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    • It is interesting that of

    2021-04-06

    It is interesting that of the control groups, female TG controls only had significantly higher MB-COMT protein than non-TG male controls (Supplemental Table 9, P = 0.005), while these two groups have almost equal expression of S-COMT protein (8.54- vs. 8.34-fold) and their COMT enzyme activity is also not evidently different (558.46 vs. 511.41 nM/min/mg). In comparing the TG female control group and non-TG female controls, the only difference is COMT activity (Supplemental Table 11, P = 0.003). Therefore, functional consequences of haplotype TG carriage in control is more likely because it affects COMT activity, whereas the female specific haplotype TG-MDD vulnerability association is probably due to MB-COMT protein expression. COMT enzyme activity is not simply determined by MB-COMT and S-COMT protein expression levels in MDD and control subjects. Nonetheless, the relatively lower expression of MB-COMT and S-COMT protein did lead to low COMT enzyme activity in MDD subjects and this outcome was independent to gender and haplotype of rs4633-rs4680. S-COMT is more abundant in peripheral blood and may have higher catalytic activity than MB-COMT; however, our findings conflict with previous findings, revealing the complex nature of serum COMT activity regulation in both MDD patients and control subjects. Another previous study suggested that S-COMT encoded by low-activity and high activity NSC697923 did not show any differences in catalyzing estrogen (Goodman et al., 2002). Some yet-uncharacterized mechanisms appear to be involved in the hemostasis of S-COMT activity. Regarding the COMT haplotype and MDD treatment response, a previous study of haplotype C-C-A of exonic SNPs, rs4633, rs4818, and rs4680 correlated the treatment response phenotypes, and detected haplotype CCA more often in responders than non-responder and controls (Kocabas et al., 2010). In our study, we did not observe significant differences in initial HDRS score among different genotypic and haplotypic groups of MDD subjects. This may be because we only analyzed the first HDRS scores of the patient without integrating follow-up information on subsequent antidepressant medications. Such follow-up information as HDRS scores during and after medication, antidepressant type, gender, and age needed to be considered in the experimental setting to confirm some of the previously reported findings.
    Conclusions
    Introduction Individual differences in fear learning and reduction are believed to contribute to the development and persistence of dispositional fear, anxiety/neuroticism and anxiety disorders (Duits et al., 2015, Lissek et al., 2005, Milad and Quirk, 2012). In experimental studies, fear learning and reduction are commonly studied with differential fear conditioning and subsequent extinction. Briefly, if a conditioned stimulus (CS) is repeatedly followed by an aversive unconditioned stimulus (US), the CS becomes a conditioned threat cue (CS+) which elicits a conditioned threat response (CR), whereas CSs associated with US absence (CS−) may become safety cues that elicit a relatively reduced CR. Differential responses to CS+ vs. CS− indicate the level of conditioned fear. Repeated CS+ presentation without the US (i.e., extinction) indicates that the CS+ no longer is a valid threat cue and that the CR should be adapted. This change in CS-US contingencies causes the formation of an extinction memory, which inhibits the original excitatory CS-US association and causes a decrease in the magnitude of the conditioned fear response (Quirk & Mueller, 2008). Importantly, only successful consolidation, retention, and recall of conditioning and extinction memories eventually lead to stable conditioned or extinguished fear responses (Myers and Davis, 2007, Quirk and Mueller, 2008). Dopamine has been repeatedly associated with various learning processes including fear extinction (Abraham, Neve, & Lattal, 2014). Although both within-session extinction (i.e., decrement of the CR over the course of extinction training) and extinction retention (i.e., CR reductions to extinguished CSs in a delayed recall test) may involve prefrontal and dopaminergic mechanisms, they constitute different neuropsychological processes with different dopaminergic networks involved (Myers and Davis, 2007, Vervliet et al., 2013). Of relevance, several rodent studies have shown impaired fear extinction retention – but not within-session extinction – following selective blockage of prefrontal dopamine receptors (Hikind and Maroun, 2008, Mueller et al., 2010, Pfeiffer and Fendt, 2006; but also see Ponnusamy, Nissim, & Barad, 2005).