Behavioural Brain Research 154 (2004) 183–192 Research report The NK 1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze R.J. Rodgers a,∗ , C. Gentsch b , D. Hoyer b , E. Bryant a , A.J. Green a , K.Z. Kolokotroni a , J.L. Martin a a Behavioural Pharmacology Laboratory, School of Psychology, University of Leeds, Leeds LS2 9JT, UK b Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel CH-4002, Switzerland Received 8 September 2003; received in revised form 6 February 2004; accepted 6 February 2004 Available online 11 March 2004 Abstract The selective non-peptide NK 1 receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC 50 values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003–10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001–10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK 1 receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK 1 receptor antagonists to their potency at NK 1 receptors. © 2004 Elsevier B.V. All rights reserved. Keywords: Anxiety; Chlordiazepoxide; Mice; NK 1 receptors; NKP608; Plus-maze; Substance P; Tachykinins 1. Introduction The mammalian tachykinins, substance P, neurokinin A, neurokinin B, neuropeptide K and neuropeptide  [35,54], exert their biological actions via three G protein-coupled 7-transmembrane domain receptors, formally designated neurokinin (NK) 1 , NK 2 and NK 3 [48,58]. Substance P, a unadecapeptide and the most abundant tachykinin, is widely distributed in the peripheral and central nervous systems, and shows preferential affinity for the NK 1 receptor. Recent evidence has linked substance P not only to asthma, inflam- matory bowel disease, emesis and psoriasis, but also to the ∗ Corresponding author. Tel.: +44-113-343-5745; fax: +44-113-343-5749. E-mail address: r.j.rodgers@leeds.ac.uk (R.J. Rodgers). aetiopathology of pain syndromes, affective and anxiety dis- orders, schizophrenia and Alzheimer’s disease [36,41,45]. Both substance P and NK 1 receptors are densely localised in several brain areas long associated with the regulation of emotional behaviour, including the amygdaloid complex, hypothalamus, hippocampus, locus coeruleus and periaque- ductal gray matter (PAG) [1,17,47,51]. Consistent with this CNS distribution, substance P is released in rodent brain in response to a variety of stressors (e.g., footshock, restraint, novelty and social isolation) [3,8,21,64]. Furthermore, ad- ministration of picomolar concentrations of substance P into the lateral ventricles, basolateral amygdala, bed nu- cleus of the stria terminalis, lateral septal nucleus or dorsal PAG enhances anxiety-like behaviours in rats and mice [13,18,20,25,26,75]. Despite preferential affinity for NK 1 receptors, substance P displays appreciable affinity for all 0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2004.02.005