Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep

• Blockade of HCRTr1 reduces cocaine self-administration under high effort conditions.
• Blockade of HCRTr1 does not alter cocaine self-administration under low effort conditions.
• HCRTr1 antagonism does not promote sleep at levels that alter cocaine self-administration.

Recent evidence suggests that blockade of the hypocretin receptor 1 may act as a useful pharmacotherapy for cocaine abuse. Here we investigated the extent to which various doses of a hypocretin receptor 1 antagonist, SB-334867, affect cocaine self-administration at varying doses of cocaine and across a range of effort requirements, and tested if these SB-334867 doses produce sedative effects. First, we trained animals to self-administer one of three doses of cocaine on a progressive ratio schedule, and then tested the effects of three doses of SB-334867. Responding for cocaine was then analyzed to segregate features of relatively high and low effort requirements across the progressive ratio session. In another set of experiments, we tested potential sleep-promoting effects of the same doses of SB-334867. Our data indicate that blockade of hypocretin receptor 1 preferentially reduces high effort responding for cocaine at levels that do not promote sedation.