Targeting the Orexin (Hypocretin) System to Normalize Sleep Disturbances During Cocaine Abstinence

Background Sleep dysregulation is one of the most commonly cited reasons for returning to drug use (relapse) after an extended period of abstinence. In the case of cocaine, sleep disturbances get worse (not better) with periods of extended abstinence, yet conventional hypnotics are not suitable for use among persons with cocaine use disorder due to their high abuse liability. Thus, there is a dire need for alternative therapies to normalize sleep during drug abstinence. Separate literatures link the orexin (hypocretin) system with drug craving and sleep/wake regulation, however, how these roles might intersect to drive relapse during abstinence has not been fully explored. Aims & Objectives Here, we sought to characterize how cocaine alters orexin system function during abstinence and how these changes relate to sleep outcomes. We were particularly interested in whether cocaine might impair diurnal recruitment of 'orexin reserve' neurons and alter the expression of orexin receptors in reward and arousal regions. We also tested if normalizing orexin signaling during the inactive period sleep and reduces relapse risk. Method Male and female Sprague Dawley rats were trained to develop a cocaine conditioned place preference (CPP) or to self-administer cocaine. In one set of experiments, rats were sacrificed at 4h intervals 0-24h after the final cocaine session and brains were processed for immunohistochemical detection of orexin and Fos. Other animals were sacrificed at similar intervals and orexin receptor expression was measured in key reward and arousal brain regions using qPCR. In a second set of rats, sleep was measured using electroencephalography (EEG) and electromyography (EMG) during cocaine extinction sessions; during this period, rats were treated with the dual orexin receptor antagonist suvorexant (or vehicle) 1h prior to the inactive period and tested for cocaine seeking the following day (16h post-treatment, during the active period). Results Cocaine increased the number of immunoreactive orexin neurons and orexin mRNA, indicative of recruitment of 'reserve' orexin neurons; these changes persisted across the day/night cycle during acute abstinence. Orexin receptor levels were increased in several reward and arousal regions during acute cocaine abstinence. These changes in orexin function were associated with profound dysregulation of sleep, characterized by suppression of NREM and increased wakefulness across the inactive period. Treatment with suvorexant normalized sleep and facilitated the extinction of cocaine seeking behavior. Discussion & Conclusions Sleep dysregulation during cocaine abstinence is associated with increased orexin peptide, mRNA and receptor levels across the day-night cycle. Pharmacological normalization of orexin signaling during the inactive period normalizes sleep and reduces next-day drug seeking behavior. Thus, the orexin system represents an attractive target for new treatment approaches designed to normalize sleep and reduce relapse risk in cocaine use disorder.