PMID- 24841087 OWN - NLM STAT- MEDLINE DCOM- 20150911 LR - 20211021 IS - 1559-1166 (Electronic) IS - 0895-8696 (Linking) VI - 55 IP - 2 DP - 2015 Feb TI - Fluoxetine signature on hippocampal MAPK signalling in sex-dependent manner. PG - 335-46 LID - 10.1007/s12031-014-0328-1 [doi] AB - A growing body of evidence indicates that mitogen-activated protein kinase (MAPK) participates in various stress-induced responses and is considered to be one of the pathophysiological mechanisms in depression. Surprisingly, the effect of antidepressants on MAPKs is almost unexplored, particularly from the perspective of sexes. The present study investigates the cytoplasm-nuclear distribution of MAPK family, c-Jun N-terminal kinases (JNKs) 1, 2 and 3; extracellular signal-regulated kinases (ERKs) 1 and 2; and p38 kinases, as well as their phosphoisoforms in the hippocampus of chronically stressed female and male rats and upon chronic fluoxetine treatment. Additionally, we analysed crosstalk between MAPK signalling and depressive-like behaviour which correlated with brain-derived neurotrophic factor (BDNF) expression. Our results emphasize a gender-specific and compartment-dependent response of MAPKs to stress and fluoxetine. In females, stress decreased pp38 and pJNK and induced cytosolic retention of pERKs which reduced all nuclear pMAPKs. These changes correlated with altered BDNF expression and behaviour. Similarly, in males, stress decreased pp38 but promoted nuclear translocation of pJNKs and pERKs. These stress alterations of pMAPKs in males were not associated with BDNF expression and depressive-like behaviour. Fluoxetine treatment in stressed females upregulated whole pMAPK signalling particularly those in nucleus which was followed with BDNF expression and normalization of behaviour. In stressed males, fluoxetine affected only cytosolic pJNKs, while nuclear pMAPK signalling and BDNF expression were unaffected even though fluoxetine normalized behaviour. Overall, our results suggest existence of gender-specific mechanism of fluoxetine on nuclear pMAPK/BDNF signalling and depressive-like behaviour and reinforce the antidepressant dogma that females and males respond differently to certain antidepressants. FAU - Mitic, Milos AU - Mitic M AD - Laboratory for Molecular Biology and Endocrinology, Vinca Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522 MBE090, 11001, Belgrade, Serbia. FAU - Lukic, Iva AU - Lukic I FAU - Bozovic, Natalija AU - Bozovic N FAU - Djordjevic, Jelena AU - Djordjevic J FAU - Adzic, Miroslav AU - Adzic M LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140521 PL - United States TA - J Mol Neurosci JT - Journal of molecular neuroscience : MN JID - 9002991 RN - 0 (Antidepressive Agents, Second-Generation) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Isoenzymes) RN - 01K63SUP8D (Fluoxetine) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Active Transport, Cell Nucleus MH - Animals MH - Antidepressive Agents, Second-Generation/*pharmacology/therapeutic use MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Cell Nucleus/*metabolism MH - Cytoplasm/metabolism MH - Female MH - Fluoxetine/*pharmacology/therapeutic use MH - Hippocampus/*drug effects/metabolism MH - Isoenzymes/genetics/metabolism MH - *MAP Kinase Signaling System MH - Male MH - Mitogen-Activated Protein Kinase Kinases/genetics/metabolism MH - Rats MH - Rats, Wistar MH - Sex Factors MH - Stress, Psychological/drug therapy/*metabolism EDAT- 2014/05/21 06:00 MHDA- 2015/09/12 06:00 CRDT- 2014/05/21 06:00 PHST- 2014/04/25 00:00 [received] PHST- 2014/05/08 00:00 [accepted] PHST- 2014/05/21 06:00 [entrez] PHST- 2014/05/21 06:00 [pubmed] PHST- 2015/09/12 06:00 [medline] AID - 10.1007/s12031-014-0328-1 [doi] PST - ppublish SO - J Mol Neurosci. 2015 Feb;55(2):335-46. doi: 10.1007/s12031-014-0328-1. Epub 2014 May 21.