Hippocampal neurogenesis protects against cocaine-primed relapse

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine / administration & dosage
  • Caspase 3 / administration & dosage
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / physiopathology
  • Cocaine-Related Disorders / prevention & control*
  • Cues
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiopathology
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / pharmacology
  • Drug-Seeking Behavior / drug effects
  • Electric Stimulation / methods
  • Extinction, Psychological / physiology
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • Male
  • Neurogenesis / physiology*
  • Neurons / drug effects*
  • Rats
  • Rats, Wistar
  • Recurrence
  • Self Administration


  • Dopamine Uptake Inhibitors
  • Caspase 3
  • Bromodeoxyuridine
  • Cocaine