Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal.
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.
Surget
Alexandre
A
U930, INSERM, Université François Rabelais de Tours, Tours, France.
Saxe
Michael
M
Leman
Samuel
S
Ibarguen-Vargas
Yadira
Y
Chalon
Sylvie
S
Griebel
Guy
G
Hen
René
R
Belzung
Catherine
C
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
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