Investigating the effects of orexin receptor 1 antagonism on decision making under uncertainty

Orexins/hypocretins are neuropeptides produced by several thousand neurons in the lateral hypothalamus. They project widely through the central nervous system where they release orexins which bind to two regionally selective G-protein coupled receptors: OX₁R and OX₂R. Orexins are well known as regulators of the sleep/wake cycle, however, recent investigations into orexinergic modulation of feeding and drug-seeking behaviour suggest they also play a role in reward processing and decision making. In the present study, we investigated the effects of OX₁R antagonism on goal-directed decision making using an operant probabilistic reversal learning (PRL) task. 44 male C57/BL6 mice were dosed daily with an OX₁R selective antagonist (1-SORA-51, 45 mg/kg) or vehicle (20 % w/v TPGS) while performing a PRL task consisting of 5 sessions on 5 consecutive days of probabilistic discrimination learning, followed by 5 sessions of reversal learning, both on and off drug, in a crossover design. Behaviours were then analysed within a reinforcement learning framework. Mice treated with 1-SORA-51 show a significant decrease in learning both initial and reversed reward contingencies, mediated largely through learning from positive outcomes. 1-SORA-51 also increased exploratory behaviours, both during learning and after reward contingencies had been learned. The findings suggest that OX₁R signalling plays multiple roles in decision making in both learning and reward processing, largely by impacting the positive reward domain. As such, OX₁R antagonists may be of therapeutic interest for improving abnormal reward processing and explore-exploit behaviours, such as the heightened sensitivity to drug cues and reduced responses to natural rewards, or heightened delay discounting as observed in people with substance use disorders.