CYP2D6 genotype may moderate measures of brain structure in methamphetamine users.

Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (ß = -0.254; p = 0.035), but not in control subjects (ß = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.

No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users.

BACKGROUND: Radioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5-4 years), but clients typically present for treatment earlier in abstinence. METHODS: We used PET with [11C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation). RESULTS: Methamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [11C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant. CONCLUSIONS: The discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.

Effect of overnight smoking abstinence on a marker for microglial activation: a [11C]DAA1106 positron emission tomography study.

RATIONALE: Microglia are the main immune cells in the central nervous system and participate in neuroinflammation. When activated, microglia express increased levels of the translocator protein 18 kDa (TSPO), thereby making TSPO availability a marker for neuroinflammation. Using positron emission tomography (PET) scanning, our group recently demonstrated that smokers in the satiated state had 16.8% less binding of the radiotracer [11C]DAA1106 (a radioligand for TSPO) in the brain than nonsmokers. OBJECTIVES: We sought to determine the effect of overnight smoking abstinence on [11C]DAA1106 binding in the brain. METHODS: Forty participants (22 smokers and 18 nonsmokers) completed the study (at one of two sites) and had usable data, which included images from a dynamic [11C]DAA1106 PET scanning session (with smokers having been abstinent for 17.9 ± 2.3 h) and a blood sample for TSPO genotyping. Whole brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (overnight abstinent smoker vs. nonsmoker), site, and TSPO genotype as factors, thereby controlling for site and genotype. RESULTS: Overnight abstinent smokers had lower whole brain SUVs (by 15.5 and 17.0% for the two study sites) than nonsmokers (ANCOVA, P = 0.004). The groups did not significantly differ in injected radiotracer dose or body weight, which were used to calculate SUV. CONCLUSIONS: These results in overnight abstinent smokers are similar to those in satiated smokers, indicating that chronic cigarette smoking leads to global impairment of microglial activation which persists into early abstinence. Other explanations for study results, such as smoking leading to reduced numbers of microglia or smokers having more rapid metabolism of the radiotracer than nonsmokers, are also possible.

Parental overcontrol x OPRM1 genotype interaction predicts school-aged children's sympathetic nervous system activation in response to performance challenge.

Parental overcontrol (OC), the excessive regulation of a child's behavior, cognition, and emotion, is associated with the development of child anxiety. While studies have shown that genetic factors may increase sensitivity to stress, genetic vulnerability to parental OC has not been examined in anxiety etiology. A functional polymorphism in the mu opioid receptor OPRM1 (A118G, rs1799971) has been shown to impact stress reactivity. Using a community sample of children (N = 85, 9-12 years old), we examined the main and interactive effects of maternal OC and child OPRM1 genotype in predicting children's sympathetic nervous system reactivity during a performance stressor. Neither OC nor genotype predicted children's electrodermal activity (EDA); however, the interaction between OC and child genotype significantly predicted stress reactivity, as indexed by EDA, during the challenging task. Among children with the minor G-allele, higher maternal OC was associated with higher reactivity. In A homozygotes, maternal OC was not associated with EDA, suggesting a diathesis-stress pattern of gene x environment interaction. We discuss implications for anxiety etiology and intervention.

Interaction between the Opioid Receptor OPRM1 Gene and Mother-Child Language Style Matching Prospectively Predicts Children's Separation Anxiety Disorder Symptoms.

Recent research suggests that lower mother-child language style matching (LSM) is associated with greater physiological reactivity and insecure attachment in school-aged children, but to date no studies have explored this measure of parent-child behavioral matching for its association with children's anxiety symptoms, a well-known correlate of attachment insecurity and heightened physiological reactivity. There is also considerable evidence of genetic risk for anxiety, including possession of the OPRM1 minor allele, 118G. In the current study (N = 44), we expand upon what is known about children's genetic and environmental risk for anxiety by examining the unique and interactive effects of mother-child LSM and the OPRM1 polymorphism A118G on school-aged children's separation anxiety disorder (SAD) symptoms. SAD symptoms were measured both concurrently with LSM and OPRM1 genotype and two years later through self-report. No significant associations emerged between LSM or OPRM1 and concurrent Time 1 SAD symptoms. However, lower LSM and 118G minor allele possession were both associated with greater SAD symptoms at Time 2; further, the interaction between LSM and OPRM1 genotype significantly predicted SAD symptoms beyond the main effects of the two variables. Possession of the minor allele was only associated with greater SAD symptoms among children in low LSM dyads, whereas children with the minor allele in high LSM dyads showed non-significantly lower SAD symptoms. These findings and a proportion affected analysis provide support for a differential susceptibility model of gene by environment interactions for the OPRM1 gene. We discuss the implications for predicting children's separation anxiety across development.

Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study.

This corrects the article DOI: 10.1038/npp.2017.48.

Effect of Cigarette Smoking on a Marker for Neuroinflammation: A [11C]DAA1106 Positron Emission Tomography Study.

In the brain, microglia continuously scan the surrounding extracellular space in order to respond to damage or infection by becoming activated and participating in neuroinflammation. When activated, microglia increase the expression of translocator protein (TSPO) 18 kDa, thereby making the TSPO expression a marker for neuroinflammation. We used the radiotracer [11C]DAA1106 (a ligand for TSPO) and positron emission tomography (PET) to determine the effect of smoking on availability of this marker for neuroinflammation. Forty-five participants (30 smokers and 15 non-smokers) completed the study and had usable data. Participants underwent a dynamic PET scanning session with bolus injection of [11C]DAA1106 (with smokers in the satiated state) and blood draws during PET scanning to determine TSPO affinity genotype and plasma nicotine levels. Whole-brain standardized uptake values (SUVs) were determined, and analysis of variance was performed, with group (smoker vs non-smoker) and genotype as factors, thereby controlling for genotype. Smokers and non-smokers differed in whole-brain SUVs (P=0.006) owing to smokers having 16.8% lower values than non-smokers. The groups did not differ in injected radiotracer dose or body weight, which were used to calculate SUV. An inverse association was found between whole-brain SUV and reported cigarettes per day (P<0.05), but no significant relationship was found for plasma nicotine. Thus, smokers have less [11C]DAA1106 binding globally than non-smokers, indicating less microglial activation. Study findings are consistent with much prior research demonstrating that smokers have impaired inflammatory functioning compared with non-smokers and that constituents of tobacco smoke other than nicotine affect inflammatory processes.

Interactive effects of attachment and FKBP5 genotype on school-aged children's emotion regulation and depressive symptoms.

Attachment insecurity is influenced by both environmental and genetic factors, but few studies have examined the effects of gene-environment interactions. In the context of environmental stress, a functional variant in the glucocorticoid receptor co-chaperone FKBP5 gene has been repeatedly shown to increase risk for psychiatric illness, including depression. We expand on prior work by exploring cross-sectional attachment by gene effects on both attachment insecurity and downstream physiological and behavioral measures in a diverse community sample of school-aged children (N=99, 49% girls, Mage=10.29years, 66.6% non-White) and their mothers. Specifically, we examined moderating effects of FKBP5 rs3800373 genotype on the links between parenting insensitivity (overcontrol) and child attachment. Further, we assessed whether FKBP5 moderates the links between maternal and child attachment and children's emotion regulation self-report, respiratory sinus arrhythmia (RSA) in response to a standardized laboratory stressor, and depressive symptoms. Higher levels of overcontrol predicted lower child attachment security only in FKBP5 minor allele carriers. Among children with two minor alleles (CC), attachment security was negatively associated with emotion suppression, rumination, depressive symptoms, and RSA reactivity; similarly, for these children, maternal attachment anxiety was positively associated with depressive symptoms. The findings can be conceptualized in a differential susceptibility framework, where the FKBP5 minor allele confers either risk or resilience, depending on the parenting environment.