Neuromodulation is the physiological process by which a given neuron uses one
or more neurotransmitters to regulate diverse populations of neurons. This is
in contrast to classical synaptic transmission, in which one presynaptic
neuron directly influences a single postsynaptic partner. Neuromodulators
secreted by a small group of neurons diffuse through large areas of the
nervous system, affecting multiple neurons. Major neuromodulators in the
central nervous system include dopamine, serotonin, acetylcholine, histamine, and
norepinephrine. Neuromodulation 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 cerebrospinal fluid, influencing the
activity of several other neurons in the brain. For this reason, some
neurotransmitters are also considered to be 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 G-protein coupled receptors while in classical chemical
neurotransmission, they are ligand-gated ion channels. Neurotransmission that
involves metabotropic receptors often also involves voltage-gated ion
channels, and is relatively slow. Conversely, neurotransmission that
involves exclusively ligand-gated ion channels 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.
Neuromuscular systems Neuromodulators may alter the output of
a physiological system by acting on the associated inputs. 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. 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.
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. Volume transmission is the
diffusion through the brain extracellular fluid of neurotransmitters
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. The major neurotransmitter systems
The major neurotransmitter systems are the noradrenaline 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. Most other neurotransmitters, on the
other hand, e.g. glutamate, GABA and glycine, are used very generally
throughout the central nervous system. = Comparison=
= Noradrenaline system= 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. = Dopamine system=
Further reading: 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. 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
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-B and thus increases dopamine levels.
= Serotonin system= Further reading: Serotonin#Gross anatomy
The serotonin created by the brain comprises around 10% of total body
serotonin. The majority is found in the gastrointestinal tract. It travels
around the brain along the medial forebrain bundle and acts on serotonin
receptors. In the peripheral nervous system serotonin regulates vascular
tone. Serotonin pharmacology
Prozac or fluoxetine, a selective serotonin reuptake inhibitor, is a
widely used antidepressant that blocks the reuptake of serotonin. Although
changes in neurochemistry are found immediately after taking an
antidepressant, symptoms will not begin to improve until 4 to 6 weeks after
administration. Monoamine oxidase inhibitors are thought
to change the rate of oxidation of biogenic amines within the brain. A lack
of oxidation means that more neurotransmitters are available for
release into synapses. MOAIs take several weeks to alleviate the symptoms
of depression. Tricyclic antidepressants block the
reuptake of biogenic amines from the synapse, back into the neuron. They
typically take 4 to 6 weeks to alleviate any symptoms of depression. They are
considered to have immediate and long-term effects.
= GABA= Gamma-aminobutyric acid has an
inhibitory effect on brain and spinal cord activity.
= Neuropeptides= 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. Endorphins
Enkephalins Dynorphins
Substance P Other uses
Neuromodulation also refers to an emerging class of medical therapies that
target the nervous system for restoration of function, 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, colloquially
referred to as "brain pacemakers", spinal cord stimulators, which are
implanted using minimally invasive procedures, or transcutaneous electrical
nerve stimulation devices, which are fully external, among others.
See also 5-HT2c receptor agonist
References External links
North American Neuromodulation Society Neuromodulation and Neural Plasticity
International Neuromodulation Society Scolarpedia article on neuromodulation