Anxiolytic-like Effects of the Positive GABAB Receptor Modulator GS39783 Correlate with Mice's Individual Basal Anxiety and Stress Reactivity.

Ahmet Oguzhan Bicakci,Angel Moldes-Anaya,Mousumi Sarkar,Yu-Hsin Chang,Lorenzo Ragazzi,Markus Fendt,Evelyn Kahl

doi:10.3390/ph15020233

Abstract

Positive gamma-aminobutyric acid type B (GABAB) receptor modulators such as GS39783 have showed anxiolytic-like effects in several studies while such effects were absent in other studies. These conflicting findings led us hypothesize that the anxiolytic-like effects of such compounds depend on the individual basal anxiety and/or the anxiogenic properties of the used tests. The present study addresses this hypothesis by testing GS39783 effects on mice’s anxiety-like behavior in a light–dark box. We found that GS39783 had no effects on a whole-group level. However, after grouping the mice for their basal anxiety, GS39783 reduced anxiety-like behavior in the subgroup with highest basal anxiety. Moreover, GS39783 effects correlated with individual basal anxiety. Next, the anxiogenic properties of the light–dark box test were increased by prior stress exposure. Again, GS39783 was not effective on a whole-group level. However, GS39783 had an anxiolytic-like effect in the most stress-responsive subgroup. Moreover, GS39783 effects correlated with individual stress responsiveness. Finally, we show that GS39783 brain levels were within a behaviorally relevant range. Overall, our study demonstrates that GS39783 effects depend on individual basal anxiety and stress responsiveness. This suggests that anxiety tests should generally be designed to capture individual basal anxiety and/or stress responsiveness as well as individual compound effects.

Highlights

The present study addressed the latter explanation and tested the hypothesis whether the anxiolytic-like effects of a positive gamma-aminobutyric acid type B (GABAB) receptor modulator depend on the individual basal anxiety of the mice and/or the anxiogenic properties of the behavioral paradigms
Using the light–dark box paradigm [28] and C57BL/6J mice, we investigated the anxiolytic-like effects of the positive allosteric modulator of the GABAB receptor GS39783 [29]
An analysis of variance (ANOVA) using test day as a within-subject factor revealed that the percent time spent in the bright area of the light–dark box was not affected by repeated testing (F5,71 = 0.47, p = 0.68; Figure 1A)

Summary

Introduction

Fear and anxiety are emotions that help animals and humans to cope with threatening situations. Excessive fear and anxiety are symptoms of several neuropsychiatric disorders, including anxiety and stress-related disorders [1]. Dysfunctions of the brain circuitries mediating emotional responses, fear and anxiety, are thought to be involved in the pathogenesis of anxiety- and stress-related disorders [2,3]. A better understanding of the neuropharmacology of these brain circuitries may enable the development of improved pharmacological therapies for anxiety disorders [4]

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