In Neuromodulation several classes of neurotransmitters regulate diverse populations of central nervous system neurons (one neuron uses different neurotransmitters to connect to several neurons). This is in contrast to direct synaptic transmission, in which one presynaptic neuron directly influences a postsynaptic partner (one neuron reaching one other neuron), neuromodulatory transmitters secreted by a small group of neurons diffuse through large areas of the nervous system, having an effect on multiple neurons. Examples of neuromodulators include dopamine, serotonin, acetylcholine, histamine and others.
A neuromodulator is a relatively new concept. It can be conceptualized as a neurotransmitter that is not reabsorbed by the pre-synaptic neuron or broken down into a metabolite. Such neuromodulators end up spending a significant amount of time in the CSF (cerebrospinal fluid), influencing (or modulating) the overall activity level of the brain. For this reason, some neurotransmitters are also considered as neuromodulators, such as serotonin and acetylcholine.
Neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in neuromodulation the receptors are typically 7-membrane spanning G-protein coupled receptors while in the latter case they are ligand-gated ion channels. The former type of synaptic transmission often involves effects on voltage-gated ion channels, and is quite slow. The latter type is much faster. A related distinction is also sometimes drawn between modulator and driver synaptic inputs to a neuron, but here the emphasis is on modulating ongoing neuronal spiking versus causing that spiking.
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, 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.
Diffuse modulatory neurotransmitter systems
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.
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 affects the whole system, and explains the mode of action of many drugs.
Neurotransmitter systems System Origin  Targets  Effects 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. motor system, reward system, cognition, endocrine, nausea Serotonin system caudal dorsal raphe nucleus Serotonin receptors in: Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception. rostral dorsal raphe nucleus Serotonin receptors in: Cholinergic system Pedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex) (mainly) M1 receptors in:
- deep cerebellar nuclei
- pontine nuclei
- locus ceruleus
- raphe nucleus
- lateral reticular nucleus
- inferior olive
basal optic nucleus of Meynert (mainly) M1 receptors in: medial septal nucleus (mainly) M1 receptors in:
Further reading: Norepinephrine#Norepinephrine system
The noradrenaline system consists of just 1500 neurons on each side of the brain, primarily in the locus coeruleus. 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 caeruleus tend to be melanin-pigmented. In spite of their small number, when activated, the system plays major roles in the brain, as seen in table above. Noradrenaline is released from the neurons, and acts on adrenergic receptors.
Further reading: Dopamine#Functions in the brain
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 ceruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
- Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer.
- AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
Further reading: Serotonin#Gross anatomy
The serotonin system in the CNS contains only 1% of total body serotonin, the rest being found as transmitters in the peripheral nervous system. 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.
- Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.
Further reading: Acetylcholine#in CNS
The gamma-aminobutyric acid (GABA) system is more generally distributed throughout the brain. Nevertheless, it has an overall inhibitory effect.
- Opioid peptides - these substances block nerve impulse generation in the secondary afferent pain neurons. These peptides are called opioid peptides because they have opium-like activity. The types of opioid peptides are:
- Substance P
Neuromodulation also refers to a medical procedure used to alter nervous system function for relief of pain. It consists primarily of electrical stimulation, lesioning of specific regions of the nervous system, or infusion of substances into the cerebrospinal fluid. Electrical stimulation are devices such as Spinal Cord Stimulators (SCS) (surgically implanted) or transcutaneous electrical nerve stimulation devices (externally placed).
- ^ a b Stern, E; Fort TJ, Millier MW, Peskin CS, Brezina V (2007). "Decoding modulation of the neuromuscular transform". Neurocomputing 70 (6954): 1753. doi:10.1016/j.neucom.2006.10.117. PMC 2745187. PMID 19763188. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6V10-4M9Y1V1-8&_user=489277&_coverDate=11%2F11%2F2006&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000022679&_version=1&_urlVersion=0&_userid=489277&md5=7d1066d0824172ae9521c974325c076a#bcor1. Retrieved 2007-04-07.
- ^ 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 0-443-07145-4.
- ^ 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. PMID 2611694
- ^ 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. PMID 3742247
- North American Neuromodulation Society
- Neuromodulation and Neural Plasticity
- International Neuromodulation Society
- Scolarpedia article on neuromodulation
Nervous system (TA A14, GA 9) Central nervous system Peripheral nervous system Signaling pathways AgentsIntracellular signaling P+Ps By location Other concepts Human brain: forebrain (cerebrum · cerebral cortex · cerebral hemispheres, grey matter) (TA A14.1.09.002–240, 301–320, GA 9.818–826) Frontal lobeSuperolateralPrecentralPrecentral gyrus · Precentral sulcusMedial/inferiorPrecentralBoth Parietal lobeSuperolateralMedial/inferiorBoth Occipital lobeSuperolateralMedial/inferior Temporal lobeSuperolateralMedial/inferior Interlobar
Limbic lobeHippocampal formationOther Insular lobeLong gyrus of insula · Short gyri of insula · Circular sulcus of insula General Human brain: diencephalon (TA A14.1.08, GA 9.807) EpithalamusSurface ThalamusSurface
Mammillothalamic fasciculus · Pallidothalamic tracts (Ansa lenticularis, Lenticular fasciculus, Thalamic fasciculus) · PCML (Medial lemniscus, Trigeminal lemniscus) · Spinothalamic tract · Lateral lemniscus · Dentatothalamic tract · Acoustic radiation · Optic radiation · Subthalamic fasciculus · Anterior trigeminothalamic tractMedullary laminae
HypothalamusSurfaceAutonomic zonesAnterior (parasympathetic/heat loss) · Posterior (sympathetic/heat conservation) Subthalamus Ventricular system:
Human brain: mesencephalon (midbrain) (TA A14.1.06, GA 9.800) Tectum
Human brain: rhombencephalon, myelencephalon: medulla (TA A14.1.04, GA 9.767) DorsalSurfaceGrey: other VentralSurface Grey: Raphe/
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