Anxiolytic-like effects of the neurokinin 1 receptor antagonist GR-205171 in the elevated plus maze and contextual fear-potentiated startle model of anxiety in gerbils

Abstract

Gerbils show a neurokinin (NK)1 receptor pharmacological profile, which is similar to that observed in humans, and thus have become a commonly used species to test efficacy of NK1 receptor antagonists. The aim of this study was to determine whether systemic administration of the NK1 receptor antagonist GR-205171 produced anxiolytic-like effects in the elevated plus maze and in a novel contextual conditioned fear test using fear-potentiated startle (FPS). On the elevated plus maze, treatment with GR-205171 at 0, 0.3, 1.0, and 5.0 mg/kg doses, 30 min before testing produced anxiolytic-like effects in an increasing dose-response manner as measured by the percentage of open arm time and percentage of open arm entries. For contextual fear conditioning, gerbils were given 10 unsignaled footshocks (0.6 mA) at a 2-min variable interstimulus interval in a distinctive training context. Twenty-four hours after training, gerbils received treatment of GR-205171 at 0, 0.3, 1.0, and 5.0 mg/kg doses, 30 min before testing in which startle was elicited in the same context in which they were trained. Contextual FPS was defined as an increase in startle over pretraining baseline values. All drug dose levels (0.3, 1.0, and 5.0 mg/kg) significantly attenuated contextual FPS when compared with the vehicle control group. A control group, which received testing in a different context, showed little FPS. These findings support other evidence for anxiolytic activity of NK1 receptor antagonists and provide a novel conditioned fear test that may be an appropriate procedure to test other NK1 antagonists for preclinical anxiolytic activity in gerbils.

Figure 1

A) Mean startle responses elicited at increasing noise-burst intensities in gerbils (N=20). Startle responses in gerbils increased as a function of stimulus intensity (90, 100, 110, 120 dB). B) Effects of the NK1 antagonist GR-205171 (0, 0.3, 1.0 or 5.0 mg/kg, i.p) on mean startle responses in gerbils. Gerbils received treatment of GR-205171 at 0, 0.3, 1.0 or 5.0 mg/kg doses (n=5/group) 30 min before testing in which animals received startle stimuli at two different intensities (110- and 115-dB). Error bars denote 1 standard error of the mean. Bonferroni t-tests revealed significant startle differences among all intensities. Stars indicate p<0.001.

Figure 2

A) Mean pre-training and post-training startle response of gerbils trained and tested in the same (SAME) context (n=8; A–A and B–B) or different (DIFF) contexts (n=8; A–B and B–A). B) Mean startle responses of gerbils across blocks during the post-training startle test. Block values represent the mean startle response of two sequential test trials of different intensity (110, 115 dB). The insert panel displays the mean startle responses during the first and second halves of the post-training test. The single star indicates significant fear-potentiated startle as defined as a reliable increase from pre- to post-training startle (p<0.05). The pound sign (#) indicates significant group differences. The error bars denote 1 standard error of the mean.

Figure 3

Effects of the NK1 antagonist GR-205171 on contextual FPS. Gerbils were administered GR-205171 (0, 0.3, 1.0 or 5.0 mg/kg, i.p) 30 min before the post-training test session. The bar graph presents the mean startle response of groups before training as well as their mean startle responses during the first and second halves of the post-training test. The insert panel displays the startle responses of gerbils across blocks during the post-training startle test. Block values represent the mean startle response of two sequential test trails of different intensity (110, 115 dB). Overall startle response (SEM) collapsed across the post-training test session: 0 mg/kg=1216(73), 0.3 mg/kg=882(78), 1.0 mg/kg=931(103), and 5.0 mg/kg=753 (86). Stars indicate significant difference from vehicle (0mg/kg) group, p<0.05. Error bars denote 1 standard error of the mean.

Figure 4

Effects of the NK1 antagonist GR-205171 on elevated plus-maze performance. Gerbils were administered GR-205171 (0, 0.3, 1.0 or 5.0 mg/kg, i.p) 30 min before testing. A) Percentage of open arm time. B) Number of closed arm entries. C) Percentage of open arm entries on the elevated plus-maze. Stars indicate significant difference from vehicle (0mg/kg) group, p<0.05. Error bars denote 1 standard error of the mean.