Unlike the monoaminergic arousal systems, the cholinergic neurons based in the pedunculopontine and laterodorsal tegmental nuclei are at their most active during rapid eye movement (REM) sleep;171 see ref 158. This phenomenon has led to the suggestion that cholinergic mechanisms underlie REM atonia, a physiological phenomenon that, in narcolepsy, occurs anomalously in the awake state as cataplexy; see ref 158. The discovery that loss of Hcrt-producing neurons is a key feature of this disease172 173 has therefore fuelled interest in Hcrt-cholinergic interactions. Cholinoceptive neurons are found in the LHA;174 this population partially overlaps with the MCH neurons,21 which also are contacted by ascending cholinergic projections.175 The synaptic relationship between Hcrt neurons and cholinergic terminals remains to be elucidated. Intriguingly, and again in contrast to the monoaminergic effects, Hcrt neurons are excited and depolarise beyond firing threshold when the cholinergic agonist carbachol is applied166 (but see also ref 92). This effect involves postsynaptic mechanisms and is blocked by atropine, an antagonist to the metabotropic muscarine subtype of cholinergic receptors. However, in MCH neurons, which have been shown to express the M3 muscarinic receptor,176 muscarine itself exerts inhibitory postsynaptic effects, while simultaneously increasing neurotransmitter release from terminals innervating the MCH neuron via presynaptic mechanisms.76 In slice cultures, carbachol stimulation rapidly increases MCH transcription.175 Thus, the role of cholinergic mechanisms in the regulation of MCH is at present ambiguous. For Hcrt, the evidence suggests the existence of an excitatory loop between the LHA and cholinergic ascending systems. It remains, however, to reconcile such a pathway with the symptomatology of narcolepsy.
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