Neuromodulation is the physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons. Neuromodulators typically bind to metabotropic, G-protein coupled receptors (GPCRs) to initiate a second messenger signaling cascade that induces a broad, long-lasting signal. This modulation can last for hundreds of milliseconds to several minutes. Some of the effects of neuromodulators include: altering intrinsic firing activity,[1] increasing or decreasing voltage-dependent currents,[2] altering synaptic efficacy, increasing bursting activity[2] and reconfigurating synaptic connectivity.[3]

Major neuromodulators in the central nervous system include: dopamine, serotonin, acetylcholine, histamine, norepinephrine, nitric oxide, and several neuropeptides. Cannabinoids can also be powerful CNS neuromodulators.[4][5][6] Neuromodulators can be packaged into vesicles and released by neurons, secreted as hormones and delivered through the circulatory system.[7] A neuromodulator can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Some neuromodulators end up spending a significant amount of time in the cerebrospinal fluid (CSF), influencing (or "modulating") the activity of several other neurons in the brain.[8]

Neuromodulatory systems

See also: Neural pathways

The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system. Drugs targeting the neurotransmitter of such systems affect the whole system, which explains the mode of action of many drugs.

Most other neurotransmitters, on the other hand, e.g. glutamate, GABA and glycine, are used very generally throughout the central nervous system.

Neuromodulator systems
System Origin[9] Targets[9] Effects[9]
Noradrenaline system Locus coeruleus Adrenergic receptors in:
  • arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli)
  • reward system
Lateral tegmental field
Dopamine system Dopamine pathways: Dopamine receptors at pathway terminations.
Serotonin system caudal dorsal raphe nucleus Serotonin receptors in:
rostral dorsal raphe nucleus Serotonin receptors in:
Cholinergic system Pedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex) (mainly) M1 receptors in:
basal optic nucleus of Meynert (mainly) M1 receptors in:
medial septal nucleus (mainly) M1 receptors in:

Noradrenaline system

Further information: Norepinephrine § Norepinephrine system

The noradrenaline system consists of around 15,000 neurons, primarily in the locus coeruleus.[12] This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus coeruleus tend to be melanin-pigmented. Noradrenaline is released from the neurons, and acts on adrenergic receptors. Noradrenaline is often released steadily so that it can prepare the supporting glial cells for calibrated responses. Despite containing a relatively small number of neurons, when activated, the noradrenaline system plays major roles in the brain including involvement in suppression of the neuroinflammatory response, stimulation of neuronal plasticity through LTP, regulation of glutamate uptake by astrocytes and LTD, and consolidation of memory.[13]

Dopamine system

Further information: Dopamine § Functions in the brain

The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum or substantia nigra as examples. It acts on dopamine receptors.[14]

Parkinson's disease is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra but secondarily the noradrenergic neurons of the locus coeruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.

Dopamine pharmacology

Serotonin system

Further information: Serotonin § Gross anatomy

The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract.[15][16] It travels around the brain along the medial forebrain bundle and acts on serotonin receptors. In the peripheral nervous system (such as in the gut wall) serotonin regulates vascular tone.

Serotonin pharmacology

Although changes in neurochemistry are found immediately after taking these antidepressants, symptoms may not begin to improve until several weeks after administration. Increased transmitter levels in the synapse alone does not relieve the depression or anxiety.[17][19][22]

Cholinergic system

The cholinergic system consists of projection neurons from the pedunculopontine nucleus, laterodorsal tegmental nucleus, and basal forebrain and interneurons from the striatum and nucleus accumbens. It is not yet clear whether acetylcholine as a neuromodulator acts through volume transmission or classical synaptic transmission, as there is evidence to support both theories. Acetylcholine binds to both metabotropic muscarinic receptors (mAChR) and the ionotropic nicotinic receptors (nAChR). The cholinergic system has been found to be involved in responding to cues related to the reward pathway, enhancing signal detection and sensory attention, regulating homeostasis, mediating the stress response, and encoding the formation of memories.[23][24]


Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity.[17]


Neuropeptides are small proteins used for communication in the nervous system. Neuropeptides represent the most diverse class of signaling molecules. There are 90 known genes that encode human neuropeptide precursors. In invertebrates, there are ~50 known genes encoding neuropeptide precursors.[25] Most neuropeptides bind to G-protein coupled receptors, however some neuropeptides directly gate ion channels or act through kinase receptors.

  1. Endorphins
  2. Enkephalins
  3. Dynorphins

Neuromuscular systems

Neuromodulators may alter the output of a physiological system by acting on the associated inputs (for instance, central pattern generators). However, modeling work suggests that this alone is insufficient,[28] because the neuromuscular transformation from neural input to muscular output may be tuned for particular ranges of input. Stern et al. (2007) suggest that neuromodulators must act not only on the input system but must change the transformation itself to produce the proper contractions of muscles as output.[28]

Volume transmission

Neurotransmitter systems are systems of neurons in the brain expressing certain types of neurotransmitters, and thus form distinct systems. Activation of the system causes effects in large volumes of the brain, called volume transmission.[29] Volume transmission is the diffusion of neurotransmitters through the brain extracellular fluid released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors, and with a longer time course than for transmission at a single synapse.[30] Such prolonged transmitter action is called tonic transmission, in contrast to the phasic transmission that occurs rapidly at single synapses.[31][32]

Other uses

Neuromodulation also refers to an emerging class of medical therapies that target the nervous system for restoration of function (such as in cochlear implants), relief of pain, or control of symptoms, such as tremor seen in movement disorders like Parkinson's disease. The therapies consist primarily of targeted electrical stimulation, or infusion of medications into the cerebrospinal fluid using intrathecal drug delivery, such as baclofen for spasticity. Electrical stimulation devices include deep brain stimulation systems (DBS), colloquially referred to as "brain pacemakers", spinal cord stimulators (SCS) and vagus nerve stimulators (VNS), which are implanted using minimally invasive procedures, or transcutaneous electrical nerve stimulation and scrambler therapy devices, which are fully external, among others.[33]

See also


  1. ^ DeRiemer, S. A.; Strong, J. A.; Albert, K. A.; Greengard, P.; Kaczmarek, L. K. (24–30 January 1985). "Enhancement of calcium current in Aplysia neurones by phorbol ester and protein kinase C". Nature. 313 (6000): 313–316. Bibcode:1985Natur.313..313D. doi:10.1038/313313a0. ISSN 0028-0836. PMID 2578617. S2CID 4230710.
  2. ^ a b Harris-Warrick, R. M.; Flamm, R. E. (July 1987). "Multiple mechanisms of bursting in a conditional bursting neuron". The Journal of Neuroscience. 7 (7): 2113–2128. doi:10.1523/JNEUROSCI.07-07-02113.1987. ISSN 0270-6474. PMC 6568948. PMID 3112322.
  3. ^ Klein, M; Kandel, E R (November 1980). "Mechanism of calcium current modulation underlying presynaptic facilitation and behavioral sensitization in Aplysia". Proceedings of the National Academy of Sciences of the United States of America. 77 (11): 6912–6916. Bibcode:1980PNAS...77.6912K. doi:10.1073/pnas.77.11.6912. ISSN 0027-8424. PMC 350401. PMID 6256770.
  4. ^ Fortin DA, Levine ES (2007). "Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons". Cerebral Cortex. 17 (1): 163–74. doi:10.1093/cercor/bhj133. PMID 16467564.
  5. ^ Good CH (2007). "Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells". Journal of Neuroscience. 27 (1): 1–3. doi:10.1523/JNEUROSCI.4842-06.2007. PMC 6672293. PMID 17205618.
  6. ^ Hashimotodani Y, Ohno-Shosaku T, Kano M (2007). "Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus". Journal of Neuroscience. 27 (5): 1211–9. doi:10.1523/JNEUROSCI.4159-06.2007. PMC 6673197. PMID 17267577.
  7. ^ Marder, Eve (4 October 2012). "Neuromodulation of Neuronal Circuits: Back to the Future". Neuron. 76 (1): 1–11. doi:10.1016/j.neuron.2012.09.010. ISSN 0896-6273. PMC 3482119. PMID 23040802.
  8. ^ Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J. (1992). "Exercise and neuromodulators: Choline and acetylcholine in marathon runners". International Journal of Sports Medicine. 13 (Suppl 1): S141–2. doi:10.1055/s-2007-1024619. PMID 1483754. S2CID 36276472.[verification needed]
  9. ^ a b c Unless else specified in boxes, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. pp. 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system. ISBN 978-0-443-07145-4.
  10. ^ a b c d e f g Woolf NJ, Butcher LL (1989). "Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum". Brain Res. Bull. 23 (6): 519–40. doi:10.1016/0361-9230(89)90197-4. PMID 2611694. S2CID 4721282.
  11. ^ a b c d Woolf NJ, Butcher LL (1986). "Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain". Brain Res. Bull. 16 (5): 603–37. doi:10.1016/0361-9230(86)90134-6. PMID 3742247. S2CID 39665815.
  12. ^ Sara SJ, Bouret S (2012). "Orienting and reorienting: the locus coeruleus mediates cognition through arousal". Neuron. 76 (1): 130–41. doi:10.1016/j.neuron.2012.09.011. PMID 23040811.
  13. ^ O'Donnell J, Zeppenfeld D, McConnell E, Pena S, Nedergaard M (November 2012). "Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance". Neurochem. Res. 37 (11): 2496–512. doi:10.1007/s11064-012-0818-x. PMC 3548657. PMID 22717696.
  14. ^ Scheler, G. (2004). "Regulation of neuromodulator receptor efficacy--implications for whole-neuron and synaptic plasticity". Prog. Neurobiol. 72 (6): 399–415. arXiv:q-bio/0401039. doi:10.1016/j.pneurobio.2004.03.008. PMID 15177784. S2CID 9353254.
  15. ^ McIntosh, James. "What is serotonin? What does serotonin do?". Medical News Today. Retrieved 12 April 2015.
  16. ^ Berger M, Gray JA, Roth BL (2009). "The expanded biology of serotonin". Annu. Rev. Med. 60: 355–66. doi:10.1146/ PMC 5864293. PMID 19630576.
  17. ^ a b c d e Kandel, Eric R (1991). Principles of Neural Science. East Norwalk, Connecticut: Appleton & Lang. pp. 872–873. ISBN 978-0-8385-8034-9.
  18. ^ "Depression Medication: Antidepressants, SSRIs, Antidepressants, SNRIs, Antidepressants, TCAs, Antidepressants, MAO Inhibitors, Augmenting Agents, Serotonin-Dopamine Activity Modulators, Antidepressants, Other, Stimulants, Thyroid Products, Neurology & Psychiatry, Herbals". Retrieved 7 November 2016.
  19. ^ a b c d Coryell, William (2016). "Drug Treatment of Depression". In Porter, Robert S. (ed.). The Merck Manual (19 ed.). Whitehouse Station, N.J.: Merck. ISBN 978-0-911910-19-3.
  20. ^ "Drug Treatment of Depression". Merck Manuals Professional Edition. Retrieved 7 November 2016.
  21. ^ Bender, KJ; Walker, SE (8 October 2012). "Irreversible Monoamine Oxidase Inhibitors Revisited". Psychiatric Times. Psychiatric Times Vol 29 No 10. 29 (10). Retrieved 7 November 2016.
  22. ^ a b Wimbiscus, Molly; Kostenko, Olga; Malone, Donald (1 December 2010). "MAO inhibitors: risks, benefits, and lore". Cleveland Clinic Journal of Medicine. 77 (12): 859–882. doi:10.3949/ccjm.77a.09103. ISSN 1939-2869. PMID 21147941. S2CID 33761576.
  23. ^ Picciotto MR, Higley MJ, Mineur YS (October 2012). "Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior". Neuron. 76 (1): 116–29. doi:10.1016/j.neuron.2012.08.036. PMC 3466476. PMID 23040810.
  24. ^ Hasselmo ME, Sarter M (January 2011). "Modes and models of forebrain cholinergic neuromodulation of cognition". Neuropsychopharmacology. 36 (1): 52–73. doi:10.1038/npp.2010.104. PMC 2992803. PMID 20668433.
  25. ^ Nässel, Dick R.; Zandawala, Meet (1 August 2019). "Recent advances in neuropeptide signaling in Drosophila, from genes to physiology and behavior". Progress in Neurobiology. 179: 101607. doi:10.1016/j.pneurobio.2019.02.003. ISSN 0301-0082. PMID 30905728. S2CID 84846652.
  26. ^ Kandel, Eric R (1991). Principles of Neural Science. East Norwalk, Connecticut: Appleton & Lang. pp. 872–873. ISBN 978-0-8385-8034-9.[verification needed]
  27. ^ Froehlich, J. C. (1 January 1997). "Opioid peptides" (PDF). Alcohol Health and Research World. 21 (2): 132–136. ISSN 0090-838X. PMC 6826828. PMID 15704349.[verification needed]
  28. ^ a b Stern, E; Fort TJ; Millier MW; Peskin CS; Brezina V (2007). "Decoding modulation of the neuromuscular transform". Neurocomputing. 70 (6954): 1753–1758. doi:10.1016/j.neucom.2006.10.117. PMC 2745187. PMID 19763188.
  29. ^ Taber, Katherine H.; Hurley, Robin A. (January 2014). "Volume Transmission in the Brain: Beyond the Synapse". The Journal of Neuropsychiatry and Clinical Neurosciences. 26 (1): iv–4. doi:10.1176/appi.neuropsych.13110351. ISSN 0895-0172. PMID 24515717.
  30. ^ Castañeda-Hernández GC, Bach-y-Rita P (August 2003). "Volume transmission and pain perception". ScientificWorldJournal. 3: 677–83. doi:10.1100/tsw.2003.53. PMC 5974734. PMID 12920309.
  31. ^ Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD (October 2010). "Influence of phasic and tonic dopamine release on receptor activation". J. Neurosci. 30 (42): 14273–83. doi:10.1523/JNEUROSCI.1894-10.2010. PMC 6634758. PMID 20962248.
  32. ^ Goto Y, Otani S, Grace AA (July 2007). "The Yin and Yang of dopamine release: a new perspective". Neuropharmacology. 53 (5): 583–587. doi:10.1016/j.neuropharm.2007.07.007. PMC 2078202. PMID 17709119.
  33. ^ Krames, Elliot S.; Peckham, P. Hunter; Rezai, Ali R., eds. (2009). Neuromodulation, Vol. 1-2. Academic Press. pp. 1–1200. ISBN 978-0-12-374248-3. Retrieved 6 September 2012.