title: Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal.
abstract: BACKGROUND
  Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.
  
  
  METHODS
  Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.
  
  
  RESULTS
  Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists.
  
  
  CONCLUSIONS
  Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.
authors.affiliation: U930, INSERM, Université François Rabelais de Tours, Tours, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Surget
authors.forename: Michael
authors.initials: M
authors.lastname: Saxe
authors.forename: Samuel
authors.initials: S
authors.lastname: Leman
authors.forename: Yadira
authors.initials: Y
authors.lastname: Ibarguen-Vargas
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Catherine
authors.initials: C
authors.lastname: Belzung
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D015306:Biogenic Monoamines / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000528:radiation effects; D017619:Hemibody Irradiation / Q000009:adverse effects / Q000379:methods; D006624:Hippocampus / Q000473:pathology*; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D011759:Pyrrolidines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000528:radiation effects; D013843:Thiazines / Q000494:pharmacology; D013997:Time Factors
chemical_list: C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D006846:Hydrocarbons, Halogenated; D007211:Indoles; D011759:Pyrrolidines; C502407:SSR125543; D013843:Thiazines; D003346:Corticotropin-Releasing Hormone; D001973:Bromodeoxyuridine