Summary

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain. GABA receptors are ubiquitous and are highly expressed in many brain areas modulating states of sleep and wakefulness. The consistent finding that drugs that enhance GABAergic transmission also enhance sleep supports the conclusion that endogenous GABA promotes sleep. The effects of GABA on sleep, however, vary as a function of brain region. GABAergic transmission in the pontine reticular formation, the tuberomammillary region of the posterior hypothalamus, and the ventrolateral part of the periaqueductal gray has been shown to promote wakefulness, non-rapid eye movement (NREM) sleep, or rapid eye movement (REM) sleep, respectively. The finding that hypothalamic GABA-containing neurons project to the dorsal raphe nucleus, locus coeruleus, and pontine reticular formation encourages future studies aiming to determine the extent to which these GABAergic neurons play a causal role in the generation and maintenance of REM sleep. Functional neuroanatomical studies have identified neural pathways that contribute to REM-sleep generation. Simultaneous, in vivo single-cell recordings of identified GABAergic neurons combined with direct measures of endogenous GABA offer a productive approach for gaining future insights.

Summary

Rapid eye movement (REM) sleep is a behavioral state initiated and maintained by the interaction of multiple neurotransmitters, including acetylcholine. Numerous studies confirm that cholinergic transmission contributes to the regulation of REM sleep. Cholinergic signaling in the basal forebrain modulates the cortical activation that occurs during REM sleep. It is also well documented that cholinergic transmission in the pontine reticular formation plays a role in REM-sleep generation and maintenance. This chapter highlights evidence supporting that acetylcholine regulates REM sleep and focuses on the mechanisms that regulate cholinergic transmission within arousal-regulating brain regions. The chapter also considers how other arousal-regulating neurotransmitters, such as hypocretin, GABA, adenosine, and opioids modulate both cholinergic signaling and REM sleep. A greater understanding of how neurotransmitter interactions regulate REM sleep will further clarify the role of cholinergic transmission in REM-sleep generation. Employing new analytical techniques will facilitate understanding the effects of multiple neurotransmitter interactions on physiologically relevant time scales. Capillary electrophoresis and biosensors, which can quantify neurochemical changes on the order of seconds, will allow insights that could not be achieved with more conventional sampling techniques.

Seventy years ago Otto Loewi and Henry Dale shared the 1936 Nobel Prize for the discovery that acetylcholine (ACh) is a neurotransmitter. Loewi's Nobel Lecture provided the following historical context for their discovery (Loewi, 1936): “Up until the year 1921 it was not known how the stimulation of a nerve influenced the effector organ's function, in other words, in what way the stimulation was transmitted to the effector organ from the nerve-ending.” The significance of Loewi's and Dale's discovery is emphasized by the profound relevance of ACh for sensorimotor, autonomic, and arousal state control. At all neuromuscular junctions ACh is the transmitter. For the autonomic nervous system, all preganglionic sympathetic and parasympathetic nerves use ACh, as do postganglionic fibers of the parasympathetic nervous system. In the context of the present volume, the effector organ of sleep is the brain. Therefore, this chapter focuses on the role of cholinergic “nerve endings” through which “the effector organ” generates states of sleep and wakefulness. This chapter uses Loewi's synaptic perspective to review data from many laboratories demonstrating that cholinergic synaptic mechanisms (Fig. 5.1) regulate levels of arousal.

Blocking degradation of ACh activates the EEG and enhances REM sleep

The discovery of rapid eye movement (REM) sleep (Aserinsky & Kleitman, 1953) as a state of enhanced electroencephalographic (EEG) activity implied the existence of endogenous neurochemical mechanisms underlying rhythmic oscillations in brain excitability.