Prenatal Ethanol Exposure induce an anxiety phenotype, enhance voluntary ethanol consumption and alter both DNA methylation and gene expression of kappa opioid system

Palermo

Congreso; 1th International Conference Perinatal Origins of Neuropsychiatric Disorders: from Molecular Mechanisms to Therapeutic Perspectives; 2019

MNS

Several experiments indicate that moderate prenatal ethanol exposure (PEE, 1-2 g/kg, gestational days 17 to 20, GDs 17-20) induces a significant, facilitatory effect on subsequent ethanol consumption in infant or adolescent rats. This effect may be the consequence of PEE enhancing or reducing the appetitive and aversive motivational effects of ethanol, respectively. The mechanisms underlying PEE effects are, however, still elusive. The endogenous opioid system has been proposed as an important target of ethanol?s actions and ethanol exposure seems to alter the developmental trajectory of opioid systems, possibly affecting the hedonic effect of ethanol. The aim of this study was to describe the effect of PEE on subsequent, voluntary ethanol consumption, anxiety response and functionality of opioid system, measured at the offspring?s infancy or adolescence.Pregnant Wistar rats received daily intragastric administration of ethanol (0.0 or 2.0 g/kg, GDs 17-20). Female and male offspring were tested at infancy or adolescence for anxiety response in a Light-Dark Box Test (LDB), for shelter-seeking and risk-taking behaviours in the concentric square field (CSF) test, and for subsequent voluntary ethanol consumption, in an intermittent 18-hours intake protocol. Gene expression of the ligand [i.e., predynorphin (PDYN)] and receptor [kappa opioid receptor (KOR)] of the kappa opioid system was measured via rt-PCR in several areas of the mesocorticolimbic circuit. DNA methylation of the gene promoter of PDYN and KOR was also measured.The PEE offspring exhibited, either at infancy or at adolescence, greater avoidance of the brightly areas of the LBD and CSF, greater shelter-seeking in the CSF test, and a blunted response to the stimulant effects of ethanol. PEE, male adolescent, rats also consumed significantly higher ethanol than control peers. Moreover, PEE significantly upregulated PDYN and KOR mRNA levels in ventral tegmental area, and this effect was accompanied by a reduction of DNA methylation at the corresponding gene promoters. KOR mRNA levels at infancy were also lower in PEE vs. control rats, in the Prefrontal Cortex.These results indicated that even moderate exposure to alcohol during the last days of pregnancy is a risk factor for subsequent enhancement of alcohol intake at adolescence. The study also pinpoints alterations in anxiety response and gene expression that could underlie the facilitatory effects of PEE.