Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment.
Adult hippocampal neurogenesis has been demonstrated in several species and is regulated by both environmental and pharmacological stimuli. The present study seeks to determine whether hippocampal proliferation and neurogenesis are altered in adult animals exposed to inescapable shock (IS) in the learned helplessness model of depression. We report that exposure to avoidance testing, regardless of pre-exposure to IS, decreases cell proliferation in the hippocampus, extending previous studies demonstrating downregulation of neurogenesis by exposure to acute stressors. In addition, when the analysis was conducted 9 days after exposure to IS we observed a significant decrease in cell proliferation compared to nonshocked animals. Administration of fluoxetine, a serotonin selective reuptake inhibitor, from days 2-8 blocked the downregulation of cell proliferation resulting from IS. Fluoxetine treatment also reversed the deficit in escape latency observed in animals exposed to IS. Finally, at the 9 day time point, there was no significant difference in blood levels of corticosterone between nonshocked and IS exposed animals, indicating that the decreased cell proliferation that is observed is not due to increased levels of this adrenal steroid. These findings demonstrate that exposure to IS, which results in a state of behavioral despair, decreases hippocampal cell proliferation and that this effect can be reversed by fluoxetine treatment.
Malberg
Jessica E
JE
Wyeth Neuroscience, Princeton, NJ, USA.
Duman
Ronald S
RS
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001522:Behavior, Animal; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant; D003345:Corticosterone / Q000032:analysis; D003863:Depression / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004597:Electroshock / Q000379:methods; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000627:therapeutic use*; D006380:Helplessness, Learned; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013315:Stress, Psychological; D013997:Time Factors
D018687:Antidepressive Agents, Second-Generation; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D005473:Fluoxetine; D001973:Bromodeoxyuridine; D003345:Corticosterone