Good night and good luck: Norepinephrine in sleep pharmacology

Abstract

Sleep is a crucial biological process that is regulated through complex interactions between multiple brain regions and neuromodulators. As sleep disorders can have deleterious impacts on health and quality of life, a wide variety of pharmacotherapies have been developed to treat conditions of excessive wakefulness and excessive sleepiness. The neurotransmitter norepinephrine (NE), through its involvement in the ascending arousal system, impacts the efficacy of many wake- and sleep-promoting medications. Wake-promoting drugs such as amphetamine and modafinil increase extracellular levels of NE, enhancing transmission along the wake-promoting pathway. GABAergic sleep-promoting medications like benzodiazepines and benzodiazepine-like drugs that act more specifically on benzodiazepine receptors increase the activity of GABA, which inhibits NE transmission and the wake-promoting pathway. Melatonin and related compounds increase sleep by suppressing the activity of the neurons in the brain's circadian clock, and NE influences the synthesis of melatonin. Antihistamines block the wake-promoting effects of histamine, which shares reciprocal signaling with NE. Many antidepressants that affect the signaling of NE are also used for treatment of insomnia. Finally, adrenergic receptor antagonists that are used to treat cardiovascular disorders have considerable sedative effects. Therefore, NE, long known for its role in maintaining general arousal, is also a crucial player in sleep pharmacology. The purpose of this review is to consider the role of NE in the actions of wake- and sleep-promoting drugs within the framework of the brain arousal systems.

Introduction

Sleep is one of the most universal biological processes in existence. It is highly conserved, and creatures from Drosophila melanogaster and Caenorhabditis elegans to humans experience at least some form of it [1]. Depriving an organism of sleep altogether can be extremely detrimental, and may even lead to death [2]. Sleep is therefore considered necessary for life, but why this is so remains unclear. Sleep is subdivided into rapid eye movement (REM) sleep, which is characterized by high-frequency electroencephalogram (EEG) recordings and muscle atonia [3], and non-REM (slow-wave) sleep, characterized by low frequency EEG recordings and body rest [4].

Although sleep is a tightly controlled process orchestrated by multiple regulatory systems, sleep disorders do occur, some as a result of disruptions in sleep circuitry, some secondary to other conditions, and others as a result of modern lifestyles. Sleep complaints are in fact the second-leading cause for seeking medical attention, after pain [5]. Sleep disorders can be categorized broadly into conditions of excessive wakefulness (e.g., insomnia) and excessive sleepiness (e.g., narcolepsy, shift-work disorder, jet lag). Insomnia is defined as difficulty falling asleep and maintaining adequate sleep, and is the most commonly reported sleep problem in the United States. In addition to the associated lack of nighttime sleep, there are a host of daytime consequences, as well, such as tiredness, stress, and attentional deficits [5]. Conversely, narcolepsy and hypersomnias involve excessive daytime sleepiness and sleep attacks or unintended napping. This can have a profound impact on an individual's ability to function and limits even basic tasks like driving a car [5]. In addition to the effects these conditions have on sleep itself, problems such as cardiovascular disease and diabetes are often worsened by insufficient sleep [6]. Furthermore, patients with conditions from depression to Parkinson's and Alzheimer's diseases often experience co-morbid sleep disturbances [7], [8], [9]. Thus, medications to treat sleep disorders are a necessity in our society, and understanding the pathways and neurotransmitter systems that regulate sleep is crucial.

Sleep is a global process, controlled by regions throughout the brain and by multiple neurotransmitters and neuropeptides (Fig. 1). The first studies that attempted to localize regions of the brain responsible for sleep maintenance were conducted in the early twentieth century by von Economo, who noticed correlations between sleeping sickness and lesions in certain brain areas [10]. He reported that patients who had encephalitis lethargica and slept for 20 h a day had lesions at the base of the midbrain, and he hypothesized that this site might be the origin for an ascending arousal pathway. Subsequent studies revealed an arousal system with two main branches (reviewed in [11]). The first branch begins in the cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and projects up, relaying through the thalamus, and into the cortex; the second begins in monoaminergic neurons, the noradrenergic locus coeruleus (LC), dopaminergic neurons in the ventral periaqueductal grey (vPAG), the serotonergic dorsal raphe nucleus (DRN), and also the histaminergic tuberomammillary nucleus (TMN), and progresses to the cerebral cortex. These neurons also receive inputs from orexin neurons in the perifornical area of the lateral hypothalamus [12]. The orexins are especially important for controlling transitions between sleep and wake and between stages of sleep, and as a result, disruptions in this system cause narcolepsy [13]. These two branches also interact with the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), mainly via relay through the dorsal medial hypothalamus [14], [15]. This provides the intersection of the homeostatic regulation of sleep, based on accumulated sleep drive or tiredness, and circadian regulation of sleep, based on a 24-h cycle set by the SCN via integration of light inputs from the retina.

While the cholinergic and monoaminergic systems act to promote wakefulness in conjunction with the orexins, there are other neuronal groups that act to promote sleep. The primary population of sleep-promoting neurons is located in the preoptic area, specifically the ventrolateral preoptic area of the hypothalamus (VLPO). These neurons express c-Fos protein and have elevated discharge rates specifically during sleep, and lesions to this area prevent sleep [16], [17], [18]. In addition, these VLPO neurons project to, and share mutual inhibition with, the neuronal groups involved in the ascending arousal pathways [19], [20]. The majority of these cells are GABAergic, though some contain enkephalin and galanin [20], [21]. The interaction of the VLPO neurons with the ascending arousal systems provides what is described by Saper et al. as a “flip-flop switch” that regulates and controls transitions between sleep and wake [11].

As described above, norepinephrine (NE) is one of the main neurotransmitters involved in arousal. LC neurons fire in a wake-dependent manner; they are highly active during wake, slow-firing during non-REM sleep, and almost completely quiescent during REM sleep [22]. The A1 and A2 brainstem noradrenergic nuclei also provide input to regions of the hypothalamus known to be involved in sleep regulation [23]. Pharmacological suppression of LC activity leads to sedation and drives forebrain EEG recordings into sleep-like patterns. We know that dopamine β-hydroxylase knockout (Dbh −/−) mice, which lack norepinephrine, have altered sleep and arousal patterns. They show decreased latency to sleep after stress, require stronger stimuli to wake them after sleep deprivation, and have increased overall sleep, albeit with less REM, in a 24-h period [24], [25], [26]. Pharmacological studies have revealed robust wake-promoting effects of α1- and β-adrenergic receptor (AR) agonists when administered to the medial septal area (MSA) and the medial preoptic area (MPOA), both wake-promoting regions, reviewed in detail by Berridge [23], [27]. Conversely, blockade of ARs results in sedation. These effects appear to be mediated mostly by antagonism of α1ARs, though there are synergistic effects when combined with βAR antagonists. While one group has found that microinjection of the α1AR antagonist prazosin into the MPOA induces sleep rather than wake, the magnitude of changes in wake time were relatively small and depended on ambient temperature [28], [29]. Thus, it seems likely that NE primarily acts through α1ARs in the MPOA to increase wake, although stimulation of α1ARs in this brain region may be sedative under some conditions.

While NE is important for maintaining normal sleep states, it also plays a role in cataplexy. Cataplexy is a component of narcolepsy in which patients experience abrupt transitions from waking into a state akin to REM sleep, with complete muscle atonia. These cataplexy attacks can be spontaneous or triggered by extreme emotion. α1AR antagonism exacerbates cataplexy, as measured both by the number of attacks and duration of the attacks, whereas activation of these receptors decreases the number of attacks [30]. This indicates that disregulated NE signaling, most likely working in conjunction with acetylcholine, is responsible for cataplexy attacks.

In addition to its role in the regulation of normal and pathological sleep, NE is also critical to the efficacy of sleep pharmacotherapies, both wake- and sleep-promoting, which will be the focus of the rest of this review.