A role for the CD38 rs3796863 polymorphism in alcohol and monetary reward: evidence from CD38 knockout mice and alcohol self-administration, [11C]-raclopride binding, and functional MRI in humans.

Background: Cluster of differentiation 38 (CD38) is a transmembrane protein expressed in dopaminergic reward pathways in the brain, including the nucleus accumbens (NAc). The GG genotype of a common single nucleotide polymorphism (SNP) within CD38, rs3796863, is associated with increased social reward.Objective: Examine whether CD38 rs3796863 and Cd38 knockout (KO) are associated with reward-related neural and behavioral phenotypes.Methods: Data from four independent human studies were used to test whether rs3796863 genotype is associated with: (1) intravenous alcohol self-administration (n = 64, 30 females), (2) alcohol-stimulated dopamine (DA) release measured using 11C-raclopride positron emission tomography (n = 22 men), (3) ventral striatum (VS) response to positive feedback measured using a card guessing functional magnetic resonance imaging (fMRI) paradigm (n = 531, 276 females), and (4) resting state functional connectivity (rsfc) of the VS (n = 51, 26 females). In a fifth study, we used a mouse model to examine whether cd38 knockout influences stimulated DA release in the NAc core and dorsal striatum using fast-scanning cyclic voltammetry.Results: Relative to T allele carriers, G homozygotes at rs3796863 within CD38 were characterized by greater alcohol self-administration, alcohol-stimulated dopamine release, VS response to positive feedback, and rsfc between the VS and anterior cingulate cortex. High-frequency stimulation reduced DA release among Cd38 KO mice had reduced dopamine release in the NAc.Conclusion: Converging evidence suggests that CD38 rs3796863 genotype may increase DA-related reward response and alcohol consumption.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Validation of a Spanish Translation of the Faceted Inventory of the Five-Factor Model in Two Mexican University Student Samples.

The validity, and thus utility, of psychological instruments requires continued evaluation of their underlying psychometric properties across contexts. Measurement tools have been developed over the past few decades to assess personality constructs developed through various theoretical frameworks. The Big Five has been a particular focus of such inquiry; however, few studies have validated a Spanish version for use in Mexico. Using two separate Mexican college student samples (Sample 1: n = 289, Sample 2: n = 309) we tested factorial structure, reliability, and validity of a Spanish translation of the Faceted Inventory of the Five-Factor Model (FI-FFM; Watson, Nus, & Wu). An exploratory factor analysis showed a similar structure to the original FI-FFM, albeit with some exceptions primarily within the Extraversion and Agreeableness domains. Furthermore, the FI-FFM scales were internally consistent and highly stable over time (average interval = 5 months). Finally, the scales showed strong convergent and discriminant validity and the facet scales displayed validity in predicting outcomes.

Positive University Environment and Agreeableness as Protective Factors Against Antisocial Behavior in Mexican University Students.

Violence in schools is a global issue. Approximately 32% of Mexican students have experienced some form of violence in the school setting in their lives. Previous research has tended to focus on the causes of violence and antisocial behaviors in offenders or adolescent samples and has found evidence to suggest the underlying role of environmental and personal factors. The present study investigates the effect of positive school environment and agreeableness as protective factors against antisocial behaviors in a sample of undergraduate and graduate students (n = 304) from northwestern Mexico. Our results demonstrate that a positive school environment has a negative effect on antisocial behaviors via mood and anxiety disorders as well as in interaction with agreeableness, suggesting an interplay between personality and environment. These findings can provide some basis for the development of university programs aimed at fostering positive environments that promote student mental health and protect against antisocial behaviors.

Positive Environments and Precautionary Behaviors During the COVID-19 Outbreak.

Theoretically, a positive environment (PE) includes (a) tangible and intangible resources that satisfy human needs, (b) enablers of healthy, pro-social, and pro-environmental behaviors that guarantee socio-environmental quality and wellbeing, and (c) environmental challenges that must be faced and solved. One of the most salient challenges is the global COVID-19 pandemic. This study sought to investigate whether PEs can stimulate responsible actions (i.e., self-care and precautionary behaviors against COVID-19), while maintaining personal wellbeing. Nine hundred and forty-nine Mexicans participated in an online survey encompassing five primary factors: resources, enablers, challenges, responsible health behaviors, and wellbeing. The first three factors examine "resources" such as physical infrastructure as well as family and social support, "enablers" which include information about protective health practices and perceived legitimacy of authorities in handling the pandemic, and "challenges" encompassing threat perception and social pressure to not engage in precautionary measures. Participants also self-reported hedonic wellbeing as well as self-care and precautionary behaviors, which formed the "responsible (health) behavior" factor. Structural equations model (n = 714 after list-wise deletion) showed that "resources," "challenges," and "enablers" form a second-order factor, "positive environments," and this factor strongly covaries with "responsible behavior" and "wellbeing." These results suggest that PEs are not only buffers against the negative impact of the COVID-19 pandemic but can also stimulate effective responses against a threat while maintaining individual wellbeing. These results can be used to inform the development and maintenance of PE frameworks aimed at minimizing the spread of COVID-19 and encouraging mental and physical health.

Hypothalamic-pituitary-adrenal axis genetic variation and early stress moderates amygdala function.

Early life stress may precipitate psychopathology, at least in part, by influencing amygdala function. Converging evidence across species suggests that links between childhood stress and amygdala function may be dependent upon hypothalamic-pituitary-adrenal (HPA) axis function. Using data from college-attending non-Hispanic European-Americans (n=308) who completed the Duke Neurogenetics Study, we examined whether early life stress (ELS) and HPA axis genetic variation interact to predict threat-related amygdala function as well as psychopathology symptoms. A biologically-informed multilocus profile score (BIMPS) captured HPA axis genetic variation (FKBP5 rs1360780, CRHR1 rs110402; NR3C2 rs5522/rs4635799) previously associated with its function (higher BIMPS are reflective of higher HPA axis activity). BOLD fMRI data were acquired while participants completed an emotional face matching task. ELS and depression and anxiety symptoms were measured using the childhood trauma questionnaire and the mood and anxiety symptom questionnaire, respectively. The interaction between HPA axis BIMPS and ELS was associated with right amygdala reactivity to threat-related stimuli, after accounting for multiple testing (empirical-p=0.016). Among individuals with higher BIMPS (i.e., the upper 21.4%), ELS was positively coupled with threat-related amygdala reactivity, which was absent among those with average or low BIMPS. Further, higher BIMPS were associated with greater self-reported anxious arousal, though there was no evidence that amygdala function mediated this relationship. Polygenic variation linked to HPA axis function may moderate the effects of early life stress on threat-related amygdala function and confer risk for anxiety symptomatology. However, what, if any, neural mechanisms may mediate the relationship between HPA axis BIMPS and anxiety symptomatology remains unclear.

Variables Referentes al Capital y la Responsabilidad Social Relacionadas con Conductas de Precaución Contra el COVID-19 en Tres Muestras Mexicanas / Variables Referring to Social Capital and Responsibility Associated to Precautionary Behaviors against COVID-19 in Three Mexican Samples

Resumen Cumplir con las medidas de prevención de la salud es fundamental para controlar brotes de enfermedades infecciosas como aquellos causados por la COVID-19. Se han realizados numerosas investigaciones para comprender algunas variables psicosociales (desde personalidad hasta diferencias culturales) asociadas con las conductas de precaución en contextos de pandemia. Sin embargo, se sabe poco sobre el papel que el capital y la responsabilidad social pueden jugar en estos comportamientos de precaución en el contexto de la pandemia del COVID-19. El presente trabajo aborda variables psicológicas asociadas con el capital social y conductas socialmente responsables (e.g. amabilidad, empatía, apoyo social, justicia, impulsividad, conducta cívica), que ayudan a un grupo a desarrollar actividades socialmente valiosas propiciando el cumplimiento de las medidas de prevención. El presente estudio evaluó el efecto del capital social y variables asociadas (e.g., personalidad, apoyo social) en comportamientos precautorios relacionados con el COVID-19. Se utilizaron regresiones jerárquicas y modelos mediacionales en 3 diferentes muestras mexicanas (muestra 1: n=709, muestra 2: n=718, muestra 3: n= 309). Los resultados muestran que las variables asociadas con la responsabilidad social evaluadas aquí, con excepción de la legitimidad y la justicia distributiva, se relacionan con un mayor reporte de conductas de precaución. Estos resultados sugieren un enfoque encaminado a aumentar el capital y la responsabilidad social para reducir el efecto de enfermedades infecciosas como el COVID-19.

Abstract Compliance with health protection measures is essential to control outbreaks of infectious diseases such as COVID-19. Extensive research has been done in the pursuit of understanding psychosocial variables (e.g., personality to cultural differences) associated with precautionary behaviors. However, little is known about the role social capital and responsibility may play on these behaviors in the context of COVID-19. The present work assessed psychological variables associated with social capital and responsibility (e.g. agreeableness, empathy, social support, justice, impulsivity, civic behaviors), which help the development of socially valuable activities leading individuals to comply with preventative measures. The present study, using 3 different Mexican samples (sample 1, n=709; sample 2, n=718; sample 3, n= 309) explored the effect of social capital, civic culture, and associated variables (e.g., personality, social support) on COVID-19 related precautionary behaviors using hierarchical linear regressions and mediational models. In the first sample, we explored the relationship between empathy, impulsivity, and precautionary behaviors. In the second sample, we explored whether trust in authorities, social support, and social pressure predicted these behaviors. In the third sample, we used a longitudinal design to assess the mediating role of prosocial and socially responsible behaviors between personality and precautionary behaviors. Results from the first sample showed that empathy predicted precautionary behaviors. In the second sample, we observed that although legitimacy and distributive justice did not predict precautionary behaviors, social pressure had a negative and social support had a positive effect on these behaviors. Finally, our longitudinal data suggested that those who report higher conscientiousness and agreeableness also report more socially responsible and prosocial behaviors and in turn report higher precautionary behaviors. In general, results from all samples, showed that the variables associated with social capital and responsibility are significantly related with increased report of precautionary behaviors. These results suggest that efforts should be focused on increasing social capital and responsibility while seeking to reduce the spread and deleterious effects of infectious diseases like COVID-19.

Behavioral and self-reported sensitivity to reward are linked to stress-related differences in positive affect.

Despite the high prevalence of stress exposure healthy adaptation or resilience is a common response. Theoretical work and recent empirical evidence suggest that a robust reward system, in part, supports healthy adaptation by preserving positive emotions even under exceptionally stressful circumstances. We tested this prediction by examining empirical relations among behavioral and self-reported measures of sensitivity to reward, trait resilience, and measures of affect in the context of experimentally induced stress. Using a quasi-experimental design we obtained measures of sensitivity to reward (self-report and behavioral), as well as affective and physiological responses to experimental psychosocial stress in a sample of 140 healthy college-age participants. We used regression-based moderation and mediational models to assess associations among sensitivity to reward, affect in the context of stress, and trait resilience and found that an interaction between exposure to experimental stress and self-reported sensitivity to reward predicted positive affect following experimental procedure. Participants with high sensitivity to reward reported higher positive affect following stress. Moreover, positive affect during or after stress mediated the relation between sensitivity to reward and trait resilience. Consistent with the prediction that a robust reward system serves as a protective factor against stress-related negative outcomes, our results found predictive associations among sensitivity to reward, positive affect, and resilience.

PER1 rs3027172 Genotype Interacts with Early Life Stress to Predict Problematic Alcohol Use, but Not Reward-Related Ventral Striatum Activity.

Increasing evidence suggests that the circadian and stress regulatory systems contribute to alcohol use disorder (AUD) risk, which may partially arise through effects on reward-related neural function. The C allele of the PER1 rs3027172 single nucleotide polymorphism (SNP) reduces PER1 expression in cells incubated with cortisol and has been associated with increased risk for adult AUD and problematic drinking among adolescents exposed to high levels of familial psychosocial adversity. Using data from undergraduate students who completed the ongoing Duke Neurogenetics Study (DNS) (n = 665), we tested whether exposure to early life stress (ELS; Childhood Trauma Questionnaire) moderates the association between rs3027172 genotype and later problematic alcohol use (Alcohol Use Disorders Identification Test) as well as ventral striatum (VS) reactivity to reward (card-guessing task while functional magnetic resonance imaging data were acquired). Initial analyses found that PER1 rs3027172 genotype interacted with ELS to predict both problematic drinking and VS reactivity; minor C allele carriers, who were also exposed to elevated ELS reported greater problematic drinking and exhibited greater ventral striatum reactivity to reward-related stimuli. When gene × covariate and environment × covariate interactions were controlled for, the interaction predicting problematic alcohol use remained significant (p < 0.05, corrected) while the interaction predicting VS reactivity was no longer significant. These results extend our understanding of relationships between PER1 genotype, ELS, and problematic alcohol use, and serve as a cautionary tale on the importance of controlling for potential confounders in studies of moderation including gene × environment interactions.

An oxytocin receptor polymorphism predicts amygdala reactivity and antisocial behavior in men.

Variability in oxytocin (OXT) signaling is associated with individual differences in sex-specific social behavior across species. The effects of OXT signaling on social behavior are, in part, mediated through its modulation of amygdala function. Here, we use imaging genetics to examine sex-specific effects of three single-nucleotide polymorphisms in the human oxytocin receptor gene (OXTR; rs1042778, rs53576 and rs2254298) on threat-related amygdala reactivity and social behavior in 406 Caucasians. Analyses revealed that among men but not women, OXTR rs1042778 TT genotype was associated with increased right amygdala reactivity to angry facial expressions, which was uniquely related to higher levels of antisocial behavior among men. Moderated meditation analysis suggested a trending indirect effect of OXTR rs1042778 TT genotype on higher antisocial behavior via increased right amygdala reactivity to angry facial expressions in men. Our results provide evidence linking genetic variation in OXT signaling to individual differences in amygdala function. The results further suggest that these pathways may be uniquely important in shaping antisocial behavior in men.

Involvement of the ventral tegmental area in a rodent model of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is an anxiety disorder of considerable prevalence in individuals who have experienced a traumatic event. Studies of the neural substrate of this disorder have focused on the role of areas such as the hippocampus, the amygdala and the medial prefrontal cortex. We show that the ventral tegmental area (VTA), which directly modulates these areas, is part of this circuitry. Using a rat model of PTSD, we show that a brief but intense foot shock followed by three brief reminders can cause long-term behavioral changes as shown by anxiety-like, nociception, and touch-sensitivity tests. We show that an intraperitoneal injection of a dopamine (DA) antagonist or a bilateral inactivation of the VTA administered immediately before the traumatic event decrease the occurrence or intensity of these behavioral changes. Furthermore, we show that there is a significant decrease of baseline VTA dopaminergic but not GABAergic cell firing rates 2 weeks after trauma. Our data suggest that VTA DA neurons undergo long-term physiological changes after trauma and that this brain area is a crucial part of the circuits involved in PTSD symptomatology.