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The Journal of Neuroscience, March 5, 2008, 28(10):2516-2526; doi:10.1523/JNEUROSCI.4661-07.2008

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Behavioral/Systems/Cognitive
Withdrawal from Cocaine Self-Administration Normalizes Deficits in Proliferation and Enhances Maturity of Adult-Generated Hippocampal Neurons

Michele A. Noonan,¹ Kwang H. Choi,² David W. Self,¹ and Amelia J. Eisch¹

¹Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, and ²Stanley Laboratory of Brain Research, Rockville, Maryland 20850

Correspondence should be addressed to Amelia J. Eisch, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. Email: amelia.eisch{at}utsouthwestern.edu

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 adult-generated 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.

Key words: doublecortin; hippocampus; addiction; BrdU; subgranular zone; subventricular zone

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Received March 15, 2007; revised Jan. 10, 2008; accepted Jan. 29, 2008.

Correspondence should be addressed to Amelia J. Eisch, Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070. Email: amelia.eisch{at}utsouthwestern.edu

This article has been cited by other articles:

				A. J. Eisch, H. A. Cameron, J. M. Encinas, L. A. Meltzer, G.-L. Ming, and L. S. Overstreet-Wadiche Adult Neurogenesis, Mental Health, and Mental Illness: Hope or Hype? J. Neurosci., November 12, 2008; 28(46): 11785 - 11791. [Abstract] [Full Text] [PDF]

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