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- Vrettou, Maria, et al.
(författare)
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DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure : an explorative study
- 2021
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation and gene expression can be altered by early life stress (ELS) and/or ethanol consumption. The present study aimed to investigate whether DNA methylation of the Vesicular Glutamate Transporters (Vglut)1-3 is related to previously observed Vglut1-3 transcriptional differences in the ventral tegmental area (VTA), nucleus accumbens (Acb), dorsal striatum (dStr) and medial prefrontal cortex (mPFC) of adult rats exposed to ELS, modelled by maternal separation, and voluntary ethanol consumption. Targeted next-generation bisulfite sequencing was performed to identify the methylation levels on 61 5′-cytosine-phosphate-guanosine-3′ sites (CpGs) in potential regulatory regions of Vglut1, 53 for Vglut2, and 51 for Vglut3. In the VTA, ELS in ethanol-drinking rats was associated with Vglut1-2 CpG-specific hypomethylation, whereas bidirectional Vglut2 methylation differences at single CpGs were associated with ELS alone. Exposure to both ELS and ethanol, in the Acb, was associated with lower promoter and higher intronic Vglut3 methylation; and in the dStr, with higher and lower methylation in 26% and 43% of the analyzed Vglut1 CpGs, respectively. In the mPFC, lower Vglut2 methylation was observed upon exposure to ELS or ethanol. The present findings suggest Vglut1-3 CpG-specific methylation signatures of ELS and ethanol drinking, underlying previously reported Vglut1-3 transcriptional differences in the mesocorticolimbic brain.
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| 3. |
- Vrettou, Maria, 1988-
(författare)
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Early life experiences and alcohol use in youth : An emerging role of the Vesicular Glutamate Transporters
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Initiation of alcohol consumption usually takes place during adolescence, a period characterized by a plethora of physical and emotional changes. Towards early adulthood, hazardous drinking patterns can emerge and potentially lead to the development of Alcohol Use Disorder (AUD). Both positive and negative experiences during early life can shape brain development and, through interactions with the genetic make-up, can contribute to the vulnerability of an individual to develop AUD. Epigenetic mechanisms, such as DNA methylation, potentially mediate the effect of environmental influences on gene expression, thus serving as the missing link between gene, environment and phenotype. Among various neuroadaptive changes seen in AUD, those within the glutamatergic system appear particularly prominent, mainly in withdrawal and relapse states, but also in stress-related outcomes. The glutamatergic phenotype can be determined by the expression of the Vesicular Glutamate Transporters 1-3 (VGLUT1-3). To date, the relationship between early life experiences, alcohol consumption, and Vgluts/VGLUTs genes (rodents/humans) in the initial stage of alcohol consumption and during the sensitive period of late adolescence/young adulthood has not been investigated.The present thesis, based on three studies on rodents and one on humans, aimed to examine Vglut/VGLUT1-3 correlates of early life experiences and alcohol drinking during youth. The effect of co-exposure to nicotine, because of its high comorbidity with alcohol use, as well as the role of key DNA methylation-regulating genes was also investigated. The main finding showed that individuals exposed to early life stress were more sensitive to the effect of alcohol on Vglut1-3 mRNA expression and DNA methylation, as well as expression of the DNA methylation-regulating genes, in limbic and striatal brain regions, as compared with controls. In an independent sample, prolonged nicotine co-exposure with alcohol during adolescence was associated with higher Vglut2 expression in the ventral tegmental area of young adult rats. Lastly, the single nucleotide polymorphism rs2290045 in VGLUT2 was found to moderate the environmental sensitivity to alcohol-related problems in humans. Carriers of the minor allele (T) displayed differential susceptibility to the environment; increasing quality of parenting was associated with higher and lower alcohol-related problems in the absence and presence of previous maltreatment, respectively.In conclusion, the findings highlight for the first time the role of Vgluts/VGLUTs in early stress-mediated sensitivity towards alcohol consumption and alcohol-related problems during adolescence and young adulthood, and especially a potential Vglut2/VGLUT2-mediated molecular signature behind the interactive mechanisms of these two aversive environmental factors, as well as of nicotine co-exposure.
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| 4. |
- Vrettou, Maria, et al.
(författare)
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Vesicular glutamate transporter 2 expression in the ventral tegmental area of outbred male rats following exposure to nicotine and alcohol
- 2023
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Ingår i: DRUG AND ALCOHOL DEPENDENCE REPORTS. - : Elsevier. - 2772-7246. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Initiation of use/co-use of nicotine and alcohol, commonly occurring in an episodic manner during adolescence, can imprint vulnerability to the developing brain and lead to addiction. The ventral tegmental area (VTA) is a key heterogeneous region of the mesocorticolimbic circuit involved in the binge-drinking and intoxication step of the addiction circuit. Higher human post-mortem VTA expression of vesicular glutamate transporter 2 (VGLUT2), a marker of the glutamatergic phenotype also expressed in dopaminergic [Tyrosine Hydroxylase (Th)-positive] neurons, has been associated with chronic nicotine use and co-use with alcohol. Methods: The present study aimed to map and characterize the Vglut2- and Th-expressing neurons in the VTA of adolescent male rats exposed or not to prolonged (six-weeks) episodic (three consecutive days/week) nicotine and/or alcohol administration. Nicotine (0.35 mg/kg free base) was injected subcutaneously, whereas alcohol (2 g/kg 20%) was administrated via gavage. Vglut2 and Th mRNA was assessed in the anterior and posterior VTA by use of in situ hybridization. Results: The profile of neurons varied with substance-exposure among VTA subregions. Th-only expressing neurons were more abundant in the posterior VTA of the group exposed to nicotine-only, compared to controls. The same neurons were, on the contrary, less present in the anterior VTA of animals exposed to alcohol-only, who also displayed a higher number of Vglut2-expressing neurons in the lateral anterior VTA. Conclusions: VTA Vglut2- and Th-only neurons seem differentially involved in the effects of adolescent episodic nicotine and alcohol exposure in the anterior and posterior VTA.
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| 6. |
- Vrettou, Maria, et al.
(författare)
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VGLUT2 rs2290045 genotype moderates environmental sensitivity to alcohol-related problems in three samples of youths
- 2019
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Ingår i: European Child and Adolescent Psychiatry. - : Springer. - 1018-8827 .- 1435-165X. ; 28:10, s. 1329-1340
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Tidskriftsartikel (refereegranskat)abstract
- The importance of Vesicular Glutamate Transporter 2 (VGLUT2)-mediated neurotransmission has been highlighted in studies on addiction-related phenotypes. The single nucleotide polymorphism rs2290045 in VGLUT2 has been associated with alcohol dependence, but it is unknown whether or how this association is affected by environmental factors. The present study determined whether the association of alcohol-related problems with the rs2290045 in the VGLUT2 gene was modified by negative and positive environmental factors. Three samples were included: a clinical sample of 131 adolescents followed from age 17 to 22; a general population sample of 1794 young adults; and a general population sample of 1687 adolescents followed from age 14 to 17. DNA was extracted from saliva and the rs2290045 (T/C) was genotyped. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test. Stressful life events (SLE) and parenting were assessed by questionnaires. Gene-environment interactions were investigated using a dual statistical approach. In all samples (effect sizes 0.6-6.2%), and consistent with the differential susceptibility framework, T carriers exposed to SLE reported more alcohol-related problems if they had experienced poor parenting, and lower alcohol-related problems if they had received supportive parenting. T carriers not exposed to SLE reported higher alcohol-related problems if they had received supportive parenting and lower alcohol-related problems if they had received poor parenting. Among CC carriers, alcohol-related problems did not vary as a function of negative and positive environmental factors. In conclusion, in three samples of youths, alcohol-related problems were associated with an interaction of VGLUT2 rs2290045, SLE, and parenting.
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