List of Abbreviations: conditioned place preference (CPP); delta-opioid (DOPr); ethylketocyclazocine (EKC); Food and Drug Administration (FDA); kappa-opioid receptors (KOPr); mu-opioid receptor (MOPr); nociceptin receptor (NOPr); percentage of maximum possible effect (% MPE); Warm Water Tail Withdrawal (WWTW).

Major depressive disorder is a highly common disorder, with a lifetime prevalence in the USA of approximately 21 %. Traditional antidepressant treatments are limited by a delayed onset of action and minimal efficacy in some patients. Ketamine is effective and fast-acting, but there are concerns over its abuse liability. Thus, there is a need for safe, fast acting antidepressant drugs. The opioid buprenorphine shows promise but also has abuse liability due to its mu-agonist component. Preclinical evidence indicates that the delta-opioid system contributes to mood disorders and delta opioid agonists are effective in preclinical models of depression-and anxiety-like states. In this study we test the hypothesis that the mu-opioid antagonist diprenorphine by virtue of its partial delta opioid agonist activity may offer a beneficial profile for an antidepressant medication without abuse liability. Diprenorphine was confirmed to bind with high affinity to all three opioid receptors, and functional experiments for G protein activation verified diprenorphine to be a partial agonist at delta-and kappa-opioid receptors and a mu-antagonist. Studies in C57BL/6 mice demonstrated that an acute dose of diprenorphine produced antidepressant-like effects in the tail suspension test and the novelty-induced hypophagia test that were inhibited in the presence of the delta-selective antagonist, naltrindole. Diprenorphine did not produce convulsions, a side-effect of many delta agonists, but rather inhibited convulsions caused by the full delta agonist SNC80; however, diprenorphine did potentiate pentylenetetrazole-induced convulsions.Diprenorphine, and compounds with a similar pharmacological profile, may provide for efficient and safe rapidly acting antidepressants.