It should also be noted
It should also be noted that remarkable individual differences in extinguished fear bradycardia (i.e., CS+E vs. CS−E) during initial Day 2 recall test were observed, particularly within Met carriers. Exploratory analyses revealed that these individual differences were partly driven by the level of remaining fear at the end of the Day 1 fear extinction. The correlation of difference scores (CS+E vs. CS−E) at the end of Day 1 xanthine oxidase inhibitors and initial Day 2 recall (a) was higher in Met vs. Val/Val carriers and (b) decreased with higher levels of neuroticism/anxiety. The stronger Day-1-Day-2 relationship in Met carriers again suggests that prefrontal dopamine levels modulate long-term extinction of fear bradycardia. The impaired extinction retention in some Met carriers of the present study is consistent with increased freezing behavior to previously extinguished CS+ in Met/Met vs. Val/Val rodents (Risbrough et al., 2014). In the present study, this effect was most pronounced in individuals who previously showed poor within-session extinction. With regard to neuroticism/anxiety we did not find any direct associations with conditioned fear responses, which converges with a series of previous studies (Fredrikson and Georgiades, 1992, Grillon et al., 2006, Joos et al., 2012, Lommen et al., 2010, Martínez et al., 2012, Otto et al., 2007, Pineles et al., 2009). Instead, fearfulness significantly predicted fear bradycardia during Day 1 acquisition. Meanwhile, the two measures were uncorrelated, which is in line with weak or non-existing relationships of dispositional fear and anxiety in previous studies (Depue and Lenzenweger, 2005, Sylvers et al., 2011). Furthermore, only fearfulness was associated with the COMT Val158Met genotype. It has previously been argued that high neuroticism/anxiety levels promote risk assessment in ambiguous situations rather than stronger defensive reactions to clearly threatening stimuli per se (e.g., Blanchard et al., 2001, Perkins and Corr, 2006). As mentioned earlier, in classical fear conditioning paradigms, implications of conditioned threat stimuli are well predictable and rather unambiguous. Moreover, fear reactions can be understood as short-lived and transient responses, beginning after detection of specific threat cues (i.e., CS+) and ending shortly after threat (i.e., after time window of potential US). Meanwhile, states of anxiety are defined as prolonged periods of risk assessment within ambiguous or uncertain contexts rather than in response to specific threat cues (Depue & Lenzenweger, 2005). Here, we stress the notion that individual differences in fearfulness (i.e., the disposition to strongly react to predictable, imminent harm) are better suited to predict fear acquisition in classical conditioning paradigms compared to neuroticism/anxiety. This is an important implication given that to date most fear conditioning studies use neuroticism/anxiety-related measures of individual differences (such as the STAI) rather than measures of fearfulness (Lonsdorf & Merz, 2017). On the other hand, we showed for the first time, that neuroticism/anxiety may be linked to the Day-1-Day-2 stability of extinguished fear rather than the absolute amount of conditioned or extinguished fear at a single point in time. It is tempting to assume that emotional stability might be an important predictor for stability of extinction memory or even vice versa: the stability of safety learning may be important for emotional stability. This assumption is supported by reported associations of anxiety (but not fear) with volume and activity in the hippocampus (e.g., Kalisch et al., 2006, Montag et al., 2013, Satpute et al., 2012), a core structure in various memory processes (e.g., Izquierdo and Medina, 1997, Maren and Holt, 2000). However, as these observations were based on exploratory analyses, future studies should replicate these results on neuroticism/anxiety, COMT Val158Met, and the specific associations of fear extinction success and fear extinction recall. Our differential result pattern of (a) COMT-related differences in fearfulness, (b) fearfulness predicting short-term fear acquisition and (c) neuroticism/anxiety predicting long-term extinction stability highlights the importance of measuring sufficiently precise behavioral phenotypes in order to find associations with responses in the laboratory and with genotypes (Wacker et al., 2012).