Finally, a canine narcolepsy model (both familial and sporadic narcoleptic dogs) was used for the evaluation of replacement/supplement therapies of hypocretin ligands.26 Using a ligand deficit sporadic narcoleptic dog, we have assessed the effects on cataplexy of intravenous (IV) administration of hypocretin-1 (6 - 384 ^g/kg). In a separate experiment, we found that a small portion of hypocretin-1 penetrates to the central nervous system (by assessing the increase in CSF hypocretin levels) after high doses (96386 ^g/kg) of IV administration of hypocretin-1.26 However, hypocretin-1 at these high dose range only produced a short-lasting anticataplectic effects.26 Thus a development of centrally penetrable hypocretin agonists (i.e., small molecular synthetic agonists), are likely to be necessary for the human application.
Figure 6. Monoaminergic and cholinergic control of sleepiness and cataplexy in relation to hypocretin input: a schematic perspective. The stimulation of adrenergic transmission by adrenergic uptake inhibitors potently reduces cataplexy; this pharmacological property is likely involved in the mode of action of currently used anticataplectic agents (e.g., tricyclic antidepressants). The fact that both presynaptic alpha-2 autoreceptor stimulation and postsynaptic alpha-1 blockade aggravate cataplexy is consistent with an inhibitory role of adrenergic transmission in the control of REM sleep atonia. Dopaminergic uptake inhibitors have no effect on cataplexy, although these compounds strongly induce EEG arousal. In contrast, D2/3 autoreceptor stimulation worsens both cataplexy and sleepiness. Since DA uptake inhibitors are reported to be mostly active at the level of mesocortical and mesolimbic DA terminals, DA projections to these regions may be more involved in mediating EEG arousal. Muscarinic M2 stimulation induces behavioral wakefulness and cortical desynchrony in control dogs, while it induces cataplexy in narcoleptic dogs. Although muscarinic antagonists significnatly reduce cataplexy in the canine model, attempts to use this class of compounds in humans have not been successful mainly due to the side effects. It was recently revealed that hypocretin-containing neurons project to these previously identified monoaminergic and cholinergic and cholinoceptive regions where hypocretin receptors are enriched. Impairments of hypocretin inputs may thus result in cholinergic and monoaminergic imbalance and in generation of narcoleptic symptoms. Hypocretin neurons also project densely to TMN histaminergic neurons and Hcrtr 2 are enriched in the TMN, and it is likely that some of narcolepsy symptoms may also be mediated by the histaminergic system. 78
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