Open AccessNuclear transcriptional changes in hypothalamus of Pomc enhancer knockout mice after excessive alcohol drinking
Author(s) -
Zhou Yan,
Liang Yupu,
Low Malcolm J.,
Kreek Mary J.
Publication year - 2019
Publication title -
genes, brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.315
H-Index - 91
eISSN - 1601-183X
pISSN - 1601-1848
DOI - 10.1111/gbb.12600
Subject(s) - endocrinology , medicine , proopiomelanocortin , dynorphin , naltrexone , endogenous opioid , vasopressin , hypothalamus , knockout mouse , opioid , κ opioid receptor , receptor , chemistry , opioid peptide , biology
Abstract Persistent alterations of proopiomelanocortin ( Pomc ) and mu‐opioid receptor ( Oprm1 ) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome‐wide deletion of neuronal Pomc enhancer1 (nPE1 −/− ), had hypothalamic‐specific partial reductions of beta‐endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1 +/+ ). We used RNA‐Seq to measure steady‐state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1 +/+ and nPE1 −/− mice after 1‐day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1 −/− had lower basal Pomc and Pdyn (prodynorphin ) levels compared to nPE1 +/+ , coupled with increased basal Oprm1 and Oprk1 (kappa‐opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1 +/+ in the water group, without significant effects on Oprm1 and Oprk1 . In nPE1 +/+ , excessive alcohol intake increased Pomc and Oprm1 , with no effect on Pdyn or Oprk1 . For stress genes, nPE1 −/− had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1 +/+ . In nPE1 +/+ , excessive alcohol intake decreased Oxt and Avpi1 (AVP‐induced protein1) . Functionally examining the effect of pharmacological blockade of mu‐opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1 +/+ , but not nPE1 −/− . Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.