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  • In humans individual differences in


    In humans, individual differences in prefrontal dopamine are partially caused by the Val158Met single-nucleotide polymorphism on the catechol-O-methyltransferase gene (COMT). This gene controls activity of the COMT enzyme, which degrades extracellular catecholamines including dopamine. The Val variant of the COMT Val158Met polymorphism causes three- to fourfold COMT enzyme activity compared to the Met allele (Lachman et al., 1996, Weinshilboum et al., 1999), causing a reduction in tonic dopamine levels, especially in the prefrontal AGI5198 (PFC; Bilder et al., 2004, Meyer-Lindenberg and Weinberger, 2006, Yavich et al., 2007). Its association with prefrontal dopamine levels makes COMT Val158Met an intriguing candidate polymorphism for modulation of fear extinction retention. Of relevance, a rodent study found reduced extinction retention in Met vs. Val homozygotes, as indicated by initially increased freezing to a previously extinguished CS+ during a recall test 24 h after extinction training (Risbrough, Ji, Hauger, & Zhou, 2014). Thus far, human COMT studies have focused on within-session extinction or fear retention (rather than extinction retention), albeit with mixed findings (Gruss et al., 2016, Klucken et al., 2016, Lonsdorf et al., 2009, Norrholm et al., 2013, Raczka et al., 2011). Given the putative role of prefrontal dopamine in long-term fear extinction, a human COMT Val158Met study with a delayed extinction recall test is warranted. On the level of personality, differences in conditioning and extinction have been linked to traits such as neuroticism and extraversion (Eysenck, 1970, Zinbarg and Revelle, 1989). Neuroticism and closely linked anxiety (Depue & Lenzenweger, 2005) are strong predictors for the development of anxiety disorders (Clark, Watson, & Mineka, 1994). Neuroticism/anxiety is the most commonly investigated personality trait in fear conditioning research and higher levels of neuroticism/anxiety have been suggested to go along with enhanced fear conditioning and/or impaired fear extinction (Barlow et al., 2014, Lonsdorf and Merz, 2017). However, empirical support is mixed with regard to the question which learning phase is sensitive (i.e., initial acquisition, extinction or consolidation/retention of conditioned and extinguished fear), whether higher neuroticism/anxiety predicts stronger or weaker CS discrimination, or if there are any robust relationships at all (Gazendam et al., 2015, Gazendam et al., 2013, Grillon et al., 2006, Guimarães et al., 1991, Joos et al., 2012, Lommen et al., 2010, Martínez et al., 2012, Otto et al., 2007, Pineles et al., 2009, Pitman and Orr, 1986, Rauch et al., 2005, Sehlmeyer et al., 2011, Staples-Bradley et al., 2018, Wiggert et AGI5198 al., 2017). This result pattern, along with theoretical considerations, suggests that neuroticism/anxiety may be an invalid predictor of fear responses in the laboratory. More precisely, neuroticism/anxiety is thought to predispose individuals to behavior which is (a) proactive to avoid more distant threats, (b) includes various risk assessment strategies (e.g., worrying, increased sensory intake) and (c) is most pronounced in ambiguous situations (Blanchard et al., 2001, McNaughton, 2011, Perkins and Corr, 2006). However, classical fear conditioning paradigms usually employ conditioned stimuli which reliably predict the occurrence of a clearly aversive stimulus only seconds later. Therefore, trait fearfulness might prove more relevant as it specifically describes the disposition for (a) intense reactive behavior in response to imminent threat, (b) including fighting, fleeing, or freezing and (c) which is most pronounced in unambiguously dangerous situations (Blanchard et al., 2001, McNaughton, 2011, Perkins and Corr, 2006). Previous studies have highlighted conceptual (Depue and Lenzenweger, 2005, McNaughton, 2011, Perkins and Corr, 2006, Perkins et al., 2007, Sylvers et al., 2011) as well as biological distinctions between neuroticism/anxiety and fearfulness (McNaughton and Corr, 2004, Walker and Davis, 2002, Walker et al., 2003, White and Depue, 1999) that apparently are relevant in fear acquisition and short-term extinction (Gazendam et al., 2015). To our knowledge, no study has investigated the specific role of fearfulness in long-term fear extinction recall.