articular chemical neurotransmitters have been identified and localized in groups of cells within the reticular formation; these neurotransmitters have been found to have important roles in cortical activation and behavioral arousal (Figure 1). First, noradrenaline is contained in neurons of the locus coeruleus which project in a diffuse manner to the entire forebrain and cerebral cortex, and apparently act to maintain and enhance cortical activation (Figures 1, see also Figure 1, Part E, Brain Mechanisms of Sleep and Wakefulness). Second, dopamine is contained in neurons of the substantia nigra and ventral tegmental area which, via differential projections to the striatum and frontal cortex, also plays an important role in behavioral arousal, movement and responsiveness on the one hand and cortical activation on the other (Figure 2).
It has long been known that drugs such as amphetamine and cocaine, which enhance the release or synaptic concentrations of the catecholamines, dramatically enhance and prolong wakefulness. Conversely, drugs which deplete or decrease the catecholamines produce a decrease in activity and cortical activation, and in certain cases appear to increase sleep (Figure 1).
State-dependent changes in aminergic and cholinergic neuronal function. Schematic representation of progressive decrease of aminergic neurotransmitter release in cerebral cortex as an animal passes from wakefulness through NREM to REM sleep. Cortical concentrations of norepinephrine and serotonin are highest in waking, lowest in REM sleep, and intermediate in NREM sleep. Top panel illustrates sagittal sections of the brain with aminergic neurons of nucleus locus coeruleus (noradrenergic) and dorsal raphe nucleus (serotonergic). Bottom panel illustrates cholinergic neurons of Ch 1-4 (in basal forebrain) and of Ch 5 of peribrachial pontine tegmentum. Cholinergic neurons release levels of acetylcholine as high in REM sleep as they are in waking; release in NREM sleep is lower.
Acetylcholine has recently been localized to neurons within the reticular formation and basal forebrain (Figure 1). Via their projections to the forebrain and cortex, respectively, they form an important component of the ascending reticular activating system (Figure 2, see also Figure 1, Part E., Brain Mechanisms of Sleep and Wakefulness). Acetylcholine is released from nerve terminals in the thalamus and cortex in highest concentrations in association with cortical activation that occurs naturally during wakefulness and REM sleep (Figure 1). Nicotine, a cholinergic agonist, has long been known as a stimulant that produces prolonged and enhanced cortical activation. Blockers of both nicotinic, and even more so of muscarinic cholinergic receptors, diminish cortical activation and vigilance.
Histamine is located in neurons within the caudal hypothalamus. These neurons project in a diffuse manner to the cerebral cortex. Drugs containing antihistamine produce drowsiness and a decrease in cortical activation. However, there is evidence that it may not be the pure antihistaminic action that is critical, but that other substances that are components of these drugs may be the important substances.
Glutamate and aspartate are excitatory amino acids which are contained in many neurons that project to the cerebral cortex, forebrain and brainstem. They are released in greatest amounts during wakefulness. Glutamate or aspartate containing neurons probably make up important contingents of the ascending reticular activating system (See Figure 1, Part E., Brain Mechanisms of Sleep and Wakefulness). Glutamate agonists produce prolonged central excitation and cortical activation.
There are many peptides such as CRF (corticotropin releasing factor), TRF (thyrotropin releasing factor) and VIP (vasoactive intestinal peptide) which are contained in central neurons that may participate in the maintenance of cortical activation and wakefulness by their release into synaptic spaces or the cerebrospinal fluid. In addition, hormones such as epinephrine, histamine, TSH (thyrotropin stimulating hormone) or ACTH (adrenocorticotropin hormone), when released into the blood, can act to elicit or reinforce arousal and wakefulness by acting upon the brain in specialized areas outside the blood brain barrier. Similarly, substances such as the glucocorticoids that cross the blood brain barrier, act upon areas where specific receptors are located.
NREM sleep is an actively generated state, the initiation of which also involves an active process of inhibition of the reticular activating system. Neurons that are particularly important for this inhibition are located within the lower brainstem and in the anterior hypothalamus. Serotonin, which is contained in the raphe (midline) neurons within the brainstem, was originally believed to play an important role in the generation of NREM sleep; however, their importance in promoting this sleep state is no longer certain. Some pharmacological evidence still suggests that serotonin neurons, which provide a diffuse innervation to the brain, may facilitate the onset of sleep by dampening the response to sensory input. It is perhaps through such an influence that the serotonin precursor, tryptophan, may facilitate sleep (Figure 2). However, as shown in Figure 6, Part V, Brain Mechanisms of Sleep and Wakefulness, raphe cells begin to cease discharging during NREM sleep; therefore they are not likely to be involved in activity generating either this state or REM sleep.
NREM Sleep
Multiple centers in the brainstem, the neurons of which secrete different transmitter substances. These neurons send control signals upward into the diencephalon and cerebrum and downward into the spinal cord.
GABA, an inhibitory neurotransmitter, has long been thought to play a role in sleep, particularly in view of the sedative effects of the benzodiazepines, which are known to enhance the postsynaptic action of GABA. Similarly, the barbiturates, which produce sedation and in higher doses, anesthesia, bind at or near the chloride ionophore of the benzodiazepine receptor complex (and, hence, indirectly may enhance the effectiveness of GABA). GABA-containing neurons are located throughout the brain, including the brainstem, thalamus, hypothalamus, basal forebrain and cortex. They may shut off neurons within the reticular activating system and also inhibit transmission and activity in neurons that project to the thalamus and cortex. GABA is released from the cerebral cortex in the highest concentration during NREM sleep.
Adenosine may act to promote sleep, as suggested by the stimulant action of caffeine which blocks adenosine receptors. It is not known whether adenosine is released by specific neurons utilizing adenosine as a neurotransmitter or by all neurons as the metabolite of adenosine triphosphate when they are active. The latter mechanism would provide an explanation for fatigue as well as sleep onset.
Since the beginning of the century, evidence has been available to suggest the presence of a substance that accumulates within the brain and cerebrospinal fluid that promotes the onset of sleep-a so-called "sleep substance." Several possible sleep promoting substances have been isolated from the cerebrospinal fluid. Certain peptides, which are co-localized with smaller neurotransmitters in neurons and function as neuromodulators, may have a role in facilitating sleep onset. These peptides include the opiate peptides, alpha-acetyl-MSH (melanocyte stimulating hormone) and somatostatin. Substances released into the blood, such as insulin, cholecystokinin, prostaglandins, interleukins, growth hormone, and prolactin have been shown to have sleep promoting activities. Thus, many substances can induce, modify and, to varying degrees, influence NREM sleep, as well as REM sleep; some of the more important are illustrated in Figure 3.
REM Sleep
Many components of REM sleep are generated by neurons within the pontine tegmentum. Acetylcholine, which is contained within neurons in the pons, has been shown to be critically involved in the generation of REM sleep. By increasing the level of acetylcholine in the brain by administering physostigmine, an inhibitor of the catabolic enzyme, it is possible to precipitate REM sleep during an ongoing period of NREM sleep and enhance the phasic periods of REM sleep, including the number and frequency of eye movements. Conversely, blocking muscarinic receptors can retard the appearance of REM sleep and reduce its phasic periods. Direct injections of the cholinergic agonist, carbachol, into the pontine tegmentum, produces a full blown state of REM sleep in the cat. Thus, it appears that pontine cholinoceptive neurons act upon other reticular neurons to excite ascending circuits on the one hand and inhibit sensory and motor transmission on the other hand. Noradrenaline neurons of the locus coeruleus appear to act in a reciprocal manner to the cholinergic neurons, being selectively active during wakefulness.
In summary, some of the chemical and neuronal systems that participate in the cyclic generation and maintenance of the sleep and waking states have been identified; the dynamic process by which these systems interact to generate the alternating cycle of sleep and wakefulness remains to be elucidated.
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