Sex- and β-arrestin-dependent effects of kappa opioid receptor-mediated ethanol consumption

The kappa opioid receptor is a known regulator of ethanol consumption, but the molecular mechanisms behind its actions have been underexplored. The scaffolding protein β-arrestin 2 has previously been implicated in driving ethanol consumption at the related delta opioid receptor and has also been suggested to be a driver behind other negative kappa opioid receptor mediated effects. Here, we used kappa opioid agonists with different efficacies for recruiting β-arrestin 2 and knockout animals to determine whether there is a role for β-arrestin 2 in the modulation of voluntary ethanol consumption by the kappa opioid receptor. We find that an agonist with low β-arrestin 2 efficacy more consistently lowers ethanol consumption than agonists with high efficacy for β-arrestin 2. However, knockdown of β-arrestin 2 amplifies the ethanol consumption-promoting effects of the arrestin-recruiting kappa agonists U50,488 and nalfurafine. We control for potentially confounding sedative effects at the kappa opioid receptor and find that β-arrestin 2 is not necessary for kappa opioid receptor-mediated sedation, and that sedation does not correlate with effects on ethanol consumption. Overall, the results suggest a complex relationship between agonist profile, sex, and kappa opioid receptor modulation of ethanol consumption, with little role for kappa opioid receptor-mediated sedation.