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

Abstract

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.