology
  • Memory, Short-Term / drug effects*
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neural Pathways / drug effects
  • Neural Pathways / pathology
  • Neural Pathways / physiopathology
  • Neurons / drug effects
  • Neurons / pathology
  • Neurotoxins / adverse effects
  • Oligodendroglia / drug effects
  • Oligodendroglia / pathology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / pathology
  • Prefrontal Cortex / physiopathology
  • Rats
  • Rats, Wistar
  • Self Administration
  • Time


  • Dopamine Uptake Inhibitors
  • Neurotoxins
  • Cocaine