Carriers of the COMT Met/Met Allele Have Higher Degrees of Hypnotizability,Provided That They Have Good Attentional Control: A Case of Gene–Trait Interaction

Genetic factors may explain part of the interindividual variability in hypnotizability. A new avenue that may provide more comprehensive understanding of the phenotypic effects of genetic variations is the study of gene–trait interaction. In this study, the authors investigate the relationship of the dopamine-related COMT and the serotonin-related 5-HTTLPR polymorphisms to hypnotizability by taking individual differences in executive attention into account. Homozygosity for the COMT Met allele, putatively linked to the capability or proneness to dissociate from reality, was associated with high hypnotizability only if paired with high-attention ability. The finding can be integrated into hypnosis theory and represents a case of gene–trait interaction suggesting that investigating the effects of a gene in the context of relevant psychological traits may further elucidate gene-brain-behavior relationships.     

Amphetamine actions at the serotonin transporter rely on the availability of phosphatidylinositol-4,5-bisphosphate

Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP₂) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP₂ has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An increase in extracellular serotonin results from transporter-mediated efflux triggered by amphetamine-like psychostimulants. Herein, we altered the abundance of PIP₂ by activating phospholipase-C (PLC), using a scavenging peptide, and inhibiting PIP₂-synthesis. We tested the effects of the verified scarcity of PIP₂ on amphetamine-triggered SERT functions in human cells. We observed an interaction between SERT and PIP₂ in pull-down assays. On decreased PIP₂ availability, amphetamine-evoked currents were markedly reduced compared with controls, as was amphetamine-induced efflux. Signaling downstream of PLC was excluded as a cause for these effects. A reduction of substrate efflux due to PLC activation was also found with recombinant noradrenaline transporters and in rat hippocampal slices. Transmitter uptake was not affected by PIP₂ reduction. Moreover, SERT was revealed to have a positively charged binding site for PIP₂. Mutation of the latter resulted in a loss of amphetamine-induced SERT-mediated efflux and currents, as well as a lack of PIP₂-dependent effects. Substrate uptake and surface expression were comparable between mutant and WT SERTs. These findings demonstrate that PIP₂ binding to monoamine transporters is a prerequisite for amphetamine actions without being a requirement for neurotransmitter uptake. These results open the way to target amphetamine-induced SERT-dependent actions independently of normal SERT function and thus to treat psychostimulant addiction.     

Circulating aldosterone and mortality in female nursing home residents

Objectives

To date studies evaluating the relation between circulating aldosterone levels and mortality in elderly female individuals are lacking. We therefore aimed to assess the relationship between circulating aldosterone levels and mortality in a population-based cohort study of female nursing home residents.

Methods

Individuals aged 70 years and older were recruited from 95 nursing homes in Austria. Participants were enrolled and followed up by mobile study teams. All participants underwent an extensive health examination and were followed until death or end of the study. Serum aldosterone concentration (SAC) was measured at baseline after exclusion of twenty seven patients taking mineralocorticoid-receptor (MR) blockers.

Results

Median SAC was 171.1 (IQR: 103.2–303.4) pg/mL (normal range: 30–400) in 471 female individuals (mean age: 83.7 ± 6.2 years). After a median follow-up of 27 ± 8 months, a total of 121 (25.7%) participants died. In multivariable Cox proportional hazard analysis, SAC levels stratified in quartiles were significantly associated with all-cause mortality. Compared with the reference (first) SAC quartile, the Cox proportional hazard ratio (confidence interval 95%) for the fourth SAC quartiles was 1.94, 95% CI = 1.08–3.46, p = 0.026. We found statistically significant interaction terms between SAC-related mortality and the presence of advanced heart failure (NYHA functional class III; p = 0.038), HbA1c (p = 0.043) and eGFR levels (p = 0.030).

Conclusions

Higher circulating aldosterone levels are related to an increased mortality risk in elderly female nursing home residents. Interventional studies are needed to assess the potential influence of MR blockade on “hard” clinical outcomes in individuals aged 70 years and older.