Sleep deprivation enhances conditioned place preference in an orexin receptor modulated manner

Abstract

Drug addiction and withdrawal are characterized by sleep disruption, but the effects of sleep disruption on these states are not well characterized. Sleep deprivation (SD) immediately prior to the cocaine conditioning trials enhanced cocaine conditioned place preference (CPP) in a dose-dependent manner (3, 8 mg/kg but not 15 mg/kg) in mice. SD immediately prior to the post-conditioning test, also enhanced cocaine CPP preference in a dose dependent manner (8 mg/kg, but not 3, 15 mg/kg). Exposure to orexin-receptor antagonism (1 mg/kg SB334867, an orexin 1 receptor antagonist) just prior to cocaine-conditioning trials or the post-conditioning test, attenuated SD-enhanced preference. This suggests a potential therapeutic role for the manipulation of the orexin system to mitigate drug seeking, especially in the context of sleep loss prior to drug exposure.

Significance statement Drugs of abuse, including cocaine, disturb sleep and sleep disturbance has been implicated in probability of relapse; however, there have been few direct tests of sleep disturbance on drug seeking behavior. Here, we show that acute (4h) sleep deprivation enhances the rewarding properties of cocaine, a drug with high abuse potential. Furthermore, antagonism of the orexin system, a neuromodulator involved in motivation-based arousal, reduces this SD-induced enhancement of cocaine preference.