Effect of the Substance P (NK1 receptor) antagonist L-760735 and clomipramine on endocrine and behavioral parameters

Substance P and its preferred receptor, the neurokinin 1 receptor (NK1), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK1 antagonist MK-869 is more effective than placebo in the treatment of depression. In the present study we compared the effects of the NK1 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. 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 with 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 three weeks of drug treatment. These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.