Effects of extended access to high versus low cocaine doses on self-administration, cocaine-induced reinstatement and brain mRNA levels in rats

Psychopharmacology (Berl). 2004 Aug;175(1):26-36. doi: 10.1007/s00213-004-1778-x. Epub 2004 Mar 20.


Rationale: The investigation of rodent cocaine self-administration (SA) under conditions that promote escalating patterns of intake may provide insight into the loss of control over drug use that is central to human addiction.

Objective: This study examines the effects of daily long-access (LgA) SA of high or low cocaine doses on drug intake, extinction, reinstatement, and brain mRNA levels.

Methods: Three groups of male Sprague-Dawley rats were trained to self-administer cocaine during multiple-dose sessions. Short-access (ShA) rats were tested daily for multi-dose SA then remained in the chambers for 7 h with no cocaine available. LgA rats had access to low (0.5 mg/kg per infusion; LgA-LD) or high (2.0 mg/kg per infusion; LgA-HD) cocaine doses for 7 h after multi-dose SA. After 14 days, responding was extinguished, cocaine-induced reinstatement was determined, and preproenkephalin (ppENK), preprodynorphin (ppDYN), corticotropin releasing factor (CRF) and dopamine D(2) receptor (D(2)R) mRNA levels were measured in various brain regions using a quantitative solution hybridization RNase protection assay.

Results: Whereas SA was not altered in ShA rats and only increased during the "loading phase" in LgA-LD rats, a general escalation of intake was found in LgA-HD rats. LgA, particularly LgA-HD, rats were more susceptible to reinstatement than ShA rats. Caudate-putamen ppENK and nucleus accumbens D(2)R mRNA levels were elevated in LgA-HD rats. Overall, D(2)R mRNA levels were positively correlated with reinstatement.

Conclusions: The escalation of cocaine SA under LgA conditions is dose-dependent and is associated with heightened susceptibility to drug-induced relapse. The characterization of neurobiological alterations that accompany escalated SA should facilitate the identification of mechanisms underlying the onset of human addiction.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Addictive / psychology
  • Brain / drug effects*
  • Brain / metabolism
  • Cocaine / administration & dosage*
  • Cocaine-Related Disorders / psychology
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism
  • Dose-Response Relationship, Drug
  • Dynorphins / genetics
  • Dynorphins / metabolism
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Extinction, Psychological / drug effects
  • Male
  • Opioid Peptides / genetics
  • Opioid Peptides / metabolism
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Recurrence
  • Self Administration
  • Time Factors


  • Enkephalins
  • Opioid Peptides
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Dopamine D2
  • pre-prodynorphin
  • Dynorphins
  • Corticotropin-Releasing Hormone
  • preproenkephalin
  • Cocaine