Neurotransmitters and Sleep

The primary neurochemical/physiology of the sleep-wake cycle is well defined (Fig. 15-1). Sleep onset depends on GABAergic circuitry within the anterior hypothalamus. In contrast, the posterior hypothalamus contains histamine and orexin or hypocretin pathways that promote wakefulness. Wakefulness and consciousness are mainly acetylcholine dependent; however, contributions are also made by norepinephrine, glutamate, and serotonergic pathways. REM sleep is modulated by the serotonergic, noradrenergic system and promoted by acetylcholine and glutamate. Additionally, specific cell populations either activate or inhibit REM.

Figure 15-1 Primary Networks Involved in Sleep-Wake Cycle.

Within the brainstem several nuclei make up the REM sleep center. These normally provide inhibition of spinal motor neurons through the neurotransmitter glycine. Concomitantly these nuclei alter the electroencephalogram with rostral projections that impact thalamocortical systems.

The pineal gland releases melatonin when light-detecting cells within the retina identify the onset of darkness and transmit data to the hypothalamic suprachiasmatic nucleus (SCN). Melatonin has direct effects on the transcription of genes in the SCN that are involved in modulating the biologic clock and the circadian system. Prostaglandins and other neuropeptides may also be important in the modulation of the sleep-wake cycle. Progressive sleep deprivation leads to accumulation of adenosine within the basal forebrain and preoptic hypothalamus; going to sleep reverses this. Caffeine blocks the effects of adenosine. This provides a neurologic basis for why humans have cultivated coffee and our use of caffeine socially to promote wakefulness.

Numerous cholinergic pathways originate from the basal forebrain that project throughout the cortex along with widespread connections from the reticular activating system of the brainstem via thalamocortical projections that promote consciousness and wakefulness as witnessed by an activated EEG. In contrast, cellular networks at the thalamic level inhibit sensory stimuli from causing arousal during sleep. Generally sedatives enhance the activity of GABA, which promotes sleep by inhibiting pathways that promote wakefulness and activates pathways enhancing slow-wave sleep.

Insomnia

Insomnia, the most common sleep disorder, is defined as the inability to initiate or maintain sleep. Typically, adults require 7–9 hours of sleep daily. Disorders such as depression, musculoskeletal pain, and heart failure may significantly interfere with sleep and produce secondary insomnia. This section focuses on insomnia as a primary illness.

A small percentage of people with a complaint of insomnia have a sleep state misperception disorder. These individuals believe that they do not have an adequate amount of sleep but, when tested, they do not lack appropriate sleep. Another small subset of individuals sleeps reasonably well at night, but for a more limited period of time, perhaps 5–7 hours. Although they may feel restored and function reasonably well during the day, they are unlikely to be functioning at their best.

Among true sleep disorders, the most common insomnias are primary insomnia and psychophysiologic insomnia. Patients with primary insomnia have a history of sleeping poorly since early childhood. They are unable to sleep enough to meet their needs, and this is not secondary to depression, anxiety, or an underlying illness. Good sleep hygiene, such as avoidance of stimulants and daytime naps, with adequate daily exercise and mental stimulation may help some of these individuals to sleep longer. However, medication may also be needed to achieve adequate sleep.

Psychophysiologic insomnia is the most common cause of the inability to initiate or maintain sleep. It is defined as the inability to relax sufficiently to fall asleep, which, through repetition, then becomes reinforced as a behavior. Multiple factors contribute to this condition, including anxiety, stress, and inability to relax, resulting in a learned behavior of poor sleep. Relaxation and good sleep hygiene are important treatment modalities. Some patients sleep well when given a prescription for a hypnotic that, even if never filled or taken, removes the anxiety about sleep. For others, a program of taking a hypnotic on three predetermined nights each week, such as every Sunday, Tuesday, and Thursday, allows for sleep on some nights. This may eventually lead to reasonably good sleep without any need for medication.

Sleep Apnea Syndrome