Neuromodulation

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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]

Contents

Illustration of the brain and spinal cord connecting to a muscle, illustrating the connection between the central and peripheral nervous system. 202210 Brain spinal-cord anterior-horn-cells motor-nerves muscles.svg
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]

Neuromodulator 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

Skeletal formulae diagram of Noradrenaline Norepinephrine.svg
Skeletal formulae diagram of Noradrenaline

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]

Skeletal formulae diagram of Dopamine Dopamin - Dopamine.svg
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

Serotonin system

Skeletal formulae of Serotonin or 5-HT Serotonin-2D-skeletal.svg
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. [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 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. [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

GABA nomenclature example GABA Nomenclature Example1 V.1.svg
GABA nomenclature example

Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity. [17] 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. [25] [26] [27]

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. [28] 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, [31] 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. [31]

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. [32] 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 extra-synaptic receptors, and with a longer time course than for transmission at a single synapse. [33] Such prolonged transmitter action is called tonic transmission, in contrast to the phasic transmission that occurs rapidly at single synapses. [34] [35]

Tonic Transmission

There are three main components of tonic transmission: Continued release, sustained release, and baseline regulation. In the context of neuromodulation, continuous release is responsible for releasing neurotransmitters/neuromodulators at a constant low level from glial cells and tonic active neurons. Sustained Influence provides long-term stability to the entire process, and baseline regulation ensures that the neurons are in a continued state of readiness to respond to any signals. Acetylcholine, noradrenaline, dopamine, norepinephrine, and serotonin are some of the main components in tonic transmission to mediate arousal and attention.

Phasic Transmission

There are three main components of phasic transmission: burst release, transient effects, and stimulus-driven effects. As the name suggests, burst release is in charge of releasing neurotransmitters/neuromodulators in intense, acute bursts. Transient effects create acute momentary adjustments in neural activity. Lastly, as the name suggests, stimulus-driven effects react to sensory input, external stressors, and reward stimuli, which involve dopamine, norepinephrine, and serotonin.

Types of Neuromodulation Therapies and Treatments

There are two main categories for neuromodulation therapy: chemical and electrical.

Electrical Neuromodulator Therapies

Electrical neuromodulation has three subcategories: deep brain, spinal cord, and transcranial, each aiming to treat specific conditions. Deep brain stimulation involves electrodes being surgically implanted into specific sections of the brain that are commonly responsible for movement and motor control deficiencies and disorders like Parkinson's and tremors. Spinal cord stimulation works by being placed near the spinal cord to send electrical signals through the body to treat various forms of chronic pain like lower back pain and CRPS. This form of neuromodulator treatment is considered one of the more high-risk treatments because of its manipulation near the spinal cord. Transcranial magnetic stimulation is slightly different in that it utilizes a magnetic field to generate electrical currents throughout the brain. This treatment is widely used to remedy various mental health conditions like depression, obsessive-compulsive disorder, and other mood disorders.

Neuromodulation is often used as a treatment mechanism for moderate to severe migraines by way of nerve stimulation. These treatments work by utilizing the basic ascending pathways. There are three main modes. It works by connecting a device to the body that sends electrical pulses directly to the affected site (Transcutaneous Electrical Nerve Stimulation), directly to the brain (Transcranial Magnetic Stimulation), or by holding a device close to the neck that works to block pain signals modulation from the PNS to the CNS. and sends two of the most notable modes of that treatment, which are electrical and magnetic stimulation. Electrical nerve 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.

Chemical Neuromodular Therapies

Chemical neuromodulation mostly consists of collaborating natural and artificial chemical substances to treat various conditions. It uses both invasive and non-invasive modes of treatment, including pumps, injections, and oral medications. This mode of treatment can be used to manage immune responses like inflammation, mood, and motor disorders.

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.

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.

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.

<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.

An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded.

<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. Synapses can be chemical or electrical. In case of electrical synapses, neurons are coupled bidirectionally in continuous-time to each other and are known to produce synchronous network activity in the brain but can result in much more complicated network level dynamics like chaos. As such, signal directionality cannot always be defined across electrical synapses.

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">Reuptake enhancer</span> Drug that makes neurotransmitter transporters more active

A reuptake enhancer (RE), also sometimes referred to as a reuptake activator, is a type of reuptake modulator which enhances the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to a decrease in the extracellular concentrations of the neurotransmitter and therefore a decrease in neurotransmission.

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