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.