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Addict Biol. 2014 Jul;19(4):562-74. doi: 10.1111/adb.12019. Epub 2012 Dec 24.

Hippocampal neurogenesis protects against cocaine-primed relapse.

Author information

1
Laboratoire de Neurobiologie et Psychotraumatologie, Université de Nice Sophia Antipolis, Nice, France; Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.

Abstract

Accumulating evidence demonstrates a functional role for the hippocampus in mediating relapse to cocaine-seeking behavior and extinction-induced inhibition of cocaine seeking, and dentate gyrus neurogenesis in the hippocampus may have a role. Here, we tested the hypothesis that disruption of normal hippocampal activity during extinction alters relapse to cocaine-seeking behavior as a function of dentate gyrus neurogenesis. Adult rats were trained to self-administer cocaine on a fixed-ratio schedule, followed by extinction and cocaine-primed reinstatement testing. Some rats received low-frequency stimulation (LFS; 2 Hz for 25 minutes) after each extinction session in the dorsal or ventral hippocampal formation. All rats received an injection of the mitotic marker 5-bromo-2'-deoxyuridine (BrdU) to label developing dentate gyrus neurons during self-administration, as well as before or after extinction and LFS. We found that LFS during extinction did not alter extinction behavior but enhanced cocaine-primed reinstatement. Cocaine self-administration reduced levels of 24-day-old BrdU cells and dentate gyrus neurogenesis, which was normalized by extinction. LFS during extinction prevented extinction-induced normalization of dentate gyrus neurogenesis and potentiated cocaine-induced reinstatement of drug seeking. LFS inhibition of extinction-induced neurogenesis was not due to enhanced cell death, revealed by quantification of activated caspase3-labeled cells. These data suggest that LFS during extinction disrupts hippocampal networking by disrupting neurogenesis and also strengthens relapse-like behaviors. Thus, newly born dentate gyrus neurons during withdrawal and extinction learning facilitate hippocampal networking that mediates extinction-induced inhibition of cocaine seeking and may play a key role in preventing relapse.

KEYWORDS:

Activated caspase3; BrdU; Ki-67; dentate gyrus; low-frequency stimulation; self-administration

PMID:
23278919
PMCID:
PMC3620729
DOI:
10.1111/adb.12019
[Indexed for MEDLINE]
Free PMC Article
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