Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
Bendre Megha,Granholm Linnea,Drennan Ryan,Meyer Ann,Yan Liying,Nilsson Kent W,Nylander Ingrid,Comasco Erika
Alcohol (Fayetteville, N.Y.)
Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. Monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, and exons 5 and 6, together composed of 107 CpGs (5'-cytosine-phosphate-guanosine-3'), in a subgroup of rats. Pyrosequencing was used to analyze the methylation of 10 candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interactive effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption, and Maoa expression in reward-related brain regions.
Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence.
Enoch M-A,Gorodetsky E,Hodgkinson C,Roy A,Goldman D
The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P=0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P=0.01). Both the HTR3B Ser129 allele (P=0.014, odds ratio (OR)=1.7 (1.1-2.6)) and low 5-HTTLPR activity (P=0.011, OR=2.5 (1.3-4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR=6.0 (2.1-16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron.
Childhood Adversities are not a Predictors of SSTR4met in Alcoholics.
Berent Dominika,Pogórski Michał,Kulczycka-Wojdala Dominika,Kusideł Ewa,Macander Marian,Pawłowska Zofia
Background:Genome methylation may modulate synaptic plasticity, being a potential background for mental disorder. Adverse childhood experiences (ACEs), known to be frequently reported by patients with alcohol dependence (AD), have been proposed as one of environmental inequities influencing DNA methylation. The study is aiming 1.To assess a promoter region methylation in gene for somatostatin receptor subtype-4 (), a receptor for somatostatin, a neurotransmitter engaged in neuroplasticity and memory formation, in patients with AD; 2. To verify if promoter methylation is associated with ACEs and other selected environmental factors. Methodology: 176 patients with AD and 127 healthy controls were interviewed regarding 13 categories of ACEs; a structured self-reported questionnaire - to measure the sociodemographic and clinical characteristics; a module of Catalogue of Healthy Behavior - to assess nutritional health habits; the Alcohol Use Disorders Identification Test - to assess drinking severity. The promoter region methylation status was performed via methylation-specific PCR, and the genotyping for the rs2567608 functional polymorphism - according to the manufacturer's standard PCR protocol. Results: promoter region was found methylated in 21.6% patients with AD and 2.3% controls. None of following characteristics: current age, gender, term and kind of labor, 13 categories of childhood trauma, diet, alcohol drinking severity, age at alcohol drinking initiation, age at onset of problem drinking, cigarette smoking, and rs2567608 was a significant predictor for promoter region methylation. Conclusions: promoter region methylation in here studied participants may be either inherited epigenetic modification or secondary, but not to here assessed variables.
Epigenetic mechanisms of alcoholism and stress-related disorders.
Palmisano Martina,Pandey Subhash C
Alcohol (Fayetteville, N.Y.)
Stress-related disorders, such as anxiety, early life stress, and posttraumatic stress disorder appear to be important factors in promoting alcoholism, as alcohol consumption can temporarily attenuate the negative affective symptoms of these disorders. Several molecules involved in signaling pathways may contribute to the neuroadaptation induced during alcohol dependence and stress disorders, and among these, brain-derived neurotrophic factor (BDNF), corticotropin releasing factor (CRF), neuropeptide Y (NPY) and opioid peptides (i.e., nociceptin and dynorphin) are involved in the interaction of stress and alcohol. In fact, alterations in the expression and function of these molecules have been associated with the pathophysiology of stress-related disorders and alcoholism. In recent years, various studies have focused on the epigenetic mechanisms that regulate chromatin architecture, thereby modifying gene expression. Interestingly, epigenetic modifications in specific brain regions have been shown to be associated with the neurobiology of psychiatric disorders, including alcoholism and stress. In particular, the enzymes responsible for chromatin remodeling (i.e., histone deacetylases and methyltransferases, DNA methyltransferases) have been identified as common molecular mechanisms for the interaction of stress and alcohol and have become promising therapeutic targets to treat or prevent alcoholism and associated emotional disorders.