Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice.
It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.
Morcuende
Sara
S
Department of Anatomy and Developmental Biology, Medawar Building, UCL, Gower Street, London WC1E 6BT, UK.
Gadd
Christopher A
CA
Peters
Marco
M
Moss
Andrew
A
Harris
Elizabeth A
EA
Sheasby
Anne
A
Fisher
Amy S
AS
De Felipe
Carmen
C
Mantyh
Patrick W
PW
Rupniak
Nadia M J
NM
Giese
K Peter
KP
Hunt
Stephen P
SP
D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003213:Conditioning, Psychological; D005239:Fear / Q000187:drug effects; D005838:Genotype; D006624:Hippocampus; D007103:Immobilization; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000378:metabolism*; D010759:Phosphorus Isotopes / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D011930:Reaction Time / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D010759:Phosphorus Isotopes; D011838:Radiation-Sensitizing Agents; D018040:Receptors, Neurokinin-1; D014316:Tritium; D001973:Bromodeoxyuridine; D013936:Thymidine