PMID- 16945347
OWN - NLM
STAT- MEDLINE
DCOM- 20070417
LR  - 20220330
IS  - 0006-3223 (Print)
IS  - 0006-3223 (Linking)
VI  - 61
IP  - 5
DP  - 2007 Mar 1
TI  - A role for MAP kinase signaling in behavioral models of depression and 
      antidepressant treatment.
PG  - 661-70
AB  - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is upregulated in the 
      hippocampus by antidepressant treatments, and centrally administered BDNF can 
      produce antidepressant-like effects in rodent behavioral models of depression. 
      BDNF-regulated signaling pathways are thus potential targets for investigation of 
      antidepressant mechanisms. METHODS: We examined the effects of inhibition of MAPK 
      kinase (MEK) in mouse behavioral models for depression including interactions 
      with effects of antidepressant drugs. We also assessed the behavioral 
      consequences of a heterozygous gene deletion for BDNF combined with MEK 
      inhibition or stress. RESULTS: Acute administration of the MEK inhibitor PD184161 
      produced depressive-like behavior. PD184161 blocked the antidepressant-like 
      effects of desipramine and sertraline in the forced swim test and blocked the 
      effects of desipramine in the tail suspension test. Heterozygous deletion of BDNF 
      alone did not influence behavior in the forced swim test but resulted in a 
      depressive phenotype when combined with a low-dose MEK inhibitor or stress 
      exposure. CONCLUSIONS: We demonstrate that acute blockade of MAPK signaling 
      produces a depressive-like phenotype and blocks behavioral actions of 
      antidepressants. We also demonstrate in BDNF heterozygous knockout mice an 
      example of a how a defined genetic alteration can confer vulnerability to a 
      pharmacologic or environmental challenge resulting in a depressive behavioral 
      phenotype.
FAU - Duman, Catharine H
AU  - Duman CH
AD  - Laboratory of Molecular Psychiatry, Center for Genes and Behavior, Departments of 
      Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, 
      Connecticut, USA.
FAU - Schlesinger, Lee
AU  - Schlesinger L
FAU - Kodama, Masafumi
AU  - Kodama M
FAU - Russell, David S
AU  - Russell DS
FAU - Duman, Ronald S
AU  - Duman RS
LA  - eng
GR  - 2 P01 MH25642/MH/NIMH NIH HHS/United States
GR  - MH45481/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060830
PL  - United States
TA  - Biol Psychiatry
JT  - Biological psychiatry
JID - 0213264
RN  - 0 
      (2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide)
RN  - 0 (Aniline Compounds)
RN  - 0 (Antidepressive Agents)
RN  - 0 (Benzamides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Analysis of Variance
MH  - Aniline Compounds/pharmacology
MH  - Animals
MH  - Antidepressive Agents/*therapeutic use
MH  - Behavior, Animal/*drug effects
MH  - Benzamides/pharmacology
MH  - Brain-Derived Neurotrophic Factor/deficiency
MH  - Depression/chemically induced/*drug therapy/physiopathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Interactions
MH  - Enzyme Inhibitors/pharmacology
MH  - Helplessness, Learned
MH  - Hindlimb Suspension/methods
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase Kinases/*physiology
MH  - Motor Activity/drug effects
MH  - Signal Transduction/*physiology
MH  - Swimming
EDAT- 2006/09/02 09:00
MHDA- 2007/04/18 09:00
CRDT- 2006/09/02 09:00
PHST- 2006/03/02 00:00 [received]
PHST- 2006/03/23 00:00 [revised]
PHST- 2006/05/23 00:00 [accepted]
PHST- 2006/09/02 09:00 [pubmed]
PHST- 2007/04/18 09:00 [medline]
PHST- 2006/09/02 09:00 [entrez]
AID - S0006-3223(06)00792-X [pii]
AID - 10.1016/j.biopsych.2006.05.047 [doi]
PST - ppublish
SO  - Biol Psychiatry. 2007 Mar 1;61(5):661-70. doi: 10.1016/j.biopsych.2006.05.047. 
      Epub 2006 Aug 30.