Mateus Luz Levandowski

An overview of maternal separation effects on behavioural outcomes in mice: Evidence from a four-stage methodological systematic review.

Early life stress (ELS) developmental effects have been widely studied by preclinical researchers. Despite the growing body of evidence from ELS models, such as the maternal separation paradigm, the reported results have marked inconsistencies. The maternal separation model has several methodological pitfalls that could influence the reliability of its results. Here, we critically review 94 mice studies that addressed the effects of maternal separation on behavioural outcomes. We also discuss methodological issues related to the heterogeneity of separation protocols and the quality of reporting methods. Our findings indicate a lack of consistency in maternal separation effects: major studies of behavioural and biological phenotypes failed to find significant deleterious effects. Furthermore, we identified several specific variations in separation methodological procedures. These methodological variations could contribute to the inconsistency of maternal separation effects by producing different degrees of stress exposure in maternal separation-reared pups. These methodological problems, together with insufficient reporting, might lead to inaccurate and unreliable effect estimates in maternal separation studies.

The influence of geographical and economic factors in estimates of childhood abuse and neglect using the Childhood Trauma Questionnaire: A worldwide meta-regression analysis.

This multilevel meta-analysis examined the effects of geographical and economic factors on worldwide childhood maltreatment estimates measured by the Childhood Trauma Questionnaire (CTQ) short-form. The primary outcome extracted was continuous scores on the CTQ subscales - emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect - and total score. Geographical, economical and methodological variables were extracted for use as covariates in meta-regression models. A literature search identified 288 studies suitable for the CTQ total score analysis (N=59,692) and 189 studies suitable for maltreatment subtype analysis (N=44,832). We found that Europe and Asia were associated with lower CTQ estimates while South America presented the highest estimates among continents. Specifically, studies from China, Netherlands and United Kingdom presented the lowest maltreatment estimates. Furthermore, high-income countries presented lower CTQ physical neglect estimates in comparison to low- or middle-income countries, while per-capita gross domestic product of countries was negatively associated with childhood physical neglect estimates. Despite the influence of methodological covariates, these findings indicate that geographical and economic factors could influence variations of childhood maltreatment estimates around the world, particularly when assessed by a structured standardized questionnaire.

Early life stress and tumor necrosis factor superfamily in crack cocaine withdrawal

BACKGROUND Both early life stress (ELS) and substance abuse, especially cocaine, have robust effects on the inflammatory system. Considering the role of the tumor necrosis factor system in inflammatory signaling and its association with ELS, the aim of the study was to compare plasma levels of TNF-alpha, its soluble receptors and ligands during early abstinence of crack cocaine. METHODS This study included 24 crack cocaine-dependent women with (CRACK-ELS) and 20 without (CRACK) a history of ELS. A healthy control group (HC), containing 25 participants, was included to provide reference values. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history of patients. Plasma levels of TNF-alpha, TNF-related weak inducer of apoptosis (TWEAK), TNF-related apoptosis-inducing ligand (TRAIL), soluble receptors TNFRI (sTNFRI) and TNFRII (sTNFRII) were assessed on the 18th day of treatment. RESULTS The CRACK-ELS group had higher TNF-alpha and lower TWEAK levels compared to the CRACK and HC groups. sTNFRII was increased, but only in comparison with the crack cocaine group and the controls. TRAIL levels were slightly higher in the CRACK-ELS group, while no differences were found for sTNFRI levels. Also, TNF-alpha plasma level was positively predicted by abstinence severity and childhood maltreatment severity, and TWEAK was negatively predicted by childhood maltreatment severity. CONCLUSIONS This is the first study to evaluate the newly secreted tumor necrosis factor superfamily ligands, TWEAK and TRAIL, during crack cocaine abstinence, supporting the association between early life stress and peripheral pro-inflammatory levels.

Crack cocaine addiction, early life stress and accelerated cellular aging among women

BACKGROUND Early life stress (ELS) and addiction are related to age-related diseases and telomere shortening. However, the role of telomere length (TL) in crack cocaine addiction remains unknown. The purpose of this study was to investigate the TL in a sample of crack cocaine dependent-women who reported an ELS history and in a community-based sample of elderly women as a reference group for senescence. METHODS This study included treatment seeking crack cocaine dependents women (n=127) and elderly women without a psychiatric diagnosis (ELD, n=49). The crack cocaine sample was divided in two groups according to their Childhood Trauma Questionnaire (CTQ) scores: presence of history of childhood abuse and neglect (CRACK-ELS) and absence of ELS history (CRACK). TL was assessed by T/S ratio obtained from peripheral blood DNA using quantitative PCR assay. RESULTS CRACK and CRACK-ELS subjects exhibited shortened TL in comparison to the ELD group, despite their younger age. Among crack cocaine sample, CRACK-ELS group had significantly shorter telomeres than the CRACK group. Correlation analysis within crack cocaine group indicated that TL was negatively correlated with emotional abuse scores. CONCLUSIONS These results support previous findings associating telomere shortening with both ELS and drug addiction. This study suggests new evidence of a distinct biological phenotype for drug-dependent women with ELS. The results support the biological senescence hypothesis underpinning ELS experience.

Distinct behavioral and immunoendocrine parameters during crack cocaine abstinence in women reporting childhood abuse and neglect

AIM To assess plasma levels of cortisol and cytokines between cocaine-dependent women with and without childhood maltreatment (CM) history during cocaine detoxification treatment. METHOD We assessed immunoendocrine and clinical parameters of 108 crack cocaine female users during 3 weeks of inpatient detoxification treatment, and 24 healthy women to obtain reference values. Women with (CM+, n=53) or without (CM-, n=55) CM history were identified answering the Childhood Trauma Questionnaire (CTQ). Blood samples and clinical assessment were collected before lunch during the first, second and third week post-treatment admission. Flow cytometry was used to assess TNF-α, IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-17A plasma levels and ELISA assay was used to measure plasma cortisol levels. RESULTS At baseline, lower Th1 and Th17-related cytokines levels and higher Th2 cytokines levels were observed in crack cocaine users compared with reference values. Cytokines levels of cocaine dependents gradually became closer to reference values along detoxification treatment. However, when CM+ and CM- groups were compared, increased levels of IL-6, IL-4 and TNF-α across time were observed in CM+ group only. Additionally, a Th1/Th2 immune imbalance was observed within CM+ group, which was negatively correlated with the severity of the crack withdrawal. Finally, loading trauma exposure severity, immunoendocrine and clinical parameters in factor analysis, we identified three clusters of observed variables during detoxification: (1) systemic immunity and trauma exposure, (2) pro-inflammatory immunity and (3) behavior CONCLUSION Our results suggest the existence of an immunological phenotype variant associated with CM exposure during crack cocaine detoxification of women.

Adipokines during early abstinence of crack cocaine in dependent women reporting childhood maltreatment

Childhood maltreatment has been associated with addiction and immune dysregulation, although neurobiological substrates underlying this association remain largely unknown. The aim of the study was to compare plasma levels of adipokines during early abstinence in crack cocaine dependent women with (CM+) and without history of childhood maltreatment (CM-). One hundred four crack cocaine female users were followed for 20 days in a detoxification inpatient treatment unit. Plasma levels of adiponectin, resistin and leptin were assessed every 7 days during 3 weeks of follow-up. The Childhood Trauma Questionnaire (CTQ) retrospectively assessed childhood maltreatment history. A healthy control group was included to provide adipokines reference values (HC). All crack users increased leptin plasma levels during early abstinence despite concentrations remained lower in comparison with non-users group. Crack users reporting childhood maltreatment exhibited a significant reduction in plasma levels of adiponectin and resistin when compared to CM- group. In addition, only CM- participants increased plasma levels of adiponectin during detoxification. This is the first study evaluating adipokines during crack cocaine abstinence. Our results suggest a modulator effect of childhood maltreatment on inflammatory status in treatment-seeking crack cocaine dependents during early abstinence.

Plasma interleukin-6 and executive function in crack cocaine-dependent women.

AIM The aim of this study was to investigate the association between plasma interleukin 6 (IL-6) levels and executive function (EF) in crack cocaine-dependent women. METHODS 42 crack cocaine-dependent women (CRACK) and 52 healthy women (CONTROL) were evaluated with respect to EF using the Wisconsin Card Sorting Test (WCST). Plasma IL-6 levels were quantitatively determined using the multiplexed cytometric bead assay. RESULTS The CRACK group had poor performance on WSCT scores (Non-perseverative Errors and Percent Conceptual Level Responses) and higher plasma IL-6 levels when compared with the CONTROL group. Furthermore, IL-6 was correlated with worsening of several WCST sub-scores and a linear regression model showed that IL-6 levels predicted worse cognitive flexibility within the CRACK group independently of intelligence quotient and education. CONCLUSIONS The results of this study indicated that low performances in EF task are associated with higher IL-6 levels in crack cocaine-dependent women. These data bolster previous works that link the cognitive decline observed in drug addicts with mechanisms of inflammation.

The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Methods: Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. Results: BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). Conclusion: These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

Glucocorticoid receptor gene modulates severity of depression in women with crack cocaine addiction

Crack cocaine addicted inpatients that present more severe withdrawal symptoms also exhibit higher rates of depressive symptoms. There is strong evidence that the identification of genetic variants in depression is potentialized when reducing phenotypic heterogeneity by studying selected groups. Since depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis, this study evaluated the effects of SNPs in stress-related genes on depressive symptoms of crack cocaine addicts at early abstinence and over the detoxification treatment (4th, 11th and 18th day post admission). Also, the role of these SNPs on the re-hospitalization rates after 2.5 years of follow-up was studied. One hundred eight-two women were enrolled and eight SNPs in four genes (NR3C2, NR3C1, FKBP5 and CRHR1) were genotyped. A significant main effect of NR3C1-rs41423247 was found, where the C minor allele increased depressive symptoms at early abstinence. This effect remained significant after 10,000 permutations to account for multiple SNPs tested (P=0.0077). There was no effect of rs41423247 on the course of detoxification treatment, but a slight effect of rs41423247 at late abstinence was detected (P=0.0463). This analysis suggests that the presence of at least one C allele is worse at early abstinence, while only CC genotype appears to increase depressive symptoms at late abstinence. Also, a slight effect of rs41423247 C minor allele increasing the number of re-hospitalizations after 2.5 years was found (P=0.0413). These findings are in agreement with previous studies reporting an influence of rs41423247 on sensitivity to glucocorticoids and further elucidate its resulting effects on depressive-related traits.

The effects of early life stress on reward processing

Early life stress (ELS), in the form of childhood maltreatment, abuse, or neglect, increases the risk for psychiatric sequelae later in life. The neurobiology of response to early stress and of reward processing overlap substantially, leading to the prediction that reward processing may be a primary mediator of the effects of early life stress. We describe a growing body of literature investigating the effects of early life stressors on reward processing in animals and humans. Despite variation in the reviewed studies, an emerging pattern of results indicates that ELS results in deficits of ventral striatum-related functions of reward responsiveness and approach motivation, especially when the stressor is experienced in early in development. For stressors experienced later in the juvenile period and adolescence, the animal literature suggests an opposite effect, in which ELS results in increased hedonic drive. Future research in this area will help elucidate the transdiagnostic impact of early life stress, and therefore potentially identify and intervene with at-risk youth, prior to the emergence of clinical psychopathology.