Chronic psychosocial stress in tree shrews: effect of the substance P (NK1 receptor) antagonist L-760735 and clomipramine on endocrine and behavioral parameters.
BACKGROUND
Substance P and its preferred receptor, the neurokinin 1 receptor (NK(1)R), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK(1)R antagonist MK-869 is more effective than placebo in the treatment of depression.


METHODS
In the present study, we compared the effects of the NK(1)R antagonist L-760735 with the tricyclic antidepressant clomipramine on endocrine and behavioral parameters in chronically stressed tree shrews. Animals were subjected to a 7-day period of psychosocial stress before receiving daily oral administration of L-760735 (10 mg/kg/day) or clomipramine (50 mg/kg/day). The psychosocial stress continued throughout the treatment period of 21 days. Daily morning urine was collected to measure cortisol and norepinephrine levels. All animals were videotaped daily and three types of behavior were analyzed.


RESULTS
Chronic psychosocial stress resulted in a significant increase of urinary cortisol and norepinephrine concentrations. Moreover, stressed animals displayed decreased marking behavior and locomotor activity, while grooming remained unaffected. Neither treatment with clomipramine nor L-760735 was able to normalize the stress-induced elevation of cortisol or norepinephrine. On the behavioral parameters, L-760735 had a time-dependent restorative influence on marking behavior close to normal levels, without affecting locomotor activity. Grooming behavior was significantly increased by the 3 weeks of drug treatment.


CONCLUSIONS
These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.
van der Hart
Marieke G C
MG
Clinical Neurobiology Laboratory, German Primate Center, Göttingen. m.g.c.van.der.hart@psy.umcg.nl
de Biurrun
Gabriel
G
Czéh
Boldizsár
B
Rupniak
Nadia M J
NM
den Boer
Johan A
JA
Fuchs
Eberhard
E
D000311:Adrenal Glands / Q000033:anatomy & histology / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002997:Clomipramine / Q000378:metabolism / Q000494:pharmacology*; D004703:Endocrine System / Q000187:drug effects* / Q000502:physiology; D004822:Epididymis / Q000033:anatomy & histology / Q000187:drug effects; D006120:Grooming / Q000187:drug effects; D006854:Hydrocortisone / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000652:urine; D009929:Organ Size / Q000187:drug effects; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D013373:Substance P / Q000037:antagonists & inhibitors; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D014418:Tupaiidae / Q000523:psychology*
C114226:L 760735; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D013373:Substance P; D002997:Clomipramine; D006854:Hydrocortisone; D009638:Norepinephrine