title: Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression.
abstract: BACKGROUND
  Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds.
  
  
  OBJECTIVE
  We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews.
  
  
  METHODS
  Animals were subjected to a 7 day period of psychosocial stress before being treated daily with SLV-323 (20 mg kg(-1) day(-1)). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy. Norepinephrine excretion was monitored from daily urine samples, and serum testosterone concentrations were measured at the end of the experiment. All animals were videotaped daily to analyze scent-marking behavior and locomotor activity. Cell proliferation in the dentate gyrus and hippocampal volume were measured postmortem.
  
  
  RESULTS
  Stress significantly decreased cerebral concentrations of N-acetyl-aspartate, total creatine, and choline-containing compounds in vivo and resulted in an increase of urinary norepinephrine and decrease of serum testosterone concentrations. Moreover, stressed animals displayed decreased scent-marking behavior and locomotor activity. The proliferation rate of the granule precursor cells in the dentate gyrus was reduced, and hippocampal volume was mildly decreased. The stress-induced alterations in the central nervous system were partially prevented by concomitant administration of SLV-323, while drug treatment had only a minor effect on the stress-induced behavioral changes.
  
  
  CONCLUSIONS
  The novel NK1R antagonist SLV-323 has certain antidepressant-like effects in a valid animal model of depression.
authors.affiliation: Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany. bczeh@dpz.gwdg.de
authors.forename: Boldizsár
authors.initials: B
authors.lastname: Czéh
authors.forename: Olga
authors.initials: O
authors.lastname: Pudovkina
authors.forename: Marieke G C
authors.initials: MG
authors.lastname: van der Hart
authors.forename: Mária
authors.initials: M
authors.lastname: Simon
authors.forename: Urs
authors.initials: U
authors.lastname: Heilbronner
authors.forename: Thomas
authors.initials: T
authors.lastname: Michaelis
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Jens
authors.initials: J
authors.lastname: Frahm
authors.forename: Eberhard
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000652:urine; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D014418:Tupaiidae
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013739:Testosterone; D009638:Norepinephrine
references.citation: Eur J Neurosci. 1998 Aug;10(8):2685-93
references.pmid: 9767398
references.citation: Biol Psychiatry. 2000 Dec 1;48(11):1053-61
references.pmid: 11094138
references.citation: Biol Psychiatry. 2000 Jul 1;48(1):1-8
references.pmid: 10913502
references.citation: Biol Psychiatry. 2004 Aug 1;56(3):140-5
references.pmid: 15271581
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3973-8
references.pmid: 15001711
references.citation: Neuropsychopharmacology. 2004 Feb;29(2):385-92
references.pmid: 14666114
references.citation: Br J Pharmacol. 1991 Oct;104(2):292-3
references.pmid: 1665729
references.citation: J Psychiatr Res. 2001 Jul-Aug;35(4):231-7
references.pmid: 11578641
references.citation: Eur J Neurosci. 2003 Oct;18(7):1828-36
references.pmid: 14622216
references.citation: Pharmacol Biochem Behav. 2002 Aug;73(1):247-58
references.pmid: 12076743
references.citation: Science. 1998 Sep 11;281(5383):1640-5
references.pmid: 9733503
references.citation: NMR Biomed. 1999 Aug;12(5):309-14
references.pmid: 10484820
references.citation: Neuropsychopharmacology. 2003 Apr;28(4):720-5
references.pmid: 12655317
references.citation: J Neurosci. 1996 May 15;16(10):3534-40
references.pmid: 8627386
references.citation: Neuropsychopharmacology. 2005 Jan;30(1):67-79
references.pmid: 15470372
references.citation: Eur J Neurosci. 2003 Oct;18(8):2292-300
references.pmid: 14622190
references.citation: Pharmacol Biochem Behav. 2000 Mar;65(3):539-46
references.pmid: 10683496
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):791-800
references.pmid: 11063975
references.citation: Pharmacol Biochem Behav. 1996 May;54(1):219-28
references.pmid: 8728561
references.citation: Science. 2003 Aug 8;301(5634):805-9
references.pmid: 12907793
references.citation: Curr Opin Investig Drugs. 2002 Feb;3(2):257-61
references.pmid: 12020057
references.citation: APMIS. 1988 May;96(5):379-94
references.pmid: 3288247
references.citation: Neurosci Biobehav Rev. 1999 Nov;23(7):937-47
references.pmid: 10580308
references.citation: Am J Psychiatry. 2000 Jan;157(1):115-8
references.pmid: 10618023
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:877-906
references.pmid: 11264480
references.citation: Trends Pharmacol Sci. 1999 Dec;20(12):485-90
references.pmid: 10671176
references.citation: J Neurosci. 1993 Mar;13(3):981-9
references.pmid: 8441018
references.citation: Neuropharmacology. 1995 Dec;34(12):1697-9
references.pmid: 8788968
references.citation: Eur J Neurosci. 2003 May;17(9):1736-46
references.pmid: 12752772
references.citation: J Neurosci. 2000 Dec 15;20(24):9104-10
references.pmid: 11124987
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12796-801
references.pmid: 11675510
references.citation: Biol Psychiatry. 2000 Mar 15;47(6):475-81
references.pmid: 10715353
references.citation: J Neurosci. 2001 Sep 1;21(17):6706-17
references.pmid: 11517260
references.citation: Stress. 2002 Feb;5(1):37-46
references.pmid: 12171765
references.citation: Int J Androl. 2003 Aug;26(4):202-10
references.pmid: 12846795
references.citation: Magn Reson Med. 1993 Dec;30(6):672-9
references.pmid: 8139448
references.citation: Biol Psychiatry. 2000 Feb 15;47(4):305-13
references.pmid: 10686265
references.citation: Behav Pharmacol. 2004 Sep;15(5-6):315-25
references.pmid: 15343055
references.citation: Biol Psychiatry. 1997 Apr 15;41(8):837-43
references.pmid: 9099409
references.citation: Physiol Behav. 1999 Jul;66(5):855-61
references.pmid: 10405114
references.citation: Andrologia. 1985 May-Jun;17(3):262-75
references.pmid: 4025846
references.citation: Biol Psychiatry. 2004 Aug 1;56(3):146-50
references.pmid: 15271582
references.citation: J Psychiatr Res. 1998 Nov-Dec;32(6):411-20
references.pmid: 9844958
references.citation: Hippocampus. 2004;14(6):742-51
references.pmid: 15318332
references.citation: Biol Psychiatry. 2004 Mar 15;55(6):563-9
references.pmid: 15013824
references.citation: Mol Psychiatry. 2002;7(9):933-41
references.pmid: 12399945
references.citation: Mol Psychiatry. 2000 May;5(3):262-9
references.pmid: 10889528
references.citation: Ann Pharmacother. 2002 Oct;36(10):1577-89
references.pmid: 12243609