Neuromodulation

(Redirected from Neuromodulator)

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 reconfiguring synaptic connectivity.[3]

Illustration of the brain and spinal cord connecting to a muscle, illustrating the connection between the central and peripheral nervous system.

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] When discussing neuromodulation, there are two forms of non-invasive stimulation when treating migraines. One is electrical stimulation, and some of the characterizations include transcranial alternating stimulation and transcranial direct current stimulation. The other is magnetic stimulation, which includes single pulse and repetitive transcranial stimulation. [User:Ngwinn]/Editing User:Ngwinn/Neuromodulation - Wikipedia].[9]

Neuromodulatory systems

edit

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[10] Targets[10] Effects[10]
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

edit
 
Skeletal formulae diagram of Noradrenaline

The noradrenaline system consists of around 15,000 neurons, primarily in the locus coeruleus.[13] 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.[14]

Dopamine system

edit

The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum or substantia nigra as examples. It acts on dopamine receptors.[15]

 
Skeletal formulae diagram of Dopamine

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

edit

Serotonin system

edit
 
Skeletal formulae of Serotonin or 5-HT

The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract.[16][17] 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

edit
  • Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are widely used antidepressants that specifically block the reuptake of serotonin with less effect on other transmitters.[18][19][20]
  • Tricyclic antidepressants also block reuptake of biogenic amines from the synapse, but may primarily affect serotonin or norepinephrine or both. They typically take four to six weeks to alleviate any symptoms of depression. They are considered to have immediate and long-term effects.[18][20][21]
  • Monoamine oxidase inhibitors allow reuptake of biogenic amine neurotransmitters from the synapse, but inhibit an enzyme which normally destroys (metabolizes) some of the transmitters after their reuptake. More of the neurotransmitters (especially serotonin, noradrenaline and dopamine) are available for release into synapses. MAOIs take several weeks to alleviate the symptoms of depression.[18][20][22][23]

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.[18][20][23]

Cholinergic system

edit

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.[24][25]

GABA

edit
 
GABA nomenclature example

Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity.[18] GABA is an amino acid that is the primary inhibitory neurotransmitter for the central nervous system (CNS). It reduces neuronal excitability by inhibiting nerve transmission. GABA has a multitude of different functions during development and influences the migration, proliferation, and proper morphological development of neurons. It also influences the timing of critical periods and potentially primes the earliest neuronal networks. There are two main types of GABA receptors: GABAa and GABAb. GABAa receptors inhibit neurotransmitter release and/or neuronal excitability and are a ligand-gated chloride channel. GABAb receptors are slower to react due to a GCPR that acts to inhibit neurons. GABA can be the culprit for many disorders ranging from schizophrenia to major depressive disorder because of its inhibitory characteristics being dampened.[26][27][28]

Neuropeptides

edit

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.[29] Most neuropeptides bind to G-protein coupled receptors, however some neuropeptides directly gate ion channels or act through kinase receptors.

  • Opioid peptides – a large family of endogenous neuropeptides that are widely distributed throughout the central and peripheral nervous system. Opiate drugs such as heroin and morphine act at the receptors of these neurotransmitters.[30][31]
  1. Endorphins
  2. Enkephalins
  3. Dynorphins

Neuromuscular systems

edit

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,[32] 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.[32]

Volume transmission

edit

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.[33] 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.[34] Such prolonged transmitter action is called tonic transmission, in contrast to the phasic transmission that occurs rapidly at single synapses.[35][36]

Other uses

edit

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.[37]

See also

edit
  • 5-HT2c receptor agonist
  • Natural neuroactive substance
  • Symptom Validity Assessment definition- an examinee's validity is tested by examining their truthfulness and accuracy about a specific behavioral presentation, self-reports, and neuropsychological performance. [38] Performance Validity Testing definition- an examiner's way of measuring the overall efficacy of an evaluation method. [39] [User:Ngwinn]/Editing User:Ngwinn/Neuromodulation - Wikipedia]

References

edit
  1. ^ DeRiemer SA, Strong JA, Albert KA, Greengard P, Kaczmarek LK (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. PMID 2578617. S2CID 4230710.
  2. ^ a b Harris-Warrick RM, Flamm RE (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. PMC 6568948. PMID 3112322.
  3. ^ Klein M, Kandel ER (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. PMC 350401. PMID 6256770.
  4. ^ Fortin DA, Levine ES (January 2007). "Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons". Cerebral Cortex. 17 (1): 163–174. doi:10.1093/cercor/bhj133. PMID 16467564.
  5. ^ Good CH (January 2007). "Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells". The 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 (January 2007). "Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus". The Journal of Neuroscience. 27 (5): 1211–1219. doi:10.1523/JNEUROSCI.4159-06.2007. PMC 6673197. PMID 17267577.
  7. ^ Marder E (October 2012). "Neuromodulation of neuronal circuits: back to the future". Neuron. 76 (1): 1–11. doi:10.1016/j.neuron.2012.09.010. PMC 3482119. PMID 23040802.
  8. ^ Conlay LA, Sabounjian LA, Wurtman RJ (October 1992). "Exercise and neuromodulators: choline and acetylcholine in marathon runners". International Journal of Sports Medicine. 13 (Suppl 1): S141–S142. doi:10.1055/s-2007-1024619. PMID 1483754. S2CID 36276472. [verification needed]
  9. ^ Tiwari V, Agrawal S (November 2022). "Migraine and Neuromodulation: A Literature Review". Cureus. 14 (11): e31223. doi:10.7759/cureus.31223. PMC 9729750. PMID 36505141.
  10. ^ 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.
  11. ^ a b c d e f g Woolf NJ, Butcher LL (December 1989). "Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum". Brain Research Bulletin. 23 (6): 519–540. doi:10.1016/0361-9230(89)90197-4. PMID 2611694. S2CID 4721282.
  12. ^ a b c d Woolf NJ, Butcher LL (May 1986). "Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain". Brain Research Bulletin. 16 (5): 603–637. doi:10.1016/0361-9230(86)90134-6. PMID 3742247. S2CID 39665815.
  13. ^ Sara SJ, Bouret S (October 2012). "Orienting and reorienting: the locus coeruleus mediates cognition through arousal". Neuron. 76 (1): 130–141. doi:10.1016/j.neuron.2012.09.011. PMID 23040811.
  14. ^ 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". Neurochemical Research. 37 (11): 2496–2512. doi:10.1007/s11064-012-0818-x. PMC 3548657. PMID 22717696.
  15. ^ Scheler G (April 2004). "Regulation of neuromodulator receptor efficacy--implications for whole-neuron and synaptic plasticity". Progress in Neurobiology. 72 (6): 399–415. arXiv:q-bio/0401039. Bibcode:2004q.bio.....1039S. doi:10.1016/j.pneurobio.2004.03.008. PMID 15177784. S2CID 9353254.
  16. ^ McIntosh J. "What is serotonin? What does serotonin do?". Medical News Today. Retrieved 12 April 2015.
  17. ^ Berger M, Gray JA, Roth BL (2009). "The expanded biology of serotonin". Annual Review of Medicine. 60: 355–366. doi:10.1146/annurev.med.60.042307.110802. PMC 5864293. PMID 19630576.
  18. ^ a b c d e Kandel ER (1991). Principles of Neural Science. East Norwalk, Connecticut: Appleton & Lang. pp. 872–873. ISBN 978-0-8385-8034-9.
  19. ^ "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". emedicine.medscape.com. Retrieved 7 November 2016.
  20. ^ a b c d Coryell W (2016). "Drug Treatment of Depression". In Porter RS (ed.). The Merck Manual (19th ed.). Whitehouse Station, N.J.: Merck. ISBN 978-0-911910-19-3.
  21. ^ "Drug Treatment of Depression". Merck Manuals Professional Edition. Retrieved 7 November 2016.
  22. ^ 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.
  23. ^ a b Wimbiscus M, Kostenko O, Malone D (December 2010). "MAO inhibitors: risks, benefits, and lore". Cleveland Clinic Journal of Medicine. 77 (12): 859–882. doi:10.3949/ccjm.77a.09103. PMID 21147941. S2CID 33761576.
  24. ^ Picciotto MR, Higley MJ, Mineur YS (October 2012). "Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior". Neuron. 76 (1): 116–129. doi:10.1016/j.neuron.2012.08.036. PMC 3466476. PMID 23040810.
  25. ^ 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.
  26. ^ Allen MJ, Sabir S, Sharma S (2024). "GABA Receptor". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30252380. Retrieved 27 June 2024.
  27. ^ Sigel E, Steinmann ME (November 2012). "Structure, function, and modulation of GABA(A) receptors". The Journal of Biological Chemistry. 287 (48): 40224–40231. doi:10.1074/jbc.R112.386664. PMC 3504738. PMID 23038269.
  28. ^ Sorge R (2020). Dynamics of Pain. Great River. ISBN 978-1-64496-496-5.
  29. ^ Nässel DR, Zandawala M (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. PMID 30905728. S2CID 84846652.
  30. ^ Kandel ER (1991). Principles of Neural Science. East Norwalk, Connecticut: Appleton & Lang. pp. 872–873. ISBN 978-0-8385-8034-9. [verification needed]
  31. ^ Froehlich JC (1 January 1997). "Opioid peptides" (PDF). Alcohol Health and Research World. 21 (2): 132–136. PMC 6826828. PMID 15704349. [verification needed]
  32. ^ a b Stern E, Fort TJ, Miller MW, Peskin CS, Brezina V (June 2007). "Decoding modulation of the neuromuscular transform". Neurocomputing. 70 (10): 1753–1758. doi:10.1016/j.neucom.2006.10.117. PMC 2745187. PMID 19763188.
  33. ^ Taber KH, Hurley RA (January 2014). "Volume transmission in the brain: beyond the synapse". The Journal of Neuropsychiatry and Clinical Neurosciences. 26 (1): iv, 1-iv, 4. doi:10.1176/appi.neuropsych.13110351. PMID 24515717.
  34. ^ Castañeda-Hernández GC, Bach-y-Rita P (August 2003). "Volume transmission and pain perception". TheScientificWorldJournal. 3: 677–683. doi:10.1100/tsw.2003.53. PMC 5974734. PMID 12920309.
  35. ^ Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD (October 2010). "Influence of phasic and tonic dopamine release on receptor activation". The Journal of Neuroscience. 30 (42): 14273–14283. doi:10.1523/JNEUROSCI.1894-10.2010. PMC 6634758. PMID 20962248.
  36. ^ Goto Y, Otani S, Grace AA (October 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.
  37. ^ Krames ES, Peckham PH, Rezai AR, eds. (2009). Neuromodulation, Vol. 1-2. Academic Press. pp. 1–1200. ISBN 978-0-12-374248-3. Retrieved 6 September 2012.
  38. ^ Bush SS, Ruff RM, Tröster AI, Barth JT, Koffler SP, Pliskin NH, et al. (June 2005). "Symptom validity assessment: practice issues and medical necessity NAN policy & planning committee". Archives of Clinical Neuropsychology. 20 (4): 419–426. doi:10.1016/j.acn.2005.02.002. PMID 15896556.
  39. ^ Greher MR, Wodushek TR (March 2017). "Performance Validity Testing in Neuropsychology: Scientific Basis and Clinical Application-A Brief Review". Journal of Psychiatric Practice. 23 (2): 134–140. doi:10.1097/PRA.0000000000000218. PMID 28291039.
edit