Positive gamma-aminobutyric acid type B (GABA_B) 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.

Positive GABAB receptor modulators such as GS39783 showed anxiolytic-like ef-fects in several studies while others failed to find such effects. These contradictory findings led us to hypothesize that the anxiolytic-like effects of positive GABAB re-ceptor modulators are dependent on basal anxiety levels of individual animals and/or on the anxiogenic properties of the test paradigm. The present study ad-dresses this hypothesis by testing the effects of intraperitoneally administered GS39783 (10 and 30 mg/kg) on anxiety-like behavior of mice in the light-dark box paradigm. Our findings show that GS39783 had no anxiolytic-like effects on a whole group level. However, after grouping the mice for their basal anxiety levels, GS39783 reduced anxiolytic-like behavior in the animal group with most basal anx-iety. Furthermore, individual GS39783 effects were correlated with individual basal anxiety levels. In a further experiment, the anxiogenic properties of the light-dark box test were increased. Again, GS39783 was not effective on a whole group level. However, GS39783 had anxiolytic-like effects in the most stress-responsive sub-group of mice. In addition, GS39783 effects were correlated with individual stress responsiveness. Last, we also demonstrate that GS39783 brain levels were in a range where GS39783 effects has been observed in vitro. Taken together, our study demonstrates that GS39783 effects are dependent of individuals’ basal anxiety and stress responsiveness. This suggests that anxiety tests should be generally de-signed in a way that individual basal anxiety levels and/or stress responsiveness, as well as individual compound effects can be evaluated.