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1.
Artigo em Russo | MEDLINE | ID: mdl-33244961

RESUMO

OBJECTIVE: To identify polymorphisms in the genes of dopaminergic and serotonergic systems associated with the risk of suicidal behavior in individuals with dependence on synthetic cathinones. MATERIAL AND METHODS: One hundred and eighty-two men with the diagnosis of Substance dependence (ICD-10 F15) tested positive for metabolites of synthetic cathinones (a-PVP, MDPV) in the urine were studied. Genotyping was performed for rs1800497 DRD2, rs4646984 DRD4, VNTR 40 b.p. SLC6A3, rs27072 SLC6A3, rs6313 HTR2A and rs6296 HTR1B using PCR and RFLP technique. RESULTS AND CONCLUSION: It was found that the genes of the serotonergic system HTR2A and HTR1B are predictors of the development of some endophenotypes of suicidal behavior in individuals with dependence on synthetic cathinones.


Assuntos
Alcaloides , Transtornos Relacionados ao Uso de Substâncias , Suicídio , Proteínas da Membrana Plasmática de Transporte de Dopamina , Endofenótipos , Humanos , Masculino , Polimorfismo Genético , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT2A de Serotonina/genética , Transtornos Relacionados ao Uso de Substâncias/genética
2.
Subst Use Misuse ; 55(14): 2438-2442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957797

RESUMO

BACKGROUND: The overwhelming fatalities of the global COVID-19 Pandemic will have daunting epigenetic sequala that can translate into an array of mental health issues, including panic, phobia, health anxiety, sleep disturbances to dissociative like symptoms including suicide. Method: We searched PUBMED for articles listed using the search terms "COVID 19 Pandemic", COVID19 and genes," "stress and COVID 19", Stress and Social distancing: Results: Long-term social distancing may be neurologically harmful, the consequence of epigenetic insults to the gene encoding the primary receptor for SARS-CoV2, and COVID 19. The gene is Angiotensin I Converting-Enzyme 2 (ACE2). According to the multi-experiment matrix (MEM), the gene exhibiting the most statistically significant co-expression link to ACE2 is Dopa Decarboxylase (DDC). DDC is a crucial enzyme that participates in the synthesis of both dopamine and serotonin. SARS-CoV2-induced downregulation of ACE2 expression might reduce dopamine and serotonin synthesis, causing hypodopaminergia. Discussion: Indeed, added to the known reduced dopamine function during periods of stress, including social distancing the consequence being both genetic and epigenetic vulnerability to all Reward Deficiency Syndrome (RDS) addictive behaviors. Stress seen in PTSD can generate downstream alterations in immune functions by reducing methylation levels of immune-related genes. Conclusion: Mitigation of these effects by identifying subjects at risk and promoting dopaminergic homeostasis to help regulate stress-relative hypodopaminergia, attenuate fears, and prevent subsequent unwanted drug and non-drug RDS type addictive behaviors seems prudent.


Assuntos
Comportamento Aditivo/genética , Infecções por Coronavirus/metabolismo , Dopamina/metabolismo , Pneumonia Viral/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Betacoronavirus , Infecções por Coronavirus/psicologia , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Regulação para Baixo , Epigênese Genética , Humanos , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/psicologia , Recompensa , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Suicídio , Síndrome
3.
J Pharmacol Sci ; 144(2): 89-93, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763057

RESUMO

l-3,4-dihydroxyphenylalanine (l-DOPA) is a candidate neurotransmitter. l-DOPA is released by nicotine through nicotinic receptors. Recently, G-protein coupled receptor GPR143, was identified as a receptor for l-DOPA. In this study, genetic association studies between GPR143 genetic polymorphisms and smoking behaviors revealed that the single-nucleotide polymorphism rs6640499, in the GPR143 gene, was associated with traits of smoking behaviors in Japanese individuals. In Gpr143 gene-deficient mice, nicotine-induced hypolocomotion and rewarding effect were attenuated compared to those in wild-type mice. Our findings suggest the involvement of GPR143 in the smoking behaviors.


Assuntos
Proteínas do Olho/genética , Deleção de Genes , Estudos de Associação Genética , Glicoproteínas de Membrana/genética , Nicotina/efeitos adversos , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Receptores de Neurotransmissores/genética , Reforço Psicológico , Transtornos Relacionados ao Uso de Substâncias/genética , Animais , Grupo com Ancestrais do Continente Asiático , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de Doença
4.
PLoS Med ; 17(6): e1003137, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479557

RESUMO

BACKGROUND: Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. METHODS AND FINDINGS: Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error. CONCLUSIONS: In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.


Assuntos
Comportamento Autodestrutivo/genética , Idoso , Idoso de 80 Anos ou mais , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Bases de Dados como Assunto , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fatores de Risco , Esquizofrenia , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/etiologia , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , Inquéritos e Questionários , Reino Unido/epidemiologia
5.
Am J Addict ; 29(2): 105-110, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31957106

RESUMO

BACKGROUND AND OBJECTIVES: We examined the allelic variants of N-methyl- d-aspartate receptor 2B (GRIN2B) and analyzed the associations between GRIN2B gene polymorphism with ketamine use conditions and psychopathological symptoms in chronic ketamine users. METHODS: A total of 231 subjects were recruited. Four single nucleotide polymorphisms of GRIN2B, rs1805502, rs7301328, rs890, and rs1806201 were examined in 151 male chronic ketamine users and 80 controls. Psychopathological symptoms in chronic ketamine users were evaluated using the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. RESULTS: The genotype CC of rs1806201 had a lower frequency in ketamine users than that in control subjects (χ2 = 8.167, P = .004) and the T allele frequency of rs1806201 in ketamine users was higher than that in the control subjects (P = .009, odds ratio = 2.019 [1.196-3.410]). Ketamine users of genotype TT and CC of rs1806201 had an earlier onset of ketamine use than subjects of genotype TC (P = .038, P = .049, respectively). The dose of ketamine consumption per day of use was higher in genotype GG of rs7301328 than that in those with CG in ketamine users (P = .026). There were no significant differences of the severity of psychopathologic symptoms among different genotypes tested. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: GRIN2B gene polymorphism may play a role in ketamine abuse. (Am J Addict 2020;29:105-110).


Assuntos
Drogas Ilícitas , Ketamina , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Estudos de Casos e Controles , Doença Crônica , Frequência do Gene , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/psicologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-31948125

RESUMO

Presently, a growing popularity of electronic cigarettes may be observed. Used as a means of obtaining nicotine they allow to substitute traditional cigarettes. The origins of substance use disorders are conditioned by dopaminergic signaling which influences motivational processes being elementary factors conditioning the process of learning and exhibiting goal-directed behaviors. The study concentrated on analysis of three polymorphisms located in the dopamine receptor 2 (DRD2) gene-rs1076560, rs1799732 and rs1079597 using the PCR method, personality traits determined with the Big Five Questionnaire, and anxiety measured with the State Trait Anxiety Inventory. The study was conducted on a group of 394 volunteers, consisting e-cigarette users (n = 144) and controls (n = 250). Compared to the controls the case group subjects achieved significantly higher scores in regard to the STAI state and the trait scale, as well as the NEO-FFI Neuroticism and Openness scale. Likewise, in the case of the STAI state for DRD2 rs1076560 significant differences were found. Furthermore, while comparing the groups (e-cigarette users vs. controls) we noticed interactions for the NEO FFI Neuroticism and DRD2 rs1076560. The same was observed in the case of interactions significance while comparing groups (e-cigarette users vs. controls) for the STAI trait/scale and DRD2 rs1799732. Findings from this study demonstrate that psychological factors and genetic determinants should be analyzed simultaneously and comprehensively while considering groups of addicted patients. Since the use, and rapid increase in popularity, of electronic cigarettes has implications for public health, e-cigarette users should be studied holistically, especially younger groups of addicted and experimenting users.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Personalidade , Receptores de Dopamina D2/genética , Transtornos Relacionados ao Uso de Substâncias/psicologia , Vaping/psicologia , Adolescente , Adulto , Ansiedade/psicologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Neuroticismo , Nicotina , Inventário de Personalidade/estatística & dados numéricos , Fenótipo , Polimorfismo Genético , Transtornos Relacionados ao Uso de Substâncias/genética , Inquéritos e Questionários , Vaping/genética , Adulto Jovem
7.
Genet Test Mol Biomarkers ; 24(1): 17-23, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31940240

RESUMO

Background: Heroin use disorder (HUD) is a complex brain disease that includes multiple phenotypes. Heroin acts primarily as a mu-opioid receptor (OPRM1) agonist. The κ opioid receptor 1 (OPRK1) is critically involved in abstinence and remission. Multiple studies confirm that the OPRM1 and OPRK1 genes are associated with HUD. However, their relationship with the addictive phenotype is still unclear. This study was designed to identify the genetic polymorphisms within OPRM1 and OPRK1 with six HUD phenotypes. Methods: A total of 801 patients with HUD were recruited from the Methadone Maintenance Treatment Program in Xi'an. We identified eight potential functional single nucleotide polymorphisms (SNPs) in the two genes that were genotyped using SNaPshot SNP technology. We then performed a case-control association analysis, investigated particular disease phenotypes, and assessed the extent of epistasis among the variants of the two genes. Results: The OPRK1 rs3802279, rs3802281, and rs963549 genotypes were significantly associated with methadone dosage analyzed by Pearson's chi-square test or binary logistic regression to correct for covariates. The rs3802279 CC, rs3802281 TT, and rs963549 CC genotype carriers required a lower methadone maintenance dose per day. Multifactor dimensionality reduction analysis indicated strong interactions between sex and OPRK1 rs963549. The results of the OPRM1 genotyping did not reveal any associations with the various HUD phenotypes. Conclusion: These findings support an important role of the OPRK1 polymorphism in determining the daily methadone dose and may guide future studies in identifying additional genetic risk factors for HUD.


Assuntos
Dependência de Heroína/genética , Receptores Opioides kappa/genética , Receptores Opioides mu/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Farmacológicos , Estudos de Casos e Controles , China/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Metadona/farmacologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Transtornos Relacionados ao Uso de Substâncias/genética
8.
Drug Alcohol Depend ; 206: 107733, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790978

RESUMO

BACKGROUND: The National Institute on Drug Abuse (NIDA) recently released a Request for Information (RFI) soliciting comments on nonhuman animal models of substance use disorders (SUD). METHODS: A literature review was performed to address the four topics outlined in the RFI and one topic inspired by the RFI: (1) animal models that best recapitulate SUD, (2) animal models that best balance the trade-offs between resources and ecological validity, (3) animal models whose translational value are frequently misrepresented or overrepresented by the scientific community, (4) aspects of SUD that are not currently being modeled in animals, and (5) animal models that are optimal for examining the basic mechanisms by which drugs produce their abuse-related effects. RESULTS: Models that employ response-contingent drug administration, use complex schedules of reinforcement, measure behaviors that mimic the distinguishing features of SUD, and use animals that are phylogenetically similar to humans have the greatest translational value. Models that produce stable and reproducible baselines of behavior, lessen the number of uncontrolled variables, and minimize the influence of extraneous factors are best at examining basic mechanisms contributing to drug reward and reinforcement. CONCLUSIONS: Nonhuman animal models of SUD have undergone significant refinements to increase their utility for basic science and translational value for SUD. The existing literature describes numerous examples of how these models may best be utilized to answer mechanistic questions of drug reward and identify potential therapeutic interventions for SUD. Progress in the field could be accelerated by further collaborations between researchers using animals versus humans.


Assuntos
Modelos Animais , Reforço Psicológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Pesquisa Médica Translacional/tendências , Animais , Humanos , National Institute on Drug Abuse (U.S.)/tendências , Recompensa , Especificidade da Espécie , Transtornos Relacionados ao Uso de Substâncias/genética , Pesquisa Médica Translacional/métodos , Estados Unidos
9.
Drug Alcohol Depend ; 206: 107710, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734033

RESUMO

Heredity is an important risk factor for alcoholism. Several studies have been conducted on small groups of alcohol naïve adolescents which show lowered fractional anisotropy of frontal white matter in individuals with a family history of alcohol and substance use disorder (FH+). We compare large adult FH+ and FH- groups using white matter connectometry, different from the previously used global tractography method, as it is more sensitive to regional variability. Imaging and behavioral data from the Human Connectome Project (WU-MINN HCP 1200) was analyzed. Groups of participants were positive (n = 109) and negative (n = 109) for self-reported alcohol and substance use disorders in at least one parent, and stringently matched. Connectometry was performed on diffusion MRI in DSI-Studio using q-space diffeomorphic reconstruction, and multiple regression was completed with 5000 permutations. Analyses showed decreased major tract (>40 mm) connectivity in the FH+ group in left inferior longitudinal fasciculus, bilateral cortico-striatal pathway, left cortico-thalamic pathway, and corpus callosum, compared to the FH- group. For cognitive tasks related to reward processing, inhibition, and monitoring, there were a number of interactions, such that the relationship between identified tracts and behavior differed significantly between groups. Self-reported family history was associated with decreased connectivity in reward signaling pathways, controlling for alcohol consumption and alcohol use disorder. This is the first connectometry study of FH+, and extends the neural basis of the hereditary diathesis of alcoholism beyond that demonstrated with global tractography. Regions associated with FH+ are similar to those associated with alcohol use disorder.


Assuntos
Alcoolismo/fisiopatologia , Conectoma , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Substância Branca/fisiopatologia , Adolescente , Adulto , Alcoolismo/diagnóstico por imagem , Alcoolismo/genética , Anisotropia , Estudos de Casos e Controles , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Inibição Psicológica , Masculino , Anamnese , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Autorrelato , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Transtornos Relacionados ao Uso de Substâncias/genética , Substância Branca/diagnóstico por imagem , Adulto Jovem
10.
Curr Pharm Biotechnol ; 21(6): 528-541, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31820688

RESUMO

BACKGROUND/AIMS: This case series presents the novel Genetic Addiction Risk Score (GARS®) coupled with a customized pro-dopamine regulator matched to polymorphic reward genes having a hypodopaminergic risk. METHODS: The proband is a female with a history of drug abuse and alcoholism. She experienced a car accident under the influence and voluntarily entered treatment. Following an assessment, she was genotyped using the GARS, and started a neuronutrient with a KB220 base indicated by the identified polymorphisms. She began taking it in April 2018 and continues. RESULTS: She had success in recovery from Substance Use Disorder (SUD) and improvement in socialization, family, economic status, well-being, and attenuation of Major Depression. She tested negative over the first two months in treatment and a recent screening. After approximately two months, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) both showed improvement in various behavioral issues. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD. CONCLUSION: This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided "Pro-Dopamine Regulator" in recovery and enhancement of life.


Assuntos
Comportamento Aditivo/genética , Dopamina/deficiência , Dopamina/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/psicologia , Catecolaminas/uso terapêutico , Criança , Feminino , Predisposição Genética para Doença , Humanos , Monoaminoxidase/uso terapêutico , Neprilisina/uso terapêutico , Núcleo Familiar , Polimorfismo Genético , Recompensa , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia
11.
Drug Alcohol Depend ; 206: 107703, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785998

RESUMO

BACKGROUND: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. METHODS: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. RESULTS: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. DISCUSSION: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.


Assuntos
Usuários de Drogas/psicologia , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Sangue/metabolismo , Encéfalo/metabolismo , Perfilação da Expressão Gênica , Humanos , Metanálise como Assunto , Fenótipo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transcriptoma/genética
12.
Gene ; 733: 144267, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31809838

RESUMO

Genetic variations in the dopamine D4 receptor (DRD4) gene and the serotonin transporter (SLC6A4) gene are involved in the aetiology of substance abuse disorder (SUD). The main aim of this study is to evaluate the genetic association of DRD4 (48 bp-VNTR) and SLC6A4 (rs25531 and 5-HTTLPR VNTR) gene polymorphisms with SUD susceptibility among the Jordanian Arab population. This study included 500 SUD patients and 500 healthy matched controls. The VNTR Genetic polymorphisms of DRD4 and SLC6A4 genes were genotyped using conventional polymerase chain reaction (PCR). While, the rs25531 SNP was genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) technique. The genetic association was analysed using different statistical analyses including chi-square, Fisher exact test and one way ANOVA test. The DRD4 exon III VNTR polymorphism was associated with SUD significantly in case of alleles 4, 7 and genotype 7/7 (P = 0.004, 0.0005 and 0.01, respectively). While, there was no genetic association between the 5-HTTLPR (LL, LS, SS), rs25331 (AA, AG, GG) and tri-allelic (SASA, LASG, LASA, LALG, LALA) genotypes (P = 0.26, 0.71 and 0.52, respectively) and SUD. Moreover, using multinomial regression analysis, the homozygous 7/7 and 2/2 VNTR genotypes of DRD4 gene were nominally significantly associated with a lower risk of addiction (OR = 0.285 with P = 0.003 and OR = 0.447 with P = 0.031, respectively) after adjusting for other covariates. Our findings showed that 4 and 7 repeats and the genotype 7/7 of DRD4 exon III VNTRs polymorphism are involved in the aetiology of SUD among Jordanian population in compared to the 5-HTTLPR polymorphisms.


Assuntos
Receptores de Dopamina D4/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Alelos , Árabes/genética , Estudos de Casos e Controles , Éxons/genética , Frequência do Gene/genética , Genótipo , Homozigoto , Humanos , Jordânia/epidemiologia , Masculino , Repetições Minissatélites/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Receptores de Dopamina D4/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
13.
Psychiatr Genet ; 30(1): 34-38, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31568069

RESUMO

Studying the relationship between mental illnesses and their environmental and genetic risk factors in low-income countries holds excellent promises. These studies will improve our understanding of how risk factors identified predominantly in high-income countries also apply to other settings and will identify new, sometimes population-specific risk factors. Here we report the successful completion of two intertwined pilot studies on khat abuse, trauma, and psychosis at the Gilgel Gibe Field Research Center in Ethiopia. We found that the Gilgel Gibe Field Research Center offers a unique opportunity to collect well-characterized samples for mental health research and to perform genetic studies that, at this scale, have not been undertaken in Ethiopia yet. We also supported service development, education, and research for strengthening the professional profile of psychiatry at the site.


Assuntos
Catha/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto , Estudos Transversais , Etiópia/epidemiologia , Estudos de Viabilidade , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Fenótipo , Transtornos Psicóticos , Fatores de Risco
14.
Handb Exp Pharmacol ; 258: 31-60, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31628598

RESUMO

Excessive abuse of psychoactive substances is one of the leading contributors to morbidity and mortality worldwide. In this book chapter, we review translational research strategies that are applied in the pursuit of new and more effective therapeutics for substance use disorder (SUD). The complex, multidimensional nature of psychiatric disorders like SUD presents difficult challenges to investigators. While animal models are critical for outlining the mechanistic relationships between defined behaviors and genetic and/or molecular changes, the heterogeneous pathophysiology of brain diseases is uniquely human, necessitating the use of human studies and translational research schemes. Translational research describes a cross-species approach in which findings from human patient-based data can be used to guide molecular genetic investigations in preclinical animal models in order to delineate the mechanisms of reward circuitry changes in the addicted state. Results from animal studies can then inform clinical investigations toward the development of novel treatments for SUD. Here we describe the strategies that are used to identify and functionally validate genetic variants in the human genome which may contribute to increased risk for SUD, starting from early candidate gene approaches to more recent genome-wide association studies. We will next examine studies aimed at understanding how transcriptional and epigenetic dysregulation in SUD can persistently alter cellular function in the disease state. In our discussion, we then focus on examples from the literature illustrating molecular genetic methodologies that have been applied to studies of different substances of abuse - from alcohol and nicotine to stimulants and opioids - in order to exemplify how these approaches can both delineate the underlying molecular systems driving drug addiction and provide insights into the genetic basis of SUD.


Assuntos
Transtornos Relacionados ao Uso de Substâncias/genética , Pesquisa Médica Translacional , Animais , Estudo de Associação Genômica Ampla , Humanos , Recompensa , Transtornos Relacionados ao Uso de Substâncias/terapia
15.
Rev. toxicol ; 37(1): 3-5, 2020. tab
Artigo em Inglês | IBECS | ID: ibc-194437

RESUMO

Previous work revealed that the levels of cluster in in biological fluids are associated with loss of control over eating and with the duration and intensity of tobacco use in humans. In non-human primates, chronic cocaine upregulates clusterin gene expression in the nucleus accumbens, a key area in addiction. All these findings have led to suggest that clusterin could be associated with the presence of different kind of addictive behaviours. In this work possible associations between clusterin gene polymorphisms and drug use disorder were studied. Forty-four selected single nucleotide polymorphisms (SNPs) of the clusterin gene were studied in DNA samples from 499 subjects diagnosed of substance use disorder (addicted to alcohol, cocaine or both) and 500 control subjects. Genotyping was performed by using a multiplexing assay and data were analysed with logistic regression. Four SNPs(rs867231, rs867232, rs9331896 and rs11787077) were found significantly associated with the presence of substance use disorder. These associations further extend the hypothesis that clusterin could be a relevant protein in addiction


Estudios previos han encontrado una asociación entre los niveles de clusterina en fluidos biológicos y la pérdida de control sobre la ingesta, así como entre dichos niveles y la duración e intensidad del consumo de tabaco. Por otra parte, la administración crónica de cocaína a primates no humanos incrementa la expresión del gen de clusterina en el Núcleo Accumbens, una región cerebral clave en las adicciones. Estos antecedentes sugieren que la clusterina podría estar implicada en distintos tipos de trastornos adictivos. En este trabajo se han estudiado posibles asociaciones entre polimorfismos de un solo nucleótido (single nucleotide polymorphisms, SNP) del gen de clusterina y trastornos por consumo de sustancias (TCS). Se genotiparon 44 SNP en muestras de ADN procedentes de 499 sujetos diagnosticados de TCS (adictos al alcohol, cocaína o ambas drogas) y 500 sujetos control. Para la secuenciación y el genotipado se utilizó la plataforma Sequenom y el análisis estadístico de los resultados se realizó mediante regresión logística. Se detectó una asociación significativa entre 4 SNP (rs867231, rs867232, rs9331896 y rs11787077) y la presencia de TCS. Estos resultados apoyan la hipótesis de que clusterina es una proteína relevante en las adicciones


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/genética , Polimorfismo de Nucleotídeo Único/genética , Polimorfismo Genético/genética , Clusterina/genética , Estudos de Casos e Controles , Genótipo
16.
Syst Rev ; 8(1): 298, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31787100

RESUMO

BACKGROUND: The present protocol was designed for a systematic review and meta-analysis aimed at determining the association of telomere length with substance use disorders with the exclusion of nicotine addiction, and to identify potential moderators of the effect of telomere length. Such methodological information may provide guidance to improve the quality of future research on this important topic. METHODS: Potential studies will be identified through electronic databases (PubMed/MEDLINE, EMBASE, PsycINFO, and Web of Science) up from inception onwards. The inclusion criteria will include published or unpublished observational studies (cohort, case-control, and cross-sectional studies) reporting telomere length in adult patients with substance use disorder compared with a control group. Non-human studies or other study designs such as reviews, case-only, family-based, and/or population studies with only healthy participants will be excluded, as well as those focused solely on nicotine addiction. The main outcome will be telomere length in adults with substance use disorder (primary) and, specifically, in those with alcohol use disorder (secondary). Two investigators will independently evaluate the preselected studies for possible inclusion and will extract data following a standardized protocol. Disagreements will be resolved by consensus. The risk of bias of all included studies will be assessed using the Newcastle-Ottawa Quality Assessment Scale for non-randomized studies. Data will be converted into standardized mean differences as effect size index, and random-effects models will be used for the meta-analysis. Cochran's Q statistic, I2 index, and visual inspection of the forest plot will be used to verify study heterogeneity. Subgroup analyses and meta-regressions will be conducted to ascertain heterogeneity. Several sensitivity analyses will be conducted to address the influence of potential confounding factors. Publication bias will be examined using the "funnel plot" method with Duval and Tweedie's trim-and-fill method and Egger test. DISCUSSION: This systematic review will assess the association of telomere length with substance use disorders aside from nicotine addiction. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019119785.


Assuntos
Metanálise como Assunto , Projetos de Pesquisa , Transtornos Relacionados ao Uso de Substâncias/genética , Revisões Sistemáticas como Assunto , Homeostase do Telômero , Humanos
17.
Int J Mol Sci ; 20(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31771126

RESUMO

The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor (GPCR), plays an essential role in the control of many physiological processes such as hunger, memory loss, gastrointestinal activity, catalepsy, fear, depression, and chronic pain. Therefore, it is an attractive target for drug discovery to manage pain, neurodegenerative disorders, obesity, and substance abuse. However, the psychoactive adverse effects, generated by CB1R activation in the brain, limit the use of the orthosteric CB1R ligands as drugs. The discovery of CB1R allosteric modulators during the last decade provided new tools to target the CB1R. Moreover, application of the site-directed mutagenesis in combination with advanced physical methods, especially X-ray crystallography and computational modeling, has opened new horizons for understanding the complexity of the structure, function, and activity of cannabinoid receptors. In this paper, we present the latest advances in research on the CB1R, its allosteric modulation and allosteric ligands, and their translational potential. We focused on structural essentials of the cannabinoid 1 receptor- ligand (drug) interactions, as well as modes of CB1R signaling regulation.


Assuntos
Agonistas de Receptores de Canabinoides/química , Receptor CB1 de Canabinoide , Regulação Alostérica , Animais , Agonistas de Receptores de Canabinoides/uso terapêutico , Cristalografia por Raios X , Humanos , Mutagênese Sítio-Dirigida , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Dor/tratamento farmacológico , Dor/genética , Dor/metabolismo , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo
18.
Drug Alcohol Depend ; 205: 107696, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726429

RESUMO

BACKGROUND: Cannabis use patterns vary considerably, with many users reporting simultaneous and non-simultaneous use (co-use) of other substances. Despite this, little research has examined the extent to which subtypes of cannabis users may be identified based on their simultaneous and co-use behaviors. METHODS: The sample consisted of adult Australian twins and siblings who reported lifetime cannabis use (n = 2590). A latent class analysis was conducted to determine subtypes of cannabis users based on five indicators of substance co-use and simultaneous use. Adolescent correlates (age of substance initiation and conduct disorder) and adult correlates (substance use/disorder and depression) of class membership were assessed. Twin similarity for class membership was also examined. RESULTS: Four subtypes of users were identified: 1) alcohol co-users, 2) simultaneous alcohol users, 3) simultaneous tobacco users, and 4) simultaneous alcohol, tobacco, and drug users. Compared to co-users of alcohol, simultaneous alcohol users were at increased risk for alcohol problems. Patterns of use that involved simultaneous tobacco and cannabis use (i.e., simultaneous tobacco users and simultaneous alcohol, tobacco, and drug users) were associated with the most problematic outcomes, including substance use and disorder. There was evidence for genetic influences (12-58%) on cannabis use patterns, with higher concordance for latent class membership among monozygotic compared to dizygotic twins (χ2 (1) = 7.19, p = 0.007). CONCLUSIONS: The current study identified four classes of cannabis users at varying degrees of risk. Results suggest that simultaneous tobacco and cannabis use may be especially associated with deleterious outcomes.


Assuntos
Fumar Maconha/epidemiologia , Fumar Maconha/genética , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Austrália/epidemiologia , Estudos de Coortes , Usuários de Drogas/psicologia , Feminino , Humanos , Masculino , Fumar Maconha/psicologia , Sistema de Registros , Transtornos Relacionados ao Uso de Substâncias/psicologia , Gêmeos Dizigóticos/psicologia , Gêmeos Monozigóticos/psicologia , Adulto Jovem
19.
Adv Exp Med Biol ; 1192: 53-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31705490

RESUMO

Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.


Assuntos
Comportamento Aditivo/genética , Depressão/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Esquizofrenia/genética , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Marcadores Genéticos , Humanos , Psiquiatria
20.
Transl Psychiatry ; 9(1): 247, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586043

RESUMO

Playing an important role in the etiology of substance use disorder (SUD), dopamine (DA) neurons are subject to various regulations but transcriptional regulations are largely understudied. For the first time, we report here that the Human Immunodeficiency Virus Type I Enhancer Binding Protein 2 (HIVEP2) is a dopaminergic transcriptional regulator. HIVEP2 is expressed in both the cytoplasm and nuclei of DA neurons. Therein, HIVEP2 can target the intronic sequence GTGGCTTTCT of SLC6A3 and thereby activate the gene. In naive rats from the bi-directional selectively bred substance-preferring P vs -nonpreferring NP rat model of substance abuse vulnerability, increased gene activity in males was associated with the vulnerability, whereas decreased gene activity in the females was associated with the same vulnerability. In clinical subjects, extensive and significant HIVEP2-SLC6A3 interactions were observed for SUD. Collectively, HIVEP2-mediated transcriptional mechanisms are implicated in dopaminergic pathophysiology of SUD.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Fatores de Transcrição/genética , Animais , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Ratos , Fatores Sexuais , Transtornos Relacionados ao Uso de Substâncias/etiologia , Fatores de Transcrição/metabolismo
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