Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice.
A dysregulated hypothalamic-pituitary-adrenal axis (HPA) has been implicated in major depressive disorder and most commonly used animal models of depression have been shown to elevate circulating levels of plasma corticosterone. We have compared the effects of chronic and acute corticosterone administration on hippocampal cell proliferation (as measured by BrdU immunohistochemistry), hippocampal volume and the appearance of anxiety (light dark box) and depression (forced swim test) like behaviours in CD1 mice. We have also examined the effects of chronic administration of fluoxetine and imipramine on these parameters. Chronic (14 days) but not acute treatment with corticosterone resulted in reduced hippocampal cell proliferation and granule cell layer volume, these changes were prevented by co-administration of imipramine and fluoxetine. In contrast, acute and 7 day but not 14 or 21 day treatment with corticosterone gave rise to a "depressed" phenotype in the forced swim test. Mice treated for 14 days with corticosterone also developed an anxious phenotype in the light dark box but only upon repeated testing. The results presented here demonstrate that moderately elevated corticosterone for a prolonged period is sufficient to induce cellular changes in the hippocampus that are prevented by chronic administration of antidepressants.
Murray
Fraser
F
Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR. United Kingdom. Fraser.Murray@astrazeneca.com <Fraser.Murray@astrazeneca.com>
Smith
David W
DW
Hutson
Peter H
PH
D000311:Adrenal Glands / Q000187:drug effects; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000963:Antimetabolites; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology*; D003863:Depression / Q000523:psychology*; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000033:anatomy & histology / Q000166:cytology* / Q000187:drug effects; D007099:Imipramine / Q000494:pharmacology; D007150:Immunohistochemistry; D008029:Lighting; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D013550:Swimming / Q000523:psychology
D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D000963:Antimetabolites; D005473:Fluoxetine; D001973:Bromodeoxyuridine; D007099:Imipramine; D003345:Corticosterone