NKP608, an NK₁ receptor antagonist, has an anxiolytic action in the social interaction test in rats

Abstract.

Rationale: Evidence is starting to accumulate that NK₁ receptor antagonists might have anxiolytic effects in animal tests and in patients. Objective: To examine the effects of NKP608, a substance P antagonist acting at NK₁ receptors, in various conditions of the social interaction test of anxiety and to determine its effects after 3 and 6 weeks of treatment. Methods: Rats were tested after vehicle, 0.01 or 0.1 mg/kg PO in three conditions of the social interaction test that varied in the level of anxiety generated. Thus pairs of rats were tested in an arena with which they were unfamiliar that was lit by high (HU) or low (LU) light and in the condition that generated the lowest level of anxiety, i.e. an arena with which they were familiar, lit by low light (LF). They were also tested after 3 and 6 weeks of treatment with 0.03 mg/kg and after 24 h withdrawal from these chronic treatments. Results: NKP608 had significant anxiolytic effects at 0.01, 0.03 and 0.1 mg/kg PO in the HU and LU test conditions, but was without effect in the LF condition, except for an increased incidence of bite attacks at 0.1 mg/kg. The anxiolytic effect of 0.03 mg/kg remained after 3 weeks of chronic treatment and there was no anxiogenic effect after 24 h of drug withdrawal. Following 6 weeks of chronic treatment (0.03 mg/kg per day), tolerance had developed, but no anxiogenic withdrawal effect was seen 24 h after the last dose. Conclusions: These results provide further evidence that substance P may play a role in mediating states of anxiety and suggest that the selective NK₁ receptor antagonist NKP608 may prove a useful anxiolytic compound.