With regard to genetics we found that COMT Val

With regard to genetics, we found that COMT Val158Met predicted successful fear and IPA-3 recall on Day 2 as measured with fear bradycardia and the LPP. At the beginning of the recall test, one day after conditioning and extinction, Val homozygotes but not Met carriers showed significantly enhanced LPP amplitudes and enhanced cardiac slowing to the non-extinguished vs. extinguished CS+. Meanwhile, Met homozygotes initially showed enhanced LPP amplitudes to both, previously extinguished and non-extinguished CS+. These results are consistent with previous rodent data, where Met homozygotes showed more freezing to an extinguished CS+ in the first four trials of an extinction recall test compared to Val homozygotes (Risbrough et al., 2014) and suggest an advantage for the Val allele in long-term fear extinction. When comparing genotype groups, differences in fear and extinction recall were mainly qualified by (a) reduced non-extinguished fear responses (but comparably low extinguished fear responses) in Met carriers relative to Val homozygotes and (b) failed reduction in extinguished fear bradycardia in Val/Met compared to Val/Val carriers. Taken together, Val homozygotes showed the most adaptive response pattern, reflecting actual Day 1 CS-US contingencies in their responses while Met carriers showed patterns inconsistent with previous CS-US contingencies. Exploratory analyses revealed that failure of Met carriers to produce a reduced fear bradycardia to previously extinguished fear stimuli was particularly driven by those Met carriers who already failed to reduce fear during Day 1 extinction. As stated above, this Day-1-Day-2 transfer was also compromised in individuals with high neuroticism/anxiety such that emotionally instable individuals showed high Day-1-Day-2 fluctuations. While COMT Val158Met modulated long-term learning, there was no direct relation to within-session/short-term fear acquisition or extinction. This pattern of findings indicates that the COMT Val158Met polymorphism contributes to individual differences in long-term fear learning (Bellander et al., 2015). As the COMT enzyme is primarily related to prefrontal dopamine degradation (e.g., Yavich et al., 2007), the present study supports the notion that prefrontal dopamine modulates retention of fear extinction rather than within-session extinction (Abraham et al., 2014). Consistent with other studies we found no COMT Val158Met effects for Day 1 extinction (Gruss et al., 2016, Norrholm et al., 2013, Raczka et al., 2011) but instead for Day 2 recall. One previous study in humans found stronger fear responses in Met homozygotes (Lonsdorf et al., 2009) during extinction 24 h after initial fear conditioning which was later interpreted as increased long-term fear retention (Lonsdorf & Kalisch, 2011). In line with the present result pattern, this supports a role of COMT Val158Met for memory retention rather than fear responding per se. As our results suggest generally more stable fear retention in Val/Val carriers rather than Met/Met carriers, follow-up studies may inform about possible determinants of the relationship between COMT Val158Met and long-term fear retention inherent to the experimental design. One advantage of the present study is the use of a fully crossed (i.e., 2 × 2) differential conditioning and differential extinction design, which allows to disentangle COMT Val158Met effects on long-term fear retention and long-term extinction retention. Taken together, the present results indicate that Val homozygotes show better fear and extinction retention than Met carriers in the LPP and HP, at least at a group level when individual differences in Day 1 extinction success are discarded.