title: Hippocampal neurogenesis protects against cocaine-primed relapse.
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.
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Deschaux
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.forename: Luis
authors.initials: L
authors.lastname: Diaz-Aguilar
authors.forename: Clara J
authors.initials: CJ
authors.lastname: Yuan
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Sobieraj
authors.forename: Olivier
authors.initials: O
authors.lastname: George
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.forename: Chitra D
authors.initials: CD
authors.lastname: Mandyam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D053148:Caspase 3 / Q000008:administration & dosage; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology / Q000517:prevention & control*; D003463:Cues; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D058999:Drug-Seeking Behavior / Q000187:drug effects; D004558:Electric Stimulation / Q000379:methods; D005108:Extinction, Psychological / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration
chemical_list: D018765:Dopamine Uptake Inhibitors; D053148:Caspase 3; D001973:Bromodeoxyuridine; D003042:Cocaine
keywords: Activated caspase3; BrdU; Ki-67; dentate gyrus; low-frequency stimulation; self-administration