Neuromodulators

Neuromodulators are signaling molecules that influence neural circuits by regulating the activity of neurons and synapses rather than by conveying fast, point-to-point messages. They typically produce slower, longer-lasting effects than classic neurotransmitters and can affect large groups of neurons over a region. Neuromodulation often involves volume transmission, where chemicals diffuse away from the release site to modulate multiple targets, thereby shaping overall network states and responsiveness.

Common neuromodulators include monoamines such as dopamine, serotonin, norepinephrine, and histamine; acetylcholine in various brain circuits can also function as a neuromodulator; and neuropeptides such as substance P, neuropeptide Y, and enkephalins. Gaseous transmitters like nitric oxide and lipid-derived endocannabinoids also act as neuromodulators. While acetylcholine is a classical neurotransmitter at fast synapses, it often exerts diffuse modulatory effects in the brain, highlighting the overlap between neurotransmitters and neuromodulators.

Mechanistically, neuromodulators typically act through metabotropic receptors, including G-protein–coupled receptors, to alter neuronal excitability, synaptic strength, and plasticity. They can modify the probability of release of other transmitters at presynaptic terminals and influence postsynaptic responsiveness, network oscillations, and learning processes. Their effects are context-dependent and can vary with brain state, receptor distribution, and the presence of other modulators.

Dysregulation of neuromodulatory systems is linked to various disorders, including depression, schizophrenia, Parkinson’s disease, and attention-related conditions. Research uses pharmacology, imaging, electrophysiology, and modern techniques such as optogenetics and chemogenetics to study their roles and therapeutic potential.