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

Introduction: 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 (KORs) is less clear. There is evidence that changes in KOR system function can decrease or increase EtOH drinking, depending on test conditions. For example, female mice lacking preprodynorphin - the precursor to the endogenous KOR ligand dynorphin - have reduced EtOH intake. Considering that KORs can regulate dopamine (DA) transmission, we hypothesized that KORs expressed on DA neurons would play a prominent role in EtOH intake in females. Methods: We used a Cre/loxP recombination strategy to ablate KORs throughout the body or specifically on dopamine uptake transporter (DAT)-expressing neurons to investigate the role of KORs 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 EtOH, although this effect was less pronounced when EtOH intake increased beyond relatively low levels. Discussion: Our findings indicate that KOR activation increases EtOH drinking via effects mediated, at least in part, by KORs 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 EtOH can affect preference and intake.