The antidepressant-like effects of combination buprenorphine/naltrexone 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). Buprenorphine is a partial mu-opioid receptor agonist and a kappa-antagonist, while naltrexone is a non-selective opioid antagonist. 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 in mice. Here, we report the effects of this combination treatment on depression-related behaviour. 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 alone (1 mg/kg), naltrexone alone (1 mg/kg), buprenorphine/naltrexone combination (1 mg/kg), norBNI (10mg/kg) or fluoxetine (20 mg/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 (5, 54) =8.5, P<0.001) but not consumption (F (5, 54) =1, P=0.4). The combination of buprenorphine/naltrexone produced antidepressant-like effects, significantly reducing the latency to drink in the novel cage, compared with controls. Interestingly, the effects of the combination treatment were similar to naltrexone alone. We have previously shown that mixed mu-/kappa-opioid receptor antagonists have antidepressant and anxiolytic potential (Casal-Dominguez et al. 2013 J Psychopharm 27:192-202). We are investigating whether combination buprenorphine/ naltrexone may also have anxiolytic potential in mice.