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Neuromodulators do not transmit a discrete message from one neuron to another, as glutamate or GABA do, but adjust the gain and tone of entire circuits: they change how excitable neurons are, how long their responses last and how easily they communicate. They act in a more diffuse and prolonged way, and that is why they shape global states such as wakefulness, calm, attention or appetite.
Adenosine builds up throughout the day and generates sleep pressure; caffeine produces alertness precisely because it blocks its receptors. Brain histamine sustains wakefulness —which is why many antihistamines cause drowsiness—. Endocannabinoids, such as anandamide, work as a feedback signal that dampens excessive activity and take part in appetite, stress and pain regulation.
Neurosteroids, derived from hormones such as progesterone (allopregnanolone), potentiate the GABA-A receptor and produce a natural calming, anxiolytic effect; their drops explain part of premenstrual and postpartum irritability. Melatonin sets the circadian clock and prepares the brain for sleep, and nitric oxide, a gas that diffuses freely between cells, modulates both vascular tone and synaptic plasticity.
Looking at the brain through its neuromodulators explains why coffee wakes you up, why certain moments of the hormonal cycle change mood, or why light and schedules affect sleep so much: it is not about switching specific neurons on or off, but about turning the volume of entire systems up or down.
Educational information, not medical advice.