Changes in behavioral effects of delta opioid receptor agonists with ethanol consumption

Alcohol use disorders (AUDs) are a common problem with few effective treatment options. There are only three FDA-approved drugs for the treatment of AUDs, all of which show limited treatment efficacy and none alleviate comorbid anxiety and/or depression. Thus, there is a significant need to identify novel targets for the treatment of AUDs, and the delta opioid receptor (DOR) could represent such a target. DOR agonists have been demonstrated to reduce EtOH consumption in rodent models and have well-established roles in motivation and anxiety. Importantly, the expression and function of DORs are known to change dynamically with a variety of perturbations including EtOH exposure, stress, and pain. This manuscript examines some ways in which the DOR regulation of reward and anxiety behaviors changes with behavioral state. We examined the preference to the DOR-1 agonist DPDPE and the DOR-2 agonist deltorphin in the conditioned place preference paradigm in animals that were either naive or ethanol consuming, as well as either stressed or un-stressed. While neither DPDPE nor deltorphin induced a place preference in naive unstressed animals, deltorphin induced a significant place preference in unstressed ethanol consuming animals. In stressed animals, DPDPE does not induce a place preference whether or not the animals were consuming ethanol. In contrast, deltorphin induces a place preference in ethanol naive stressed animals, however not in animals that were both stressed and ethanol consuming. We also examined the effects of the DOR-1 agonist TAN 67 and the DOR-2 agonist SNC 80 on anxiety-like behavior measured by the marble burying task in both naive and ethanol consuming animals. We found that while SNC 80 showed anxiolytic-like effects in naive animals, TAN 67 did not. However, neither DOR agonist showed an anxiolytic-like effect in ethanol consuming animals. This is in contrast to previous findings with the light/dark transition test in which DOR agonists increased anxiolytic efficacy with ethanol consumption. Together these studies examine DOR effects on reward and anxiety behaviors and further our understanding of how the effects of DOR agonists are dynamically changed by physiological state to help to refine targets for therapeutic development.