Neuropharmacology of Sleep and Wakefulness: 2012 Update

Abstract

The development of sedative/hypnotic molecules has been empiric rather than rational. The empiric approach has produced clinically useful drugs but for no drug is the mechanism of action completely understood. All available sedative/hypnotic medications have unwanted side effects and none of these medications creates a sleep architecture that is identical to the architecture of naturally occurring sleep. This chapter reviews recent advances in research aiming to elucidate the neurochemical mechanisms regulating sleep and wakefulness. One promise of rational drug design is that understanding the mechanisms of sedative/hypnotic action will significantly enhance drug safety and efficacy.

Figure 1. Brain regions modulating sleep and wakefulness

Sagittal drawing of the rat brain (modified from) schematizes the location, shape, and size of some brain regions that regulate sleep and wakefulness. The name of each brain region appears in bold print, the major neurotransmitters used for signaling to other brain regions are in parentheses, and neurochemical analytes relevant for arousal-state control that have been measured in that brain region are listed under the header “Quantified”. The microdialysis probe is drawn to scale and is shown sampling from the prefrontal cortex. Abbreviations: XII – hypoglossal nucleus; BF – basal forebrain; DRN – dorsal raphé nucleus; LC – locus coeruleus; LDT – laterodorsal tegmental nucleus; LH – lateral hypothalamus; MPO – medial preoptic area; PFC – prefrontal cortex; PPT – pedunculopontine tegmental nucleus; PnC – pontine reticular formation, caudal part; PnO – pontine reticular formation, oral part; TMN – tuberomamillary nucleus; TNC – trigeminal nucleus complex; VLPO – ventrolateral preoptic area; VTA – ventral tegmental area; 5HT – serotonin; ACh – acetylcholine; Ado – adenosine; Asp – aspartate; DA – dopamine; GABA – γ-aminobutyric acid; Glu – glutamate; Gly – glycine; His – histamine; Hcrt – hypocretin; NE – norepinephrine; NO – nitric oxide; Noc – nociceptin; Ser – serine; 5HT – serotonin; Tau – taurine. Figure reprinted from Watson et al., 2010 with permission.

Figure 2. GABA levels in pontine reticular formation during wakefulness, NREM sleep, and REM sleep

These comparative data illustrate two key points. First, that in both rat (A) and cat (B) there are parallel, state-dependent changes in GABA levels. In rat and cat GABA levels are significantly lower in REM sleep than during wakefulness. Second, methodological differences in the collection of GABA preclude direct comparison of GABA levels between these two species. GABA levels shown in A and B reflect differences in microdialysis flowrate (0.4 μL/min for rat and 2.0 μL/min for cat), molecular weight cut-off of the microdialysis probe membrane (18000 Daltons for rat and 6 Daltons for cat) and possibly membrane material (regenerated cellulose for rat and cuprophane for cat). Figures modified from Watson et al., 2011 and Vanini et al., 2011 with permission.

Figure 3. Intravenous administration of eszopiclone to intact, behaving rats decreases acetylcholine (ACh) release in the pontine reticular formation (PRF)

Top: schematic coronal section of rat brain stem illustrates placement of a microdialysis probe in the PRF. Ringer’s solution is pumped into the probe and samples are collected for quantification of ACh. Schematized at top right of brain are electrodes and an amplifier for recording the cortical electroencephalogram (EEG), and a representative trace showing EEG activity after intravenous administration of eszopiclone. Bottom: Histograms summarize the significant decrease in ACh release within the PRF caused by intravenous administration of eszopiclone. Data reprinted from Hambrecht-Wiedbusch et al., 2010 with permission.

Figure 4. Leptin replacement restores the olanzapine-induced increase of acetylcholine (ACh) release in the prefrontal cortex of leptin-deficient mice

Dialysis administration of olanzapine (100 μM) to the prefrontal cortex of C57BL/6J (B6), leptin-deficient, or leptin-replaced mice caused an increase in ACh release in the prefrontal cortex. The increase in ACh release was significantly smaller in leptin-deficient mice compared to B6 controls. The olanzanpine-induced increase in ACh release was not significantly different between B6 controls and leptin-replaced mice. This suggests that leptin modulates the release of ACh within the prefrontal cortex and may also play a role in the cortical activation that occurs during wakefulness and REM sleep. Data reprinted from Wathen et al., 2012 with permission.