Although retention effects might stem from differences in bo

Although retention effects might stem from differences in both consolidation and/or recall of extinction memory, prefrontal dopamine – and thereby COMT enzyme AZD1390 sale – might be particularly relevant for consolidation as indicated by studies on endogenous prefrontal dopamine release in rats after extinction training (Hugues, Garcia, & Léna, 2007) and the finding that L-DOPA administration after extinction training improves long-term fear extinction in humans (Haaker et al., 2013, Haaker et al., 2015). Future studies using COMT inhibitors could test directly to which extent COMT Val158Met modulates extinction consolidation and recall, respectively (Farrell et al., 2012, Giakoumaki et al., 2008). We suggest that COMT Val158Met influences long-term fear extinction via prefrontal dopamine, with relatively lower dopamine levels (i.e., Val/Val) promoting generally better consolidation across all subjects, independent of individual differences in Day 1 extinction success. Nevertheless, the underlying mechanisms might go beyond a linear and direct effect of prefrontal dopamine levels on long-term fear extinction success. First, relationships between prefrontal functioning and extracellular dopamine levels seem to be inversely U-shaped (Durstewitz and Seamans, 2008, Farrell et al., 2012, Mueller et al., 2014a, Mueller et al., 2011). Beyond the PFC, the relevant neural network likely extends to the ventral striatum which is involved in fear extinction via prediction error coding (Abraham et al., 2014). Moreover, concurrent dopaminergic activation of striatum and amygdala may be necessary for long-term learning (LaLumiere & Nawar, 2005). COMT Val158Met affects phasic dopaminergic firing in the striatum in a more subtle way than in the PFC (Bilder et al., 2004) and likely interacts with other dopaminergic genotypes (Felten et al., 2011, Raczka et al., 2011). Interestingly, the agency facet of extraversion, which has been consistently related to individual differences in dopamine in general and to COMT Val158Met in specific (Depue and Collins, 1999, Mueller et al., 2014b), was unrelated to both COMT Val158Met and Day 2 extinction recall in the present study. Although variations in agentic extraversion have been linked to differences in frontostriatal dopaminergic activity, different psychological processes (e.g., incentive motivation in agentic extraverts vs. extinction retention processes) may be mediated via different neuron populations or distinct frontostriatal connections (Bromberg-Martin et al., 2010, Salamone and Correa, 2012). Future studies might combine neuroimaging with pharmacological challenges and assess more genotypes in order to disentangle these complex mechanisms. 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 extinction 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.