Sleep, And How Cocaine Changes The Brain To Make Treatment So Difficult

• Sleep, sleep disturbances, and circadian rhythms of our biological clock interact with such neurological diseases as drug addiction.
• As a result of cocaine addiction, changes occur within the nucleus accumbens, a brain area involved in reward- and pleasure-motivated behaviors, narrowing the behavioral repertoire to drug-seeking.
• Compulsive cocaine-seeking can develop in rats after extended cocaine use, and an alternative reinforcer enhances the animals' tendency to abstain from drug-seeking when punished by a mild electrical foot shock.
• Intense sweetness can be more addictive than cocaine.
• The changes in neural processing that are induced by cocaine can increase the influence of motor habits and decrease the influence of motivation.

"These new studies focus on three novel but exciting areas in the study of the neurobiology of addiction: the rearrangement of motivational circuits in the basal forebrain, which includes the nucleus accumbens and dorsal striatum, to convey the compulsivity of addiction; the interplay between natural rewards and addiction, with insights into how the natural reward system can be usurped or strengthened; and the profound effects of chronic drugs of abuse on sleep and how this domain is a key area for understanding protracted abstinence and relapse," says George Koob, PhD, of the Scripps Research Institute.

Harold Gordon, PhD, of the National Institute on Drug Abuse, says, "Sleep research is an important gateway to understanding the etiology, course, and implications for improving the treatment of patients who have both sleep disturbances and neurological diseases including addiction."

"Only recently has research focused specifically on the underlying mechanisms of sleep or on natural biological clocks, or circadian rhythms, as an integral part of the disease process of addiction," Gordon says.

According to a recent Institute of Medicine report, about 90 sleep disorders are linked to such diseases as hypertension, diabetes, obesity, depression, and drug addiction.

Studies have found that addictive drugs such as cocaine affect many circadian, or biological clock, genes including CLOCK and NPAS2, which have been shown to regulate dopamine, a brain chemical that underlies the rewarding effects of cocaine.

By administering such addictive drugs as alcohol, the narcotic painkiller fentanyl, and nicotine to animals, scientists have been able to entrain laboratory rats to perform behaviors controlled by a circadian timer, such as running on an exercise wheel. Research with human patients has also underscored the connection between sleep disturbances and addiction.

For example, in one study, human patients addicted to cocaine took much longer to fall asleep. Also, electroencephalographic (EEG) measures of their brain activity showed that they experienced much less deep sleep than did people who did not use the drug. When the subjects were sleep deprived, their immune system had a reduced ability to fight infection.

In another study, heroin patients with less than one year of methadone treatment had poor sleep, the possible cause of which could be measured at the molecular level, Gordon says. Magnetic resonance spectroscopy imaging of these patients showed some energy-indicating molecules in their brain had failed to recover properly after sleep deprivation.

Scientists also have determined that cognitive deficits characteristic of people who regularly use the street drug ecstasy may be based on drug-induced changes in sleep neurobiology. Their altered sleep patterns, cognitive deficits, and impulsivity may be exacerbated by high levels of catecholamines, brain chemicals that the body produces in response to stress.

Studies of former cocaine users demonstrated that they experienced a combination of deficits: They were less vigilant and less able to learn. They also produced deficient sleep EEG recordings. However, these same patients reported that their sleep had improved. Gordon says this disconnect between physiological measures and cognitive self-awareness involved different areas of the brain, including reward and arousal circuits.

"Although the neurobiology underlying the sleep disturbance can be directly related to the disease process itself, it is often impossible to determine cause and effect," Gordon says. "Therefore, it is important to study both sleep and the disease simultaneously to get a full understanding."

Researchers also are trying to identify the neurobiological factors that help explain a recovering addict's vulnerability to relapse.

"Drug addiction is characterized by compulsive drug taking, which occurs even though addicts understand that the behavior is harmful to them. It is also a chronic disorder. Addicts find it extremely difficult to suppress drug taking and often relapse, even after years of abstinence," says Laura Peoples, PhD, of the University of Pennsylvania Medical School.

"The compulsive nature of the behavior and the enduring vulnerability to relapse suggests that drug addiction is accompanied by long-lasting changes in those parts of the brain that underlie motivation and behavioral choice," says Peoples, who will chair a symposium titled "Reconciling Molecular and Electrophysiological Evidence of Cocaine-Induced Neural Plasticity."

She adds that many such changes, or neuroadaptations, have been discovered in studies of animal models of addiction as well as in neuroimaging studies of human addicts. "However, it is not clear which adaptations in which neurons are critically involved in compulsive drug-seeking behavior," Peoples says. "How the adaptations might cause the persistent and compulsive behavior is also not understood. It is thus difficult to develop effective addiction treatments."

One region of the brain that regulates behavioral choice is the accumbens. Previous laboratory animal studies have suggested that repeated cocaine self-administration increases the expression of excitatory neurotransmitter receptors in the accumbens. However, other studies have suggested that repeated cocaine is associated with decreases in activity of the neurons. Peoples says new findings may reconcile these seemingly contradictory observations.

New research also shows that the consequences of repeated cocaine on accumbal neural activity and receptor expression can be either excitatory or inhibitory, depending on the history of cocaine use, duration of abstinence, the level of activity of the neurons during acute cocaine exposure, and the presence or absence of a recent re-exposure to cocaine.

Recent findings have led to a new working hypothesis, that experience- and activity-dependent adaptations cause a progressive and persistent increase in the response of accumbal neurons to excitatory signals that promote drug-seeking relative to the signals that facilitate other motivated behaviors.

This persistent shift in the activity of accumbal neurons would be expected to chronically promote drug-seeking and -taking and could underlie compulsive drug-taking and the enduring vulnerability to relapse, Peoples says.

In other studies, scientists have developed a model system that provides both positive and negative incentives capable of turning animals away from the pursuit of drugs, says Yann Pelloux, PhD, of the University of Cambridge.

To develop new therapeutic strategies for drug addiction, scientists must study animal models that are not based on simple drug self-administration, Pelloux says. Although data from studies with humans are limited, he says they suggest that the negative consequences of drug abuse persuade individuals to abstain from cocaine. Thus, a wide spectrum of social and nonsocial rewards might help people to shift their focus from illicit drugs, he says.

In the study, rats self-administered cocaine and concurrently worked for sucrose. However, when their self-administration was intermittently punished by a mild foot shock, most of the laboratory animals consumed less drug. The presence of sucrose facilitated this punishment-induced suppression of cocaine-seeking. But even though punished, some rats did not decrease their drug use.

"These rats represent a good model of addiction, defined as persistence or compulsive drug-seeking despite its adverse consequences, even in the presence of alternative reinforcers," Pelloux says. "This new model may in the future facilitate the development of novel treatments that promote abstinence."

In another study, scientists determined that a large majority of rats preferred the sweet taste of saccharin when they were allowed to choose mutually exclusively between water with the intense calorie-free sweetener and intravenous cocaine. "The preference for saccharin was not attributable to its unnatural ability to induce sweetness without calories, because the same preference was also observed with sucrose, a natural sugar," says Magalie Lenoir of CNRS, the French National Center for Scientific Research, in Bordeaux. Increasing the doses of cocaine did not lessen the animals' preference for saccharin, which occurred when the animals were intoxicated by cocaine, sensitized to the drug, or when their drug intake escalated. A hallmark of cocaine addiction is increased drug consumption.

"Our findings clearly demonstrate that intense sweetness can surpass cocaine reward, even in drug-sensitized and -addicted individuals," Lenoir says. "We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet taste types."

In most mammals, sweet receptors evolved in ancestral environments poor in sugars. Thus, rats and humans are not adapted to high concentrations of sweet taste types. Lenoir says that the supranormal stimulation of these receptors by sugar-rich diets, such as those now widely available in modern societies, would generate a much higher than normal reward signal in the brain. This increased reward signal potentially could override self-control mechanisms and thus lead to addiction, she says.

Lenoir points out that these results suggest that the current, widespread availability of sugar-rich diets in modern human societies may provide an unsuspected, though highly costly, shield against the further spread of drug addiction.

In other research, scientists found that cocaine-induced changes in neural processing in the striatum increased the influence of motor habits while reducing the influence of affective or motivational information.

Scientists at the University of Maryland at Baltimore examined the effect of previous cocaine-exposure on cue processing in two regions of the striatum, a brain area that plays a critical role in promoting habitual behavior.

Prior cocaine exposure had divergent effects on the processing of reward/punishment-predicting cues in the two striatal regions: It abolished neural activity evoked by these cues in the ventral striatum while marginally enhancing such activity in the dorsolateral striatum.

"This somewhat surprising result suggests that rather than generally enhancing striatal processing of cues, consistent with a generalized effect on habit learning, prior cocaine exposure actually shifts the balance of striatal processing from ventral to dorsal regions," says Yuji Takahashi, PhD.

It has been suggested that repeated exposure to psychostimulants such as cocaine produces long-term changes in the structure and function of several brain regions, including the striatum. Because of the putative role of the striatum in promoting habitual behaviors, changes within this brain area could play a critical role in the development of compulsive or uncontrollable drug-seeking, Takahashi says.

In this study, Geoffrey Schoenbaum, MD, PhD, and Takahashi recorded activity in both the ventral and dorsolateral striatum of two groups of rats: normal, or control, rats and rats previously exposed to a two-week course of cocaine. The control rats were treated with saline while the other rats received cocaine.

Then, between four and 12 weeks after the end of drug treatment, neural activity in the dorsolateral and ventral striatum was recorded while the rats performed a simple odor-guided decision-making task. In this task, a positive odor cue predicted the delivery of a rewarding sucrose solution at a nearby fluid well and a negative odor cue signaled the delivery of an aversive quinine solution. Rats had to use the cues to decide whether to respond at the well on each trial. After the rats learned to respond correctly, the scientists reversed the odor-outcome contingencies to determine whether their decision-making was flexible or habit-like.

"Our finding suggests that drug exposure causes regionally specific effects on neural processing in striatum," Takahashi says. "This would increase the influence of motor habits while decreasing the influence of affective or motivational information."