Studying experimental factors to optimize the translational value of the rat fear-potentiated startle paradigm

Considering that abnormal fear conditioning is involved in the pathogenesis of anxiety disorders, studies on the development of fear conditioning can contribute to the understanding of anxiety disorders. The rat fear-potentiated startle paradigm is widely used as a tool to study fear conditioning. Several lines of evidence have suggested that this paradigm has translational value for exploring the underlying mechanisms of anxiety disorders and screening anxiolytic effects of compounds. There are, however, still several factors lacking careful examination, which could partly challenge the validity and application of the rat fear-potentiated startle paradigm. This thesis, therefore, aimed at identifying and studying factors that help to further understand the paradigm. To this end, a systematic review of the literature about the pharmacological interventions in the rodent fear-potentiated startle paradigm was provided to identify relevant factors. According to the systematic review, the effect of sex on anxiolytic drug effects is uncertain as limited studies involve female animals. In addition, the contextual effect on the baseline startle response may influence the interpretation of anxiolytic drug effects. The studies then evaluated the effect of sex and context in the fear-potentiated startle paradigm and their influences on drug effects in this paradigm. We found that female and male rats did not differ in the fear-potentiated startle response (cued fear). Moreover, female and male rats did not respond differently to the anxiolytic effects of benzodiazepines. Also, the startle response of female rats appeared similar across different estrous cycle phases. In addition, by training and testing rats in different contexts, we found that chlordiazepoxide inhibited contextual fear in the absence of non-specific drug effects. Based on these results, we studied the role of 5-HT1A receptors in the fear-potentiated startle response of male rats, and the animals were trained and tested in different contexts. We found that somatodendritic 5-HT1A autoreceptors play an important role in modulating conditioned fear since activation of somatodendritic 5-HT1A autoreceptors seemed to reduce the cued fear acquisition and the expression of cued and contextual fear. However, 5-HT1A receptors do not seem to play a major role in the acquisition of contextual fear. According to these findings, contextual fear in the fear-potentiated startle paradigm appears to be a good predictor of anxiolytic properties. With the adjustment shown above, the rat fear-potentiated startle paradigm can be applied to precisely study contextual fear. Therefore, studying contextual fear in the rat fear-potentiated startle paradigm can yield a better understanding of the mechanisms underlying anxiety disorders and aid the development of anxiolytic drugs.