The antidepressant-like effects of BU10119, a novel kappa opioid receptor antagonist, in the novelty-induced hypophagia task in mice

Antagonists at kappa-opioid receptors have been proposed as novel antidepressants. The standard high-affinity, selective kappa-antagonists have a long lasting duration of action which potentially limits their use (Carroll and Carlezon 2013. J Med Chem 56: 2178-2195). We have previously shown that the combination of buprenorphine (1mg/kg) with naltrexone (1mg/kg) produced a functional short-acting kappa-antagonist, that was non-sedating and non-rewarding, with antidepressant like effects in the forced swim test and novelty-induced hypophagia task (Almatroudi et al. 2015. J. Psychopharmacol. In Press). We have developed a novel compound that combines the properties of buprenorphine/naltrexone combination into a single compound (Cueva et al. 2015. J Med Chem, In Press), thereby simplifying dosing and treatment regimens and avoiding abuse potential. Here, we present preliminary data that BU10119 is a functional kappa antagonist with antidepressant-like effects in mice. Adult male CD-1 mice (8-9 weeks) were used. For novelty-induced hypophagia, mice were individually housed and trained for 3 days to consume condensed milk. On test days, mice were injected intraperitoneally (10 ml/kg) with saline, buprenorphine/naltrexone combination (1 mg/kg), fluoxetine (20 mg/kg) or BU10119 (1mg/kg) one hour prior to testing behaviour. The latency to drink and consumption were recorded in the home cage (day 4) and in the novel cage (day5). One-way ANOVA, revealed that there was a significant effect of drug treatment on the latency to drink in the novel cage (F (4, 45) =9.15, P<0.001) but not consumption (F (4, 45) =1.25, P=0.3). BU10119 is a relatively short acting kappa-antagonist with little efficacy at the mu-opioid receptor. BU10119 has demonstrated activity in the novelty-induced hypophagia test that is consistent with the behavioural effects of fluoxetine and therefore has an antidepressant-like profile.