Inhibition of shock-induced foot tapping behaviour in the gerbil by a tachykinin NK₁ receptor antagonist

Abstract

The selective tachykinin NK₁ receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine (MK-869), has been recently described as a novel therapeutic approach for anxiety/depression. A frequently used model to establish the central nervous system (CNS) activity of tachykinin NK₁ receptor antagonists is the inhibition of NK₁ agonist-induced foot tapping in gerbils. In the present study, we demonstrate that foot tapping can also be induced in most, but not all, gerbils by footshock and associated cues. MK-869 (0.3–3 mg/kg, i.p.) dose-dependently blocked this foot tapping response. This effect was further shown to be due to selective NK₁ receptor blockade, since (2S,3S)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 3 mg/kg, i.p.) inhibited foot tapping, whereas its less active enantiomer (2R,3R)-cis-3(2-methoxybenzylamino)-2-phenylpiperidine (CP-100,263; 3 mg/kg, i.p.) had no effect. Diazepam (1–10 mg/kg, i.p.) also inhibited foot tapping, whereas fluoxetine (10–30 mg/kg, i.p.) markedly increased this behaviour. The present data support the view that foot tapping in the gerbil is a behavioural response to an aversive stimulus, and is robustly inhibited by two NK₁ receptor antagonists. The data support a role for tachykinin NK₁ receptor antagonists as novel anxiolytic/antidepressants.

Introduction

Following the recent publication of Kramer et al. (1998), there has been considerable interest in Neurokinin (NK)1 receptor antagonists as novel treatments for anxiety and depression. These workers reported that in a 6-week double-blind, placebo-controlled study in patients with major depression, the selective NK₁ receptor antagonist, 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine (MK-869) (300 mg/day), produced a positive outcome as measured by both the Hamilton depression (HAM-D21) and anxiety (HAM-A) scales. The effects were equivalent to that of the selective serotonergic reuptake inhibitor, paroxetine (20 mg/day), and side effects typically associated with this drug class, e.g. nausea, sexual dysfunction were diminished in the MK-869 group. Taken together, the study of Kramer et al. (1998) may represent an important advance in the search for novel treatments of anxiety and depression (Nutt, 1998).

In gerbils, a species whose NK₁ receptor pharmacology resembles that of the human Gitter et al., 1991, Beresford et al., 1991, the intracerebroventricular (i.c.v.) administration of the NK₁ agonist, GR73632 (d-Ala [l-Pro9, Met-Leu10]-substance P-(7–11)), produces a characteristic rhythmic tapping of the hind feet (Graham et al., 1993). This robust and readily quantifiable response is inhibited by brain-penetrating antagonists of the NK₁ receptor Graham et al., 1993, Rupniak and Williams, 1994, Bristow and Young, 1994. Consequently, NK₁ agonist-induced foot tapping in the gerbil has become a valuable in vivo assay for the identification of centrally acting tachykinin NK₁ receptor antagonists Rupniak et al., 1997, Hale et al., 1998. Since foot tapping in the gerbil has also been reported following electroshock or offset of reward it is postulated to be a species specific response to an aversive stimulus (Routtenberg and Kramis, 1967). Given the clinical evidence that NK₁ receptor antagonists may have antidepressant/anxiolytic properties (Kramer et al., 1998), and the robust nature of foot tapping behaviour following NK₁ agonist administration, we sought to investigate ways of non-pharmacologically inducing this behaviour in gerbils.

In the present study, we have used a Pavlovian fear-conditioning procedure. In a variety of species, the pairing of specific cues (conditioned stimulus) with an aversive stimulus (unconditioned stimulus), typically electroshock, subsequently results in the conditioned stimulus inducing a variety of fear related behaviours (see LeDoux, 1998, Davis, 1999 for reviews). In rodents, this typically involves freezing or increased startle responses, as well as autonomic signs such as defaecation, increased heart rate and arterial blood pressure LeDoux et al., 1988, Davis, 1999. Following the establishment of suitable shock parameters in gerbils, we studied their behaviour both during the conditioning session and also in a retest session, performed 24 h later where the animals are presented with the conditioned stimulus in the absence of the unconditioned stimulus. We found that foottapping behaviour could be induced in some, but not all, gerbils during both the conditioning and retest session. Consequently, we studied the effect of the tachykinin NK₁ receptor antagonists MK-869 (Hale et al., 1998) and (2S,3S)-cis-3(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994) (McLean et al., 1993), as well as a clinically efficacious anxiolytic (diazepam) and antidepressant (fluoxetine) against this shock-induced foot tapping. Some of this work has been published in abstract form (Ballard et al., 1999).