Behavioral and Pharmacological Validation of the Gerbil Forced-Swim Test: Effects of Neurokinin-1 Receptor Antagonists

Abstract

Several studies have suggested that neurokinin-1 (NK1) receptor antagonists may have therapeutic potential as novel antidepressant drugs. To test these compounds preclinically, gerbils have become one of the preferred species in that they demonstrate close NK1 receptor homology with humans and bind NK1 antagonists with higher affinity than rats and mice. The intent of the present study was to determine whether the forced-swim test (FST), one of the most commonly used animal tests of antidepressant-like activity, could be adapted for use with the gerbil. Critical factors in the establishment of this assay included swim tank diameter, weight, and sex of the animals tested. Pharmacological validation of the FST using standard antidepressant compounds (eg fluoxetine, paroxetine, desipramine) resulted in decreased immobility time during the test, indicative of an antidepressant-like effect. Similar to results reported for the rat and mouse FST, the antipsychotic drug haloperidol increased immobility, whereas the psychostimulant, amphetamine decreased immobility, and anxiolytic drugs (eg buspirone) had no effect. Investigation into the locomotor effects of all compounds tested was consistent with previous reports in other species, with the exception of paroxetine, which produced hyperactivity at therapeutically effective doses in gerbils. In addition to standard antidepressants, NK1 antagonists (L-733060, MK-869, and CP-122721) all reduced immobility in the gerbil FST without affecting locomotor activity. Overall, these results suggest that the gerbil is an ideal species for use in the FST, and that this paradigm may have predictive validity for identifying novel antidepressant compounds.

A Translational Rodent Assay of Affective Biases in Depression and Antidepressant Therapy

“…The doses used were also in a similar range to those published in our previous behavioral studies using monoamine reuptake inhibitors (Robinson, 2012; Humpston et al , 2013). Doses for agomelatine (Bourin et al , 2004), aprepitant (Wallace-Boone et al , 2007), FG7142 (Rogers et al , 1995), rimonabant (Tzavara et al , 2003), and 13-cis-retinoic acid (Ferguson et al , 2005; O'Reilly et al , 2006) were based on previous studies in rodents. Doses used for diazepam were based on previous studies showing anxiolytic effects in other animal models (Wieland and Lucki, 1990).…”

Involvement of substance P and the NK-1 receptor in human pathology

“…However, in another clinical trial, a lack of efficacy of aprepitant (Table 1) has been reported in the treatment of major depression (Keller et al 2006). It is also known that oral administration of NK-1 receptor antagonists (aprepitant, L-733,060, CP-122,721) ( Table 1) produces anxiolytic-like effects in the gerbil elevated plus-maze, and NK-1 antagonists reduce immobility in the gerbil forced-swim test without affecting locomotor activity (Wallace-Boone et al 2008). This is important, since it is known that the gerbil NK-1 receptor is similar in homology to the human NK-1 receptor.…”

Psychosomatic factors in pruritus

“…106 NKR-1 is a receptor for substance P, an important itch mediator. 110–113 NKR-1 antagonists were found to also have effects in modulating mood disorders: vestipitant is under development as a potential anxiolytic and possibly antidepressant agent, 114 and L-733,060 (Merck Sharp & Dohme, New Jersey, United States) was shown to have antidepressant 115,116 and anxiolytic 117 effects in animal studies. Aprepitant, though, was found not to be efficacious in treating major depressive disorder in clinical trials 118 and plans to market it as an antidepressant have since been abandoned.…”