Pharmacological Treatment of Alcohol Cravings.

(1) Background: The treatment of substance addiction is challenging and has persisted for decades, with only a few therapeutic options. Although there are some recommendations for specific treatments for Alcohol Use Disorder (AUD), there is no specific medication used to treat alcohol cravings, which could benefit millions of patients that are suffering from alcoholism. Cravings, or the urge to use drugs, refer to the desire to experience the effects of a previously experienced psychoactive substance. (2) Methods: We included original studies of alcohol abuse or dependence extracted from a controlled, blind, pharmacological treatment study which presented measures and outcomes related to alcohol cravings. (3) Results: Specific drugs used for the treatment of alcoholism, such as Naltrexone and Acamprosate, have had the best results in relieving craving symptoms, as well as promoting abstinence. Baclofen and anticonvulsants such as Gabapentin and Topiramate have shown good results in promoting abstinence and the cessation of cravings. (4) Conclusions: Specific drugs used for the treatment of alcoholism to obtain the best results can be considered the gold standard for promoting abstinence and relieving cravings. Anticonvulsants and Baclofen also had good results, with these medications being considered as second-line ones. Varenicline is an option for alcohol dependents who also concomitantly ingest tobacco.

Exploring the Role of Alcohol Metabolizing Genotypes in a 12-Week Clinical Trial of Naltrexone for Alcohol Use Disorder.

Background: The efficacy of naltrexone in the treatment of alcohol use disorder (AUD) has been associated with a set of variables not directly related with the expression of opioid receptors. All the variables have been found to be highly associated with AUD itself or more severe clinical levels of AUD. Objectives: Given the high association between alcohol metabolizing enzymes (AME) and the outcome of AUD, the present study aims to investigate the role of AME genotype variants in the treatment of AUD with naltrexone. Methods: We carried out a 12-week longitudinal clinical trial based on the treatment of AUD patients with naltrexone (N = 101), stratified by different alcohol metabolization genotypes. Genotyping was performed after the inclusion of the patients in the study, based on the individual presence of single nucleotide polymorphisms (SNPs) in the ADH (alcohol dehydrogenase)1B (ADH1B*2 and ADH1B*3), ADH1C (ADHC*1) and ALDH (aldehyde dehydrogenase) 2 (ALDH2*2) genes. The outcome of alcohol use has been monitored employing the timeline follow-back during the treatment. Results: The ADH1C*1 (Ile350Val, rs698) and ALDH2*2 (Glu504Lys, rs671) polymorphisms were associated with a better response to naltrexone treatment, whereas the ADH1B*3 (Arg370Cys, rs2066702) allelic variant showed a negative outcome. Conclusions: The present study explores a genomic setting for the treatment of AUD with naltrexone. According to our findings, the association between ADH1C*1 and ALDH2*2 variants and better outcomes suggests a successful treatment, whereas the ADH1B*3 mutated allele might lead to an unsuccessful treatment. Further studies should be performed to investigate the relationship between alcohol metabolizing genotypes, the family history of alcohol use disorders and the effect of naltrexone on the outcomes. Genotyping may be a valuable tool for precision-medicine and individualized approach, especially in the context of alcohol use disorders. The small number of subjects was the main limitation of the present study.

Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents

Objective: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. Methods: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. Results: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. Conclusion: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.

Genome-wide DNA methylation profile in the peripheral blood of cocaine and crack dependents.

OBJECTIVE: Cocaine use disorders (CUDs) represent a major public health problem in many countries. To better understand the interaction between the environmental modulations and phenotype, the aim of the present study was to investigate the DNA methylation pattern of CUD patients, who had concomitant cocaine and crack dependence, and healthy controls. METHODS: We studied DNA methylation profiles in the peripheral blood of 23 CUD patients and 24 healthy control subjects using the Illumina Infinium HumanMethylation450 BeadChip arrays. RESULTS: Comparison between CUD patients and controls revealed 186 differentially methylated positions (DMPs; adjusted p-value [adjP] < 10-5) related to 152 genes, with a subset of CpGs confirmed by pyrosequencing. DNA methylation patterns discriminated CUD patients and control groups. A gene network approach showed that the EHMT1, EHMT2, MAPK1, MAPK3, MAP2K1, and HDAC5 genes, which are involved in transcription and chromatin regulation cellular signaling pathways, were also associated with cocaine dependence. CONCLUSION: The investigation of DNA methylation patterns may contribute to a better understanding of the biological mechanisms involved in CUD.

Amerindian (but not African or European) ancestry is significantly associated with diurnal preference within an admixed Brazilian population.

Significant questions remain unanswered regarding the genetic versus environmental contributions to racial/ethnic differences in sleep and circadian rhythms. We addressed this question by investigating the association between diurnal preference, using the morningness-eveningness questionnaire (MEQ), and genetic ancestry within the Baependi Heart Study cohort, a highly admixed Brazilian population based in a rural town. Analysis was performed using measures of ancestry, using the Admixture program, and MEQ from 1,453 individuals. We found an association between the degree of Amerindian (but not European of African) ancestry and morningness, equating to 0.16 units for each additional percent of Amerindian ancestry, after adjustment for age, sex, education, and residential zone. To our knowledge, this is the first published report identifying an association between genetic ancestry and MEQ, and above all, the first one based on ancestral contributions within individuals living in the same community. This previously unknown ancestral dimension of diurnal preference suggests a stratification between racial/ethnic groups in an as yet unknown number of genetic polymorphisms.

Cohort profile: the Baependi Heart Study-a family-based, highly admixed cohort study in a rural Brazilian town.

PURPOSE: Cardiovascular disease (CVD) is a major challenge to global health. The same epidemiological transition scenario is replayed as countries develop, but with variations based on environment, culture and ethnic mixture. The Baependi Heart Study was set up in 2005 to develop a longitudinal family-based cohort study that reflects on some of the genetic and lifestyle-related peculiarities of the Brazilian populations, in order to evaluate genetic and environmental influences on CVD risk factor traits. PARTICIPANTS: Probands were recruited in Baependi, a small rural town in the state of Minas Gerais, Brazil, following by first-degree and then increasingly more distant relatives. The first follow-up wave took place in 2010, and the second in 2016. At baseline, the study evaluated 1691 individuals across 95 families. Cross-sectional data have been collected for 2239 participants. FINDINGS TO DATE: Environmental and lifestyle factors and measures relevant to cardiovascular health have been reported. Having expanded beyond cardiovascular health outcomes, the phenotype datasets now include genetics, biochemistry, anthropometry, mental health, sleep and circadian rhythms. Many of these have yielded heritability estimates, and a shared genetic background of anxiety and depression has recently been published. In spite of universal access to electricity, the population has been found to be strongly shifted towards morningness compared with metropolitan areas. FUTURE PLANS: A new follow-up, marking 10 years of the study, is ongoing in 2016, in which data are collected as in 2010 (with the exception of the neuropsychiatric protocol). In addition to this, a novel questionnaire package collecting information about intelligence, personality and spirituality is being planned. The data set on circadian rhythms and sleep will be amended through additional questionnaires, actimetry, home sleep EEG recording and dim light melatonin onset (DLMO) analysis. Finally, the anthropometric measures will be expanded by adding three-dimensional facial photography, voice recording and anatomical brain MRI.

Shared Genetic Factors of Anxiety and Depression Symptoms in a Brazilian Family-Based Cohort, the Baependi Heart Study.

To investigate the phenotypic and genetic overlap between anxiety and depression symptoms in an admixed population from extended family pedigrees. Participants (n = 1,375) were recruited from a cohort of 93 families (mean age±SD 42±16.3, 57% female) in the rural town of Baependi, Brazil. The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety symptoms. Heritability estimates were obtained by an adjusted variance component model. Bivariate analyses were performed to obtain the partition of the covariance of anxiety and depression into genetic and environmental components, and to calculate the genetic contribution modulating both sets of symptoms. Anxiety and depression scores were 7.49±4.01 and 5.70±3.82, respectively. Mean scores were affected by age and were significantly higher in women. Heritability for depression and anxiety, corrected for age and sex, were 0.30 and 0.32, respectively. Significant genetic correlations (ρg = 0.81) were found between anxiety and depression scores; thus, nearly 66% of the total genetic variance in one set of symptoms was shared with the other set. Our results provided strong evidence for a genetic overlap between anxiety and depression symptoms, which has relevance for our understanding of the biological basis of these constructs and could be exploited in genome-wide association studies.

Distribution and heritability of diurnal preference (chronotype) in a rural Brazilian family-based cohort, the Baependi study.

Diurnal preference (chronotype) is a useful instrument for studying circadian biology in humans. It harbours trait-like dimensions relating to circadian period and sleep homeostasis, but also has ontogenetic components (morningness increases with age). We used the Morningness-Eveningness questionnaire (MEQ) in the Baependi study, a family-based cohort study based in a small town in Minas Gerais, Brazil. The population is highly admixed and has a cohesive and conservative lifestyle. 825 individuals (497 female) aged 18-89 years (average ± SD = 46.4 ± 16.3) and belonging to 112 different families participated in this study. The average MEQ score was 63.5 ± 11.2 with a significant (P < 0.0001) linear increase with age. Morningness was significantly (P < 0.0001) higher in the rural (70.2 ± 9.8) than in the municipal zone (62.6 ± 11.1), and was also significantly (P = 0.025) higher in male (64.6 ± 10.9) than in female (62.8 ± 11.2) participants. Thus, in spite of universal access to electricity, the Baependi population was strongly shifted towards morningness, particularly in the rural zone. Heritability of MEQ score was 0.48 when adjusted for sex and age, or 0.38 when adjusted for sex, age, and residential zone. The reported MEQ score heritability is more akin to those of previous twin studies than previous family studies.

Mood changes after maximal exercise testing in subjects with symptoms of exercise dependence.

Considering exercise has positive and negative reinforcing properties, the mood states of sedentary, nonexercise-dependent and exercise-dependent volunteers were compared after maximal exercise testing. Mood status was evaluated by the Beck Depression Inventory, Trait-State Anxiety Inventory, and Profile of Mood States (POMS). No differences were detected before the test or after it, indicating little possibility of positive reinforcement. However, a significant reduction in the POMS Tension-Anxiety scores was observed in both exerciser groups (greater in the exercise-dependent group) but not in the sedentary group. Only in the exercise-dependent group were significant reductions in Anger and Total Mood Disorders scores observed compared with their pre-exercise scores. These data suggest that exercising has stronger negative reinforcement properties for exercise-dependent volunteers and is a factor which could increase the odds of their becoming dependent on exercise.

Emergent oscillations in a mathematical model of the human menstrual cycle.

BACKGROUND: The aim of this study was to develop a mathematical model of the hypothalamo-pituitary-gonadal axis that would reflect available data in humans. METHODS: A model of hormonal relationships at the early follicular and midluteal phases of the human menstrual cycle is proposed. FINDINGS: Two distinct temporal patterns of oscillatory behavior have been demonstrated for both pituitary and gonadal steroids in the early follicular phase: first, rapid oscillations in gonadotropin releasing hormone, follicle stimulating hormone and luteinizing hormone (Q approximate to 1 hour) that were an immediate consequence of the programmed equations. Second, there were slower, undulating, emergent rhythms in luteinizing hormone and follicle stimulating hormone, and also in estrogen, having oscillatory periods of 2-12 hours. There was also a longer-period (Q2-3 days) emergent rhythm in progesterone. In the mid-luteal phase, estrogen and progesterone rhythms were correlated, and all hormones showed an approximately 6-hour periodicity. CONCLUSIONS: To our knowledge, the oscillatory behavior of peripheral sex steroids in the follicular phase has not been previously noted.

Leptina: o diálogo entre adipócitos e neurônios / Leptine: the dialog between adipocytes and neurons

A descoberta da leptina trouxe consigo um interesse renovado sobre o estudo do controle homeostático da energia. Sabe-se agora que o tecido adiposo branco é o maior sítio de produção da leptina. Uma vez na circulação sangüínea ela se liga a receptores específicos no cérebro, levando ao sistema nervoso central um sinal de saciedade que reflete a quantidade existente de energia em forma de gordura no organismo. Agindo por intermédio de receptores que fazem uso da via JAK/SAT de transdução do sinal intracelular, a leptina modifica a expressão e a atividade de inúmeros peptídeos hipotalâmicos que regulam o apetite e o gasto de energia. Além disso, a leptina sinaliza o estado nutricional do organismo a outros sistemas fisiológicos, modulando a função de várias glândulas alvo. Mais recentemente, a leptina recombinante foi administrada com sucesso numa paciente obesa com deficiência do hormônio devido a uma mutação do gene ob. Por outro lado, os efeitos da leptina recombinante no único estudo em pacientes com obesidade e concentrações elevadas de leptina foram menos impressionantes. Nesta revisão, discutiremos a complexidade das ações da leptina com ênfase no seu papel integrativo de sinalizadora do estado nutricional para o organismo.

Diferencas na secrecao diaria de leptina em homens e mulheres: possiveis implicacoes na neuroendocrinologia dos transtornos alimentares / Daily secretion differences of leptin in men and women: neuroendocrinology possible implications of eating disorders

Introducao: alteracoes de cortisol e hormonios sexuais sao frequentes em transtornos alimentares. Leptina atua no sistema adrenal/gonadal e sinaliza saciedade para o cerebro. Estudos recentes demonstraram alteracoes de leptina em mulheres com anorexia nervosa e bulimia nervosa. Objetivos: 1) verificar se ha uma diferenca no padrao de secrecao diaria de leptina entre sexos; 2) comparar hormonios sexuais e leptina em mulheres. Metodo: a leptina plasmatica foi medida em oito homens e seis mulheres normais. Series temporais compostas de valores plasmaticos de leptina, LH (hormonio luteinizante) e estradiol foram avaliados por testes de deteccao de pulsos, analise espectral e cross-correlation. Resultados: a leptina diaria e a amplitude dos pulsos de leptina sao duas vezes maiores nas mulheres que nos homens...