Category: receptor_pharmacology
Lateral hypothalamic orexin (hypocretin) neurons project broadly to monoaminergic + cholinergic arousal nuclei (LC, raphe, TMN, BF), stabilizing wakefulness. Orexin loss (autoimmune destruction of LH neurons) is the proximal cause of narcolepsy type 1. Pharmacology: dual orexin receptor antagonists (DORAs — suvorexant, lemborexant, daridorexant) block OX1 + OX2 to induce sleep without GABA-A modulation (lower fall + cognitive risk vs benzos). Modafinil's wake-promoting action is partly via orexin-system activation (DAT-low-affinity inhibitor with downstream orexin amplification). Caffeine's wake effect is via A1/A2A adenosine antagonism — adenosine accumulates during waking + inhibits orexin neurons; caffeine removes that inhibition.