Pharmacoproteomic investigation into antidepressant response in two mouse inbred strains.
In this study, we present a pharmacoproteomic investigation of response to antidepressants two inbred strains. Our aim was to uncover molecular mechanisms underlying antidepressant action and identify new biomarkers to determine therapeutic response to two antidepressants with proven efficacy in the treatment of depression but divergent mechanisms of action. Mice were treated with the pro-noradrenergic drug nortriptyline, the pro-serotonergic drug escitalopram or saline. Quantitative proteomic analyses were undertaken on hippocampal tissue from a study design that used two inbred mouse strains, two depressogenic protocols and a control condition, (maternal separation, chronic mild stress, control), two antidepressant drugs and two dosing protocols. The proteomic analysis was aimed at the identification of specific drug-response markers. Complementary approaches, 2DE and isobaric tandem mass tagging (TMT), were applied to the selected experimental groups. To investigate the relationship between proteomic profiles, depressogenic protocols and drug response, 2DE and TMT data sets were analysed using multivariate methods. The results highlighted significant strain- and stress-related differences across both 2DE and TMT data sets and identified the three gene products involved in serotonergic (PXBD5, YHWAB, SLC25A4) and one in noradrenergic antidepressant action (PXBD6).
King's College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, UK. karim.malki@iop.kcl.ac.uk
Karim
K
Malki
James
J
Campbell
Matthew
M
Davies
Robert
R
Keers
Rudolf
R
Uher
Malcolm
M
Ward
Jose
J
Paya-Cano
Katherine J
KJ
Aitchinson
Elke
E
Binder
Frans
F
Sluyter
Karsten
K
Kuhn
Stefan
S
Selzer
Ian
I
Craig
Peter
P
McGuffin
Leonard C
LC
Schalkwyk
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D015283:Citalopram / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D015999:Multivariate Analysis; D009661:Nortriptyline / Q000494:pharmacology; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D020543:Proteome / Q000032:analysis / Q000187:drug effects*; D040901:Proteomics; D015203:Reproducibility of Results; D013315:Stress, Psychological / Q000188:drug therapy*; D053719:Tandem Mass Spectrometry; D014886:Weaning
D048948:14-3-3 Proteins; D033741:Adenine Nucleotide Translocator 1; D000928:Antidepressive Agents; D020543:Proteome; D015283:Citalopram; D009661:Nortriptyline; D054464:Peroxiredoxins