Sleep deprivation boosts effects of drugs and furthers chemical dependence

In a study using rats, sleep-deprived individuals developed amphetamine dependence after only two sessions with administration of the drug.

By José Tadeu Arantes  |  Agência FAPESP – Sleep deprivation has become a worldwide epidemic. Research conducted in the United States shows that the number of adults who slept six hours or less rose 31% between 1985 and 2012. In an interview given to UK newspaper The Guardian, Matthew Walker, director of the Center for Human Sleep Science at the University of California, Berkeley, says sleep deprivation is widespread in society today and affects every aspect of our biology. Among other consequences, he mentions powerful links between sleep loss and disorders such as obesity, diabetes, heart disease, stroke, Alzheimer’s and cancer. 

Another important consequence, which has recently been highlighted by a study in animal models conducted by researcher Laís Fernanda Berro and colleagues, is that sleep deprivation potentiates the effects of amphetamine, furthering the development of behavioral patterns associated with chemical dependence. An article on the study has been published in Neuroscience Letters.

“Sleep has become a bargaining chip for contemporary society,” Berro told Agência FAPESP. “We sacrifice sleep to many other activities, such as work, leisure, participation in social networks, and so on. An association between sleep deprivation and the use of psychostimulants such as amphetamine or cocaine, among others, has become very frequent, not just at parties and raves but also among professionals who work long shifts, such as hospital nurses and doctors, truck drivers, and so on. Our study shows that sleep deprivation exacerbates the effect of such drugs and contributes to chemical dependence.” 

Berro has a PhD in medicine and sleep biology from the Federal University of São Paulo’s Medical School (EPM-UNIFESP) in Brazil. Currently, she is completing postdoctoral research at the University of Mississippi Medical Center (UMMC). 

“The studies reported in the literature say four sessions are required to condition animals to the use of amphetamines. Our research shows that two sessions suffice when they’re associated with sleep deprivation,” she said. Her method was tailored to the investigation of “conditioned place preference” (or place conditioning), which assesses the reinforcing effects of drugs based on Pavlovian conditioning. 

“We used an apparatus consisting of two compartments, one with white walls and a black floor and the other with black walls and a metallic floor. We administered the drug of abuse – in this case amphetamine – in one of the compartments. On the following day, we put a rat without administering the drug in the other compartment. This created a ‘drug-paired’ place and a neutral place. After a few sessions, the conditioned animal tended to choose the drug-paired place even when it wasn’t given the drug,” Berro said. 

The object of the study was to determine whether sleep deprivation could lead to conditioning in a smaller number of sessions than the four described in the literature. This was indeed the case.

A total of 25 rats were used: 13 with sleep deprivation and 12 as a control group. After two sessions with amphetamine, none of the controls had developed conditioning, but all of the sleep-deprived animals had. “This confirmed our hypothesis that sleep deprivation boosts the effects of amphetamine and contributes to the establishment of chemical dependence,” Berro said.

“Of course, it’s always problematic to transpose the findings of experiments in animal models to humans, but after all, that’s why we do experiments with animals. This experiment allows us to state that a sleep-deprived person who uses amphetamine will be more likely to develop conditioning between the effects of the drug and ‘environmental cues’, meaning the characteristics of the environment.”

Drug-environment association

An association between the effects of a drug and the environment is highly prevalent in the lives of chemically dependents individuals. Indeed, environmental cue conditioning is one of the main challenges of the requisite treatment. 

“Even when chemically dependent individuals decide they want to give up a drug and have the wherewithal and sufficient willpower to spend three months in a rehabilitation clinic getting clean, it’s very hard for them to return after all this to the environment in which they previously used the drug without a relapse,” Berro said. “When people return, the environmental cues associated with the effects of the drug – ranging from just hearing a tune to meeting up with a friend – are sufficient for them to recall the effects of the drug and feel a craving to use it again.” 

The drug-environment association is multifactorial, but it has a significant biochemical basis. “There’s a specific brain region called the nucleus accumbens where drugs of abuse trigger a rise in dopamine levels. All mammals have this brain structure. Increased dopamine levels in this structure are linked to the formation of memories that are important to survival,” Berro said. 

“Eating, having sex, fight-or-flight experiences, all of these lead to a rise in dopamine, creating memories designed to perpetuate the existence of that individual and of the species. Drugs of abuse also increase dopamine levels, and they provide the biochemical substrate for the association between the rewarding effects of the drug and the environmental cues. If a person has been conditioned, all they need is to come into contact with the environment, and at once their nucleus accumbens releases more dopamine, leading to a recall of the drug’s effects and a craving for the drug.” 

The nucleus accumbens is located in the mesolimbic system, a very old and primitive brain region. From time immemorial, humans have used drugs that boost the release of dopamine there. The same is true of animals. This is why substance dependence is so recalcitrant. The prefrontal cortex, which is involved in managing complex processes such as reason, logic and problem solving, is much more recent. Its normative power is weak compared with the drives anchored in the limbic system.

“The main mechanism through which sleep deprivation boosts the effects of drugs of abuse also appears to be associated with the mesolimbic dopaminergic pathway, to which the nucleus accumbens belongs. Studies have shown that sleep deprivation in rats leads to increased dopamine levels in the basal forebrain, which plays a key role in sleep-wake control. So far, we don’t have evidence of increased dopamine levels in the nucleus accumbens, but behavioral studies strongly suggest this. Sleep deprivation makes animals behave in ways that mimic behaviors caused by psychostimulants or potentiate them,” Berro said.

“Furthermore, we know that sleep deprivation in both rodents and humans alters the availability of dopaminergic receptors in the striatum. It’s also been shown that sleep deprivation in humans heightens the mesolimbic system’s reactivity to pleasure-evoking stimuli. This may be a biochemical basis for the development of dependence on drugs of abuse.” 

The article “Sleep deprivation precipitates the development of amphetamine-induced conditioned place preference in rats” (https://doi.org/10.1016/j.neulet.2018.02.010) by Laís F. Berro, Sergio B. Tufik, Roberto Frussa-Filho, Monica L. Andersen and SergioTufik can be retrieved from sciencedirect.com/science/article/abs/pii/S0304394018300831.