Withdrawal from cocaine self-administration normalizes deficits in proliferation and enhances maturity of adult-generated hippocampal neurons

Michele A. Noonan, Kwang H. Choi, David W. Self, Amelia J. Eisch

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Relapse, a major problem in the treatment of cocaine addiction, is proposed to result in part from neuroadaptations in the hippocampus. We examined how a mediator of hippocampal neuroplasticity, adult neurogenesis in the subgranular zone (SGZ), was regulated by cocaine self-administration (CSA), and whether these changes were reversed by 4 weeks of withdrawal (CSA-WD) versus continued cocaine self-administration (CSA-CONT). Rats self-administered intravenous cocaine or saline for 3 weeks and were killed 2 h (CSA) or 4 weeks (CSA-WD, CSA-CONT) after injection with the S-phase marker bromodeoxyuridine (BrdU). Cells in several stages of adult neurogenesis were quantified: proliferating cells labeled by BrdU (2 h) or Ki-67; immature neurons labeled by doublecortin; and adultgenerated neurons labeled with BrdU (4 weeks) and the mature neuronal marker NeuN. CSA decreased proliferation in both the SGZ and the subventricular zone (SVZ), a source of adult-generated olfactory neurons, changes reversed by CSA-WD. Unexpectedly, CSA-WD and CSA-CONT resulted in more immature doublecortin-immunopositive (+) neurons in the posterior SGZ and a normal number of adult-generated BrdU neurons in the SGZ, suggesting an enduring impact of CSA regardless of whether cocaine intake was stopped or continued. However, only CSA-WD rats had more adult-generated neurons with punctate BrdU staining, an indicator of enhanced maturity. These data suggest a mechanism for the cognitive and olfactory deficits seen in cocaine addicts, and further suggest that adult-generated neurons should be considered for their potential role in cocaine addiction and hippocampal-mediated relapse after cocaine withdrawal.

Original languageEnglish (US)
Pages (from-to)2516-2526
Number of pages11
JournalJournal of Neuroscience
Issue number10
StatePublished - Mar 5 2008



  • Addiction
  • BrdU
  • Doublecortin
  • Hippocampus
  • Subgranular zone
  • Subventricular zone

ASJC Scopus subject areas

  • Neuroscience(all)

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