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

D'ADDARIO, CLAUDIO; WILLE-BILLE, ARANZA; PAUTASSI R.M.

Palermo

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

Università degli Studi di Palermo

Several experiments indicated that moderate prenatal ethanol exposure (PEE, 1-2 g/kg, gestational days 17 to 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.Pregnant Wistar rats received daily intragastric administration of ethanol (0.0 or 2.0 g/kg). Female and male offspring were tested at infancy or adolescence for anxiety response in a Light-Dark Box Test shelter-seeking and risk-taking behaviours in the concentric square field (CSF) test, subsequent voluntary ethanol consumption, in an intermittent 18-hours protocol, gene expression of kappa opioid system, predynorphin (PDYN) and kappa opioid receptor (KOR), thought rt-PCR, DNA methylation in the gene promoter of PDYN and KOR using pyrosequencing, in areas of mesocorticolimbic circuit.PEE was associated with elevated anxiety response in infants, with greater avoidance of brightly areas in the LBD and CSF tests, and greater preference for shelter compartment in the CSF test, and with a blunted response to the stimulant effects of ethanol during adolescence. PEE male, adolescent, rats consumed significantly higher amounts of alcohol than control peers. Moreover, PEE upregulated PDYN and KOR mRNA levels in ventral tegmental area, accompanied by a reduction of DNA methylation at the gene promoter, and KOR mRNA levels in the Prefrontal Cortex in infant rats.These results confirm that a 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 behaviour and gene expression that could be responsible of the facilitatory effects of PEE