Fig. 1. Cartoon of a simplified nonrapid eye movement (NREM) sleep-promoting pathway activated by dexmedetomidine. An inhibition of firing of noradrenergic neurons in the locus coeruleus (LC), which accompanies endogenous NREM sleep 30,31and is the site of initiation of α2-adrenergic anesthesia, 4,5releases a tonic noradrenergic inhibition of the ventrolateral preoptic nucleus (VLPO). The activated VLPO 14is believed to release γ-aminobutyric acid (GABA) into the tuberomammillary nucleus (TMN), 17,20,39–42which inhibits its release of arousal-promoting histamine into the cortex and forebrain to induce loss of consciousness. 19,22A number of pathways are involved in NREM sleep; the sleep-active VLPO 14projects to all the ascending monoaminergic, cholinergic, and orexinergic arousal nuclei, 17,20which project to the cortex, forebrain, and subcortical areas where they release neurotransmitters of arousal to promote wakefulness. 14This study concentrates on the TMN as representative of all of these arousal centers inhibited by the VLPO during sleep, but it seems likely that others may also be inhibited by dexmedetomidine. The LC widely innervates the brain, but only projections associated with NREM sleep are shown here. Although the TMN densely innervates the VLPO, histamine does not influence VLPO firing rates in vivo , 15but TMN neurons also contain galanin and GABA, which could influence VLPO activity. 21A simplified version of this circuitry, the portion of the pathway highlighted in black, is the focus of this investigation. Ach = acetylcholine; DR = dorsal raphe nuclei; His = histamine; 5-HT = serotonin; LDTg = laterodorsal tegmental nuclei; NE = norepinephrine; OX = orexin (hypocretin); PeF = perifornical area; PPTg = pedunculopontine tegmental nuclei.