title: Ethanol affects limbic and striatal presynaptic glutamatergic and DNA methylation gene expression in outbred rats exposed to early-life stress.
abstract: Alcohol use disorder is the outcome of both genetic and environmental influences and their interaction via epigenetic mechanisms. The neurotransmitter glutamate is an important regulator of reward circuits and implicated in adaptive changes induced by ethanol intake. The present study aimed at investigating corticolimbic and corticostriatal genetic signatures focusing on the glutamatergic phenotype in relation to early-life stress (ELS) and consequent adult ethanol consumption. A rodent maternal separation model was employed to mimic ELS, and a free-choice paradigm was used to assess ethanol intake in adulthood. Gene expression levels of the Vesicular Glutamate Transporters (Vglut) 1, 2 and 3, as well as two key regulators of DNA methylation, DNA (cytosine-5)-methyltransferase 1 (Dnmt1) and methyl-CpG-binding protein 2 (Mecp2), were analyzed. Brain regions of interest were the ventral tegmental area (VTA), nucleus accumbens (Acb), medial prefrontal cortex (mPFC) and dorsal striatum (dStr), all involved in mediating aspects of ethanol reward. Region-specific Vglut, Dnmt1 and Mecp2 expression patterns were observed. ELS was associated with down-regulated expression of Vglut2 in the VTA and mPFC. Rats exposed to ELS were more sensitive to ethanol-induced changes in Vglut expression in the VTA, Acb, and dStr and in Dnmt1 and Mecp2 expression in the striatal regions. These findings suggest long-term glutamatergic and DNA methylation neuroadaptations as a consequence of ELS, and show an association between voluntary drinking in non-preferring, non-dependent, rodents and different Vglut, Dnmt1 and Mecp2 expression depending on early-life history.
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Vrettou
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Granholm
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Todkar
authors.affiliation: Västerås Centre for Clinical Research, Uppsala University, Västerås, Sweden.
authors.forename: Kent W
authors.initials: KW
authors.lastname: Nilsson
authors.affiliation: Department of Organismal Biology/Comparative Physiology, Uppsala University, Uppsala, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Wallén-Mackenzie
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Nylander
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Comasco
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002755:Choice Behavior; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008426:Maternal Deprivation; D051783:Methyl-CpG-Binding Protein 2 / Q000187:drug effects / Q000235:genetics; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000187:drug effects / Q000235:genetics; D050599:Vesicular Glutamate Transport Protein 2 / Q000187:drug effects / Q000235:genetics; D050496:Vesicular Glutamate Transport Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: D002492:Central Nervous System Depressants; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; C493475:Slc17a6 protein, rat; C493466:Slc17a7 protein, rat; C482103:Slc17a8 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D050496:Vesicular Glutamate Transport Proteins; D000431:Ethanol; D018698:Glutamic Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619382:Dnmt1 protein, rat
keywords: Alcohol; DNA methylation; Vgluts; glutamate; rats; stress