Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression.
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.
Czéh
Boldizsár
B
Clinical Neurobiology Laboratory, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany. bczeh@dpz.gwdg.de
Pudovkina
Olga
O
van der Hart
Marieke G C
MG
Simon
Mária
M
Heilbronner
Urs
U
Michaelis
Thomas
T
Watanabe
Takashi
T
Frahm
Jens
J
Fuchs
Eberhard
E
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
D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013739:Testosterone; D009638:Norepinephrine
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