Exploring behavioral and pharmacological means of enhancing background anxiety

Oxytocin is a neurohypophyseal peptide that has recently gained attention as a potential anxiolytic compound. Experiments from our lab have found that pre-testing administration of oxytocin reduces background anxiety but not cue-specific fear-potentiated startle. This finding is of particular interest given the similarities between background anxiety and the startle enhancements seen in post-traumatic stress disorder (PTSD). However, further pursuit of this effect yielded inconsistent results related to a diminished performance of background anxiety in control subjects. Therefore, we planned a series of experiments aimed to simultaneously examine the parametric constraints of background anxiety and the role of glucocorticoids and epinephrine/norepinephrine in oxytocin's anxiolytic effect. Additionally, we conducted an analysis of pooled oxytocin experiment data in order to determine whether subject trait anxiety, measured through pre-conditioning startle performance, could predict oxytocin sensitivity. Experiment 1 revealed that background anxiety is not sensitive to manipulations of context pre-exposure. The results of Experiment 2 demonstrate that background anxiety is a form of learned fear sensitive to total stimulus pairing during training. Experiments 3 and 5 indicate that post-testing administration of corticosterone and yohimbine (respectively) do not facilitate background anxiety expression during testing. Experiment 4 reveals that pre-testing administration of corticosterone does not affect background anxiety, and therefore oxytocin does not likely affect the measure through alterations in glucocorticoid signaling. The results of Experiment 6 demonstrate that pre-testing administration of yohimbine decreases startle, but that this finding may relate to a performance effect. Lastly, the analyses in Experiment 7 indicate that oxytocin is effective in subjects that show attenuated Prefear startle responses, which may be indicative of trait anxiety. Collectively, these finding support our hypotheses that that background anxiety is a form learned fear distinct from Pavlovian context fear and cue-specific fear-potentiated startle. Given the similarities between our findings and the experimental results in studies of PTSD, we conclude that background anxiety may serve as an appropriate rodent model for PTSD symptomology.