Neuromodulation

Last updated

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]

Contents

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

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
SystemOrigin [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 systemcaudal 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

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

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

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

  • 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. [17] [18] [19]
  • Tricyclic antidepressants also block reuptake of biogenic amines from the synapse, but may primarily effect 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. [17] [19] [20]
  • 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. [17] [19] [21] [22]

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]

GABA

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

Neuropeptides

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

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

<span class="mw-page-title-main">Psychopharmacology</span> Study of the effects of psychoactive drugs

Psychopharmacology is the scientific study of the effects drugs have on mood, sensation, thinking, behavior, judgment and evaluation, and memory. It is distinguished from neuropsychopharmacology, which emphasizes the correlation between drug-induced changes in the functioning of cells in the nervous system and changes in consciousness and behavior.

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

Neurochemistry is the study of chemicals, including neurotransmitters and other molecules such as psychopharmaceuticals and neuropeptides, that control and influence the physiology of the nervous system. This particular field within neuroscience examines how neurochemicals influence the operation of neurons, synapses, and neural networks. Neurochemists analyze the biochemistry and molecular biology of organic compounds in the nervous system, and their roles in such neural processes including cortical plasticity, neurogenesis, and neural differentiation.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Neuropeptide</span> Peptides released by neurons as intercellular messengers

Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.

Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

<span class="mw-page-title-main">Dale's principle</span> Principle in neuroscience

In neuroscience, Dale's principle is a rule attributed to the English neuroscientist Henry Hallett Dale. The principle basically states that a neuron performs the same chemical action at all of its synaptic connections to other cells, regardless of the identity of the target cell. However, there has been disagreement about the precise wording.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">Neurotransmission</span> Impulse transmission between neurons

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Oxaprotiline</span> Chemical compound

Oxaprotiline, also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor belonging to the tetracyclic antidepressant (TeCA) family and is related to maprotiline. Though investigated as an antidepressant, it was never marketed.

References

  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. 1 2 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. 1 2 3 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. 1 2 3 4 5 6 7 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. 1 2 3 4 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 . Bibcode:2004q.bio.....1039S. 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/annurev.med.60.042307.110802. PMC   5864293 . PMID   19630576.
  17. 1 2 3 4 5 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". emedicine.medscape.com. Retrieved 7 November 2016.
  19. 1 2 3 4 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. 1 2 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. 1 2 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.