SECTION 1 - BASIC SLEEP SCIENCE

Pharmacology and Pharmacogenetics of Sleep and Walking

Background

The use of sedative/hypnotic and psychostimulant drugs to treat medical conditions such as Attention Deficit Hyperactivity Disorder (ADHD), Insomnia, heart disease, Narcolepsy, Restless Legs Syndrome (RLS), and other medical disorders (Section V), can result in profound effects on normal sleep/wake architecture and perceived sleep quality. In addition, over-the-counter and herbal remedy markets exist to cater to the need to either stay awake or to fall asleep. The two most common substances employed in this capacity are caffeine and ethanol.

Self-medication can lead to dose-related impairments in sleep/wake architecture and in other physiological parameters that indirectly impair sleep/wake quality. The use and misuse of other prescription and recreational drugs including psychostimulants (methamphetamine, cocaine), sedative/hypnotics (barbiturates, benzodiazepines), opiates (heroin, oxycodone), androgenic steroids and so-called "club drugs" (e.g., MDMA), can be accompanied by adverse physiological consequences, including significant alterations in circadian rhythms and sleep/wake architecture.

In addition to these drug-induced effects on normal sleep/wake rhythms, individual differences (including important gender and age factors) in the pharmacological response to drugs are also important. In addition to gender and age effects, these differences also result from genetic differences in pharmacodynamic effects and drug metabolism. However, a wide knowledge gap still exists in understanding the potential role these diverse factors play in sleep/wake pharmacology. Future insights into the pharmacology of arousal states must include greater focus on pharmacogenetic-based studies, both in humans and in appropriate animal models of sleep/wake and circadian rhythm disorders.

Progress In The Last 5 Years

The original 1996 Sleep Disorders Research Plan provided no explicit recommendations regarding the specific investigation of the pharmacology and pharmacogenetics of sleep and arousal. However, implicit in the recommendations was an appreciation of the impact and scope that drugs have on normal sleep/wake processes. Conversely, both primary and secondary sleep disorder phenotypes can be triggers for prescription and non-prescription drug use that may as a side effect exacerbate disturbances in sleep. Building on existing knowledge regarding the effects of a wide spectrum of drugs on sleep and waking behavior, the 1996 Plan has resulted in important, incremental, progress in several relevant areas.

- The increase in the number of investigator-initiated applications and responses to NIH-sponsored initiatives has led to funded research bearing directly on pharmacologic perturbations of the sleep/wake cycle. Relevant areas of research have included (1) efficacy of caffeine on sleep inertia and cognitive performance, (2) pharmacotherapy for sleep/wake disorders in aging, (3) rational pharmacotherapy of primary insomnia, (4) treatment of hypnotic dependence, and (5) the effects of hormone replacement therapy on sleep measures in post-menopausal women. Results from these and other studies have led to a better understanding of drug efficacy in several medical conditions as well as the extent of individual differences in drug effects on sleep/wake measures.

- We now have a better understanding of the effects of prenatal and postnatal cigarette smoke exposure in Sudden Infant Death Syndrome (SIDS) (Section VI), the effects of opioids on REM sleep suppression, the effects of leptin on ventilatory and respiratory control, and the effects of psychopharmacological therapy on sleep in the major mental disorders. Furthermore, there have been important advances in our understanding of the effects of the major drug classes on sleep disorders in animal models and the brain circuits where these drugs are believed to act.

- Pre-clinical neuroscience research has provided new insights into the complex circuitry, neurotransmitters and neuromodulatory substances involved in sleep/wake regulation and their interaction with brain circuits involved in circadian rhythm control. Findings from research in fruit flies, animals and humans have added considerably to our knowledge of the complex regulation of behavioral state. Because of these findings, greater opportunity exists to better understand the actions of drugs on the brain, and also to investigate novel classes of drugs that have non-traditional mechanisms of action on receptor systems within these newly refined brain circuits.

- Research has delineated the molecular basis of Narcolepsy and circadian rhythm disorders (Section V). Genes responsible for these disorders have been positionally cloned and found to code for specific proteins, some of which are receptors for other small molecules that could be targets for chemically synthesized drugs. These might be effective for sleep/wake pharmacology. Indeed, the clinical utility of drugs such as modafinil and gamma-hydroxy butyrate (GHB) for Narcolepsy, and selective dopamine receptor agonists for treatment of RLS, has been demonstrated. In addition, while short-term pharmacologic treatment for Insomnia has been demonstrated to be efficacious, most Insomnia is chronic, not short-term. There have been no carefully conducted studies examining the longer-term pharmacologic treatment of Insomnia, including issues such as efficacy, safety, or the relative advantages of different agents.

- Genome screening and single nucleotide polymorphism (SNP) analysis have been initiated in Sleep-Disordered Breathing (SDB), RLS, Alzheimer's disease, and fatal familial insomnia (Section V). These diseases have major sleep/wake disruptions and are potentially subject to new forms of pharmacotherapy. Individual differences in the response to such treatments may relate to genetic differences.

- New knowledge has been achieved regarding the pharmacotherapy of insomnia in alcoholics, the physiological correlates of chronic alcohol ingestion in both basic and clinical studies, and the interactions between adolescent sleep, life-style and alcohol use. In addition, sleep and the effects of alcohol in alcohol-dependent subjects are now better understood, although more work needs to be done. Alcohol has been shown to alter circadian clock function when exposure takes place in the early postnatal period in rat pups. Studies on selectively bred mice and rats have demonstrated both ethanol-related metabolic variations as well as wide variations in ethanol-induced narcosis, indicating strong genetic regulation of ethanol pharmacology. Ethanol appears to have sensitive, pharmacological actions primarily on brain NMDA and GABA receptor sub-types, offering the possibility of novel pharmacotherapy. In human studies, virtually every type of sleep problem has been observed in alcohol-dependent patients. Their sleep patterns are fragmented and typical encephalographic (EEG) rhythms are altered. Sleep changes persist for months or even years of abstinence, and alterations in sleep architecture appear to be predictive of relapse to alcoholism. Other studies indicate that alcohol aggravates SDB and further increases the decrements in cognitive performance resulting from sleep deprivation. Both gender and ethnic differences in the response to ethanol and other abused drugs have been studied but additional research is needed. Future studies should include studies of sleep/wake measures during drug withdrawal and during relapse to drug taking.

- Morphine and similar opioid drugs cause selective decreases in rapid-eye-movement (REM) sleep through actions on brainstem cholinergic neurons, neurons known to participate in the initiation of this sleep state. This may have relevance for the treatment of pain as well as for understanding treatment efficacy of opioids in RLS.

- Sleep effects of therapeutic psychostimulant treatment in ADHD in both adolescents and adults have received some attention, but results are so far inconsistent. Also, gender differences have not been adequately studied. Particularly in adults, underlying sleep/wake abnormalities have been reported in ADHD patients that can be exacerbated with medication, particularly dextroamphetamine.

Research Recommendations

- Consolidate the recent gains made in the descriptive anatomy and neurochemistry of sleep/wake generating systems by investigating the hierarchies of neurotransmitter interactions within these complex circuits. These studies would facilitate the development of drugs to treat sleep and waking disorders and also lead to a better understanding of the neuropharmacology of behavioral states.

- Encourage studies of the relative efficacy and safety and long-term effects of psychostimulants (e.g. methylphenidate, d-amphetamine, modafinil and caffeine), and hypnotics (particularly benzodiazepine receptor agonists and antidepressants) related to sleep/wake measures in animal models and humans, including appropriate patient populations. These pharmacological assessments should also be assessed with regard to potential interactions and efficacy of behavioral and hormonal therapies.

- In both basic and clinical populations, study inter-individual, gender, racial/ethnic and age-related differences in baseline sleep, circadian physiology, and responses to both prescription and non-prescription pharmacological agents.

- Investigate acute and long-term sleep/wake consequences of all classes of abused drugs (including ethanol) as unique, self-administered pharmacological agents. Both clinical and basic studies are needed.

- Encourage pharmacological studies of genetically/molecularly engineered animal models for sleep disorders. Existing genome databases can be used to elucidate sleep/wake-related response to drug effects and to facilitate the discovery of new targets for sleep/wake disorder medications.

- Encourage development of state-of-the art technologies to measure the effects of drugs on sleep, circadian physiology, and alertness in animal models and human subjects (e.g., genomics, expression arrays, proteomics, neurochemical, chemical, imaging, encephalographic analysis, etc).

- Evaluate whether the identification and treatment of sleep disturbances can improve the clinical course of patients with alcoholism and other substance use disorders.