Kappa‐opioid receptors differentially regulate low and high levels of ethanol intake in female mice

Studies in laboratory animals and humans indicate that endogenous opioids play an important role in regulating the rewarding value of various drugs, including ethanol (EtOH). Indeed, opioid antagonists are currently a front‐line treatment for alcoholism in humans. Although roles for mu‐ and delta‐opioid receptors have been characterized, the contribution of kappa‐opioid receptors ( KOR s) is less clear. There is evidence that changes in KOR system function can decrease or increase Et OH drinking, depending on test conditions. For example, female mice lacking preprodynorphin – the precursor to the endogenous KOR ligand dynorphin – have reduced Et OH intake. Considering that KOR s can regulate dopamine ( DA ) transmission, we hypothesized that KOR s expressed on DA neurons would play a prominent role in Et OH intake in females. Methods We used a Cre/ loxP recombination strategy to ablate KOR s throughout the body or specifically on dopamine uptake transporter ( DAT )‐expressing neurons to investigate the role of KOR s on preference for and intake of EtOH (2‐bottle choice), the transition from moderate to excessive EtOH drinking (intermittent EtOH access), and binge EtOH drinking (drinking in the dark [ DID ]). Results KOR deletion decreased preference for Et OH , although this effect was less pronounced when Et OH intake increased beyond relatively low levels. Discussion Our findings indicate that KOR activation increases Et OH drinking via effects mediated, at least in part, by KOR s on DA neurons. While the mechanisms of this regulation remain unknown, previous work suggests that alterations in negative reinforcement processes or sensitivity to the sensory properties of Et OH can affect preference and intake.