In the two-process model of sleep regulation, Process S (homeostatic sleep pressure) is primarily mediated by accumulation of:

• A Adenosine in the basal forebrain and cortex ✓
• B Serotonin in the dorsal raphe nucleus
• C GABA in the ventrolateral preoptic nucleus
• D Orexin (hypocretin) in the lateral hypothalamus

Explanation

The two-process model of sleep regulation (Borbély) involves Process S (sleep homeostatic pressure that rises during waking and dissipates during sleep) and Process C (circadian rhythm). Adenosine is the primary molecular mediator of Process S: it accumulates progressively in the basal forebrain and cortex during wakefulness as a byproduct of neuronal ATP consumption, and its action on A1 and A2A receptors promotes sleepiness. Caffeine blocks adenosine receptors to promote wakefulness. GABA release from VLPO neurons mediates the actual sleep-promoting inhibition, but adenosine is the homeostatic signal. Orexin stabilizes the wake state through Process C modulation.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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