The contribution of contextual fear in the anxiolytic effect of chlordiazepoxide in the fear-potentiated startle test

Abstract This study evaluated the extent to which a reduction in contextualfear contributes to the anxiolyticeffect of benzodiazepines in the fear-potentiated startleresponse. To this end, chlordiazepoxide, an anxiolyticoften used as positive control in preclinical drug studies, and zolpidem, known to have sedative properties and to be devoid of anxiolyticeffects, were tested in two contexts: the same context as training had taken place and an alternative context. In addition, the level of muscle relaxationwas assessed in a grip strengthtest. Chlordiazepoxide(2.5–10 mg/kg) decreased the fear-potentiated startleresponse, confirming its anxiolyticactivity. In addition, it dose-dependently decreased the overall startle response in the same, but not the alternative context, and did not affect grip strength, indicating that chlordiazepoxideinhibits contextualfear in the absence of non-specific drug effects. Zolpidem(1.0–10 mg/kg) reduced the overall startle response in both contexts equally and decreased grip strength, indicating that its effects on fear-potentiated startleare due to non-specific drug effects, and not anxiolyticeffects. The present findings show that chlordiazepoxidereduces contextualconditioned fear in the absence of non-specific drug effects. In addition, they show that training and testing rats in different contexts makes it possible to distinguish between cued, contextualand non-specific drug effects. As exaggerated contextual fear conditioningcontributes to the fear generalization processes implicated in pathological anxiety, focus in screening of anxiolyticeffects could be directed more towards the suppression of contextualfear and, therefore, this approach would be a valuable addition to standard preclinical screening.