Dual hypocretin receptor antagonism reduces oxycodone seeking and attenuates aberrant dopamine transporter function during abstinence.

A major barrier in the treatment of opioid use disorder is persistent drug craving during abstinence. While opioid-based medications have been used to treat opioid use disorder for decades, there is an urgent need for novel, non-opioid-based pharmacotherapies. The hypocretin/orexin (hypocretin) system is a promising target for treating opioid use disorder due to its influence on motivation for drugs of abuse through actions on dopamine transmission. We recently showed that intermittent access to oxycodone promoted sustained oxycodone seeking and alterations in dopamine transmission during abstinence. In the current studies, we investigated to what extent suvorexant, an FDA-approved dual hypocretin receptor antagonist, reduces oxycodone seeking and restores dopamine function during abstinence in female and male Long Evans rats. Results indicated that intermittent access to oxycodone produced sustained cue-induced oxycodone seeking after a 14-day abstinence period, which was associated with reduced dopamine uptake in the nucleus accumbens core as we have previously shown. Treatment with suvorexant 24 h prior to a cue-induced seeking test significantly reduced oxycodone seeking and attenuated aberrant dopamine uptake. These findings suggest that targeting hypocretin receptors could be a promising strategy for reducing opioid craving and associated neuroadaptations, thus lowering the risk of relapse.