Getting enough sleep, much like eating food and drinking water, is essential for human survival. We need snooze time to repair bodily damage, process the day's events and encode memories, and keep the immune system and metabolism operating smoothly.
Sleep also profoundly alters reward-seeking and behavior. Bad sleep can put people at risk for worse decisions, including using or abusing alcohol and drugs.
The team found that in mice, sleep deprivation enhanced the rewarding properties of cocaine, a shift driven by orexin activity. By blocking the orexin system, scientists could mitigate bad sleep's negative cascade of effects on drug-seeking in the animals.
"Sleep disturbance can influence the rewarding properties of cocaine in an orexin system-modulated manner," study co-author Theresa Bjorness, a psychiatry researcher at UT Southwestern, tells Inverse.
These early findings still need to be replicated in humans. But down the line, researchers say the findings could inform new ways of treating addiction and substance abuse in people.
"Therapeutically, this is important because it certainly directs attention to the fact that one might be able to treat problems with sleep and problems with addiction — which go hand in hand — with one drug," Robert Greene, also a co-author, tells Inverse. Greene is a neuroscientist at UT Southwestern.
This potential therapeutic "may not be that far away," Greene adds, noting that humans also have a similar orexin system as the mice and that there are already drugs approved by the Food and Drug Administration that manipulate this system.
The science of seeking reward — For decades, scientists have known cocaine and sleep have a bidirectional relationship: Using cocaine disrupts sleep, while too little sleep makes people likelier to use cocaine. What they haven't understood is which part of the brain is regulating this dynamic and guiding behavior, and how sleep deprivation directly contributes to cocaine addiction.
To shed light on this question, researchers conditioned a group of mice to associate a certain room with cocaine and analyzed how sleep deprivation affected their ability to develop a preference for that space.
They discovered sleep-deprived mice formed a preference for a lower dose of cocaine, a dose that did not affect rested mice. They also had a stronger preference for a standard cocaine dose, indicating they found cocaine more rewarding than rested mice. The increased cocaine-seeking was also stronger in mice who experienced sleep deprivation within four hours of the drug experiment.
Researchers then looked at where these changes originated in the brain and found that the orexin system, a group of neurons that regulate appetite, mood, and wakefulness, was engaged. Orexin activity increases when animals and people are sleep deprived.
Next, the team blocked the orexin system and in turn, reduced the increased cocaine preference driven by sleep deprivation. This result suggests that manipulating the orexin system could buffer the effects of poor sleep on drug-seeking behavior.
"The results of reward-seeking enhancement following sleep deprivation were expected based on similar experiments using amphetamine and methylphenidate and the role of the orexin system was anticipated based on numerous other studies showing that this system plays a role in motivation," Bjorness says.
What's next? — The study follows growing evidence detailing how sleep impacts drug- and reward-seeking. Other studies show chronic sleep deprivation and insomnia heighten drug cravings and can contribute to impulsivity and relapse.
"This is what happens with drug addiction," Greene says.
"When you're coming off a drug like cocaine and when you're abstinent for a little bit, this disrupts your sleep. The disruption of the sleep is going to make your orexin system more active, and that in turn, is going to bias you toward more addictive-like behavior or drug-seeking."
The team saw this dynamic at play in mice models and suspect it is also present in people, although experiments are needed to confirm this suspicion.
Interestingly, because sleep is also involved in consolidating memories, getting too little could hamper people's ability to learn — and sustain — strategies to stay sober or abstain from using substances.
"Sleep disruption results in a cumulation of risk factors that drive drug abuse, including increasing the sensitivity to pain, acting as a stressor, and biasing toward a negative effect," scientists explained in 2019 in the journal Neuropsychopharmacology.
"Despite convergent evidence linking sleep and substance abuse, and the therapeutic potential that can emerge from elucidating the biology underlying this link, this has been a relatively neglected area of research," the team wrote.
This new study brings scientists closer to mapping the underlying mechanisms linking drug use and sleep deprivation. Pinning down the mechanistic details could lead to novel therapies. In fact, research is currently ongoing to test the efficacy of suvorexant, an FDA-approved insomnia medication that acts as an antagonist at orexin receptors, in people with opioid use disorder.
"We've got to pursue this and see if this is a reasonable approach to add to our therapeutic armamentarium to help prevent drug relapse," Greene says.
For now, as research pursues these vital questions, what is known is that if anyone is struggling with addiction, sleep is a fundamental, daily practice to work on. To get better sleep, researchers suggest sleeping in a cool, dark room and establishing a regular bedtime and wake-up routine.
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.