title: Maternal separation is associated with DNA methylation and behavioural changes in adult rats.
abstract: Early life stress is known to promote long-term neurobiological changes, which may underlie the increased risk of psychopathology. Maternal separation (MS) is used as an early life stressor that causes profound neurochemical and behavioural changes in the pups that persist into adulthood. However, the exact mechanism of how MS alters these behavioural changes is not yet understood. Epigenetic modifications, such as DNA methylation, are critical regulators of persistent gene expression changes and may be related to behavioural disorders. The aim of the present study was to investigate whether early life stress on rats could alter cocaine-induced behavioural sensitisation in adulthood via aberrant DNA methylation. We have three main findings: (1) MS increased DNA methyltransferases (DNMTs) expression in the nucleus accumbens (NAc) of infant and adult rats; (2) MS induced DNA hypomethylation on a global level in the NAc, and hypermethylation of the promoter regions of the protein phosphatase 1 catalytic subunit (PP1C) and adenosine A2Areceptor (A2AR) genes, which was associated with their transcriptional downregulation in the NAc; (3) MS-induced molecular changes paralleled an increased response to cocaine-induced locomotor activity and exploratory behaviour in adult rats. Thus, our results suggest that stressful experiences in early life may create a background, via aberrant DNA methylation, which promotes the development of cocaine-induced behavioural sensitisation in adulthood.
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia.
authors: Kaili
authors: K
authors: Anier
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia.
authors: Kristina
authors: K
authors: Malinovskaja
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia.
authors: Katrin
authors: K
authors: Pruus
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia.
authors: Anu
authors: A
authors: Aonurm-Helm
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia.
authors: Alexander
authors: A
authors: Zharkovsky
authors: Department of Pharmacology, Institute of Bio- and Translational Medicine, University of Tartu, 19 Ravila street, Tartu 50411, Estonia. Electronic address: anti.kalda@ut.ee.
authors: Anti
authors: A
authors: Kalda
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008426:Maternal Deprivation; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009714:Nucleus Accumbens / Q000503:physiopathology*; D017397:Prefrontal Cortex / Q000503:physiopathology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology*; D014158:Transcription, Genetic; D000097584:DNA Methyltransferase 3B
chemical_list: D003042:Cocaine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D018765:Dopamine Uptake Inhibitors; D054645:Protein Phosphatase 1; D018341:Receptors, Adrenergic, alpha-2; D000097584:DNA Methyltransferase 3B; C547770:Adra2a protein, rat
keywords: Cocaine; DNA methylation; Maternal separation; Nucleus accumbens; Rat