Neuromodulation

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. Examples of neuromodulators in this category are serotonin and acetylcholine. More specifically, neuromodulation is often contrasted with classical fast synaptic transmission. In both cases the transmitter acts on local postsynaptic receptors, but in the former case 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.

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, 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.

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

Comparison

Neurotransmitter systems

System	Origin	Targets	Effects
Noradrenaline system	Locus coeruleus	adrenergic receptors in: spinal cord thalamus hypothalamus striatum neocortex cingulate gyrus cingulum hippocampus amygdala	arousal reward system
	Lateral tegmental field	hypothalamus
Dopamine system	dopamine pathways: mesocortical pathway mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathway	Dopamine receptors at pathway terminations.	motor system, reward system, cognition, endocrine, nausea
Serotonin system	caudal dorsal raphe nucleus	Serotonin receptors in: deep cerebellar nuclei cerebellar cortex spinal cord	Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.
	rostral dorsal raphe nucleus	Serotonin receptors in: thalamus striatum hypothalamus nucleus accumbens neocortex cingulate gyrus cingulum hippocampus amygdala
Cholinergic system	Pedunculopontine nucleus and dorsolateral tegmental nuclei (pontomesencephalotegmental complex)	(mainly) M1 receptors in: brainstem deep cerebellar nuclei pontine nuclei locus ceruleus raphe nucleus lateral reticular nucleus inferior olive thalamus tectum basal ganglia basal forebrain	learning short-term memory arousal reward
	basal optic nucleus of Meynert	(mainly) M1 receptors in: neocortex
	medial septal nucleus	(mainly) M1 receptors in: hippocampus neocortex

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 caeruleus. This is diminutive compared to the more than 100 billion neurons in the brain. As with domaminergic neruons in the substantia nigro, 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 noradreergic neurons of the locus ceruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.

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 (MAO)-B and thus increases dopamine levels.

Serotonin system

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.

Pharmacology

• Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.

Cholinergic system

Further reading: Acetylcholine#in CNS

Others

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:
  • Endorphins
  • Enkephalins
  • Dynorphins
• Substance P
• Octopamine

Other uses

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).

External links

• North American Neuromodulation Society
• Neuromodulation and Neural Plasticity
• International Neuromodulation Society
• Scolarpedia article on neuromodulation

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