Anesthesia and the cholinergic system implications from sleep research

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A host of central neurotransmitter systems subserving GABAergic, glutamatergic, adrenergic, seroto-nergic and cholinergic transmission are likely affected by anesthetics (Angel, 1993). The effect of anesthetics on cholinergic transmission has been recently reviewed (Lydic and Baghdoyan, 1997; Durieux, 1996; Yamakura et al., 2000; Tassonyi et al., 2002) and it is suggested that alteration of central cholinergic transmission is involved in mediating several effects including sedation and loss of consciousness. Compelling evidence for this suggestion derives from studies on sleep/awake states (Steriade, 1999). Early animal studies demonstrated that acetylcholine (ACh) content of the whole brain varies as a function of arousal (Richter and Crossland, 1949), cortical ACh release changes in phase with the sleep/awake cycle (Celesia and Jasper, 1966), and anesthetics suppress EEG activation and reduce cortical ACh release (Mitchell 1963). In addition, intravenous administration of cholinomi-metic drugs in decerebrate animals induces a REM-like state (Matsuzaki et al., 1968). REM sleep is considered to be a 'paradoxical' sleep state characterised by stage I EEG which is activated (as it is during wakefulness), and by rapid eye movements and muscle atonia. Moreover, administration of physostigmine, a centrally-acting anticholinesterase drug, produces arousal: REM sleep or awakening is evoked in patients in deeper stages of sleep (Sitaram et al., 1976). Anticholinergic drugs, on the other hand, decrease or abolish REM sleep and increase non-REM sleep with enhancement of stage II activity in humans (Sagales et al., 1969).

More recent studies have focused on the later-odorsal and pedunculopontine tegmental nuclei (LDT/PPT) as important regions in the CNS where cholinergic transmission is altered during loss of consciousness. These midbrain nuclei contain choli-nergic neurones that project to the medial pontine reticular formation and thalamus, and it has been shown that their energy metabolism is altered in phase with the sleep/awake cycle (Lydic et al., 1991a). Microdialysis studies have demonstrated that REM sleep is accompanied by an increase in ACh release in the medial pontine reticular formation (Lydic et al., 1991b). Injection of carbachol, a muscarinic agonist, into the medial pontine reticular formation produces REM-like sleep (Baghdoyan et al., 1993).

Anesthetic drugs interfere with cholinergic processes associated with altered states of consciousness. For example, administration of opiates (Lydic et al., 1993; Mortazavi et al., 1999), halothane (Keifer et al., 1994, 1996), isoflurane and enflurane (Keifer et al., 1996) are associated with decreased ACh release from neurones in the in the LDT/PPT nuclei projecting to the medial pontine reticular formation. Conversely, drugs that directly effect cholinergic activity also influence on MAC. For example, isoflurane MAC is decreased by hemicho-linium-3 (which reduces neuronal content of ACh) and increased by physostigmine (Zucker, 1991). In addition to these effects on MAC, physostigmine increases the end-tidal halothane concentration required to produce a generalized EEG shift from a low to high amplitude pattern corresponding to an anaesthetized state (Roy and Stullken, 1981).

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