Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
Malberg
J E
JE
Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
Eisch
A J
AJ
Nestler
E J
EJ
Duman
R S
RS
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000378:metabolism; D001973:Bromodeoxyuridine; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D014191:Tranylcypromine / Q000494:pharmacology
D000928:Antidepressive Agents; D000943:Antigens, Differentiation; D009025:Morpholines; D005473:Fluoxetine; D014191:Tranylcypromine; D000077593:Reboxetine; D001973:Bromodeoxyuridine