Early exposure to environmental enrichment modulates the effects of prenatal ethanol exposure upon opioid gene expression and adolescent ethanol intake

Neuropharmacology. 2020 Mar 15:165:107917. doi: 10.1016/j.neuropharm.2019.107917. Epub 2019 Dec 19.


Prenatal ethanol exposure (PEE) promotes ethanol consumption in the adolescent offspring accompanied by the transcriptional regulation of kappa opioid receptor (KOR) system genes. This study analysed if environmental enrichment (EE, from gestational day 20 to postnatal day 26) exerts protective effects upon PEE-modulation of gene expression, ethanol intake and anxiety responses. Pregnant rats were exposed to PEE (0.0 or 2.0 g/kg ethanol, gestational days 17-20) and subsequently the dam and offspring were reared under EE or standard conditions. PEE upregulated KOR mRNA levels in amygdala (AMY) and prodynorphin (PDYN) mRNA levels in ventral tegmental area (VTA) with the latter effect associated with lower DNA methylation at the gene promoter. These effects were normalized by exposure to EE. PEE modulated BDNF mRNA levels in VTA and Nucleus accumbens (AcbN), and EE mitigated the changes in AcbN. EE induced a protective effect on ethanol intake and preference, an effect more noticeable in males than in females, and in prenatal vehicle-treated (PV) than in PEE rats. The male offspring drank significantly less ethanol than the female offspring. The latter result suggests that the protective effect of EE on ethanol drinking may only emerge at lower levels of drinking. In the dams, PEE induced an upregulation of PDYN and KOR in AcbN. PDYN gene expression was normalized by exposure to EE. These results suggest that EE is a promising treatment to inhibit the effects of PEE. The results confirm that PEE effects are mediated by alterations in the transcriptional regulation of KOR system genes.

Keywords: Adolescents; Enviromental enrichment; Ethanol intake; Prenatal ethanol exposure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking*
  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Anxiety / chemically induced
  • Brain / drug effects*
  • Brain / metabolism*
  • Enkephalins / metabolism
  • Environment*
  • Ethanol / administration & dosage*
  • Female
  • Gene Expression Regulation*
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / metabolism
  • Protein Precursors / metabolism
  • RNA, Messenger / metabolism
  • Rats, Wistar
  • Receptors, Opioid, kappa / metabolism*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism


  • Enkephalins
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Opioid, kappa
  • Ethanol
  • preproenkephalin