Neurotransmitter

Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found abundantly in the cell. Classes of neurotransmitters include amino acids, monoamines, and peptides. Monoamines are synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide neurotransmitters, or neuropeptides, are protein transmitters which are larger than the classical small-molecule neurotransmitters and are often released together to elicit a modulatory effect.^[4] Purine neurotransmitters, like ATP, are derived from nucleic acids. Metabolic products such as nitric oxide and carbon monoxide have also been reported to act like neurotransmitters.^[5]

Neurotransmitters are generally stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. However, some neurotransmitters, like the metabolic gases carbon monoxide and nitric oxide, are synthesized and released immediately following an action potential without ever being stored in vesicles.^[6]

Generally, a neurotransmitter is released via exocytosis at the presynaptic terminal in response to an electrical signal called an action potential in the presynaptic neuron. However, low-level "baseline" release also occurs without electrical stimulation. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.^[7]

After being released into the synaptic cleft, neurotransmitters diffuse across the synapse where they are able to interact with receptors on the target cell. The effect of the neurotransmitter is dependent on the identity of the target cell's receptors present at the synapse. Depending on the receptor, binding of neurotransmitters may cause excitation, inhibition, or modulation of the postsynaptic neuron.^[8]

In order to avoid continuous activation of receptors on the post-synaptic or target cell, neurotransmitters must be removed from the synaptic cleft.^[9] Neurotransmitters are removed through one of three mechanisms:

1. Diffusion – neurotransmitters drift out of the synaptic cleft, where they are absorbed by glial cells. These glial cells, usually astrocytes, absorb the excess neurotransmitters.
   • Astrocytes, a type of glial cell in the brain, actively contribute to synaptic communication through astrocytic diffusion or gliotransmission. Neuronal activity triggers an increase in astrocytic calcium levels, prompting the release of gliotransmitters, such as glutamate, ATP, and D-serine. These gliotransmitters diffuse into the extracellular space, interacting with nearby neurons and influencing synaptic transmission. By regulating extracellular neurotransmitter levels, astrocytes help maintain proper synaptic function. This bidirectional communication between astrocytes and neurons add complexity to brain signaling, with implications for brain function and neurological disorders.^[10][11]
2. Enzyme degradation – proteins called enzymes break the neurotransmitters down.
3. Reuptake – neurotransmitters are reabsorbed into the pre-synaptic neuron. Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals (the presynaptic neuron) where they are stored for reuse.

For example, acetylcholine is eliminated by having its acetyl group cleaved by the enzyme acetylcholinesterase; the remaining choline is then taken in and recycled by the pre-synaptic neuron to synthesize more acetylcholine.^[12] Other neurotransmitters are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or medication. Cocaine blocks a dopamine transporter responsible for the reuptake of dopamine. Without the transporter, dopamine diffuses much more slowly from the synaptic cleft and continues to activate the dopamine receptors on the target cell.^[13]

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter.^[14]

To identify neurotransmitters, the following criteria are typically considered:

1. Synthesis: The chemical must be produced within the neuron or be present in it as a precursor molecule.
2. Release and response: When the neuron is activated, the chemical must be released and elicit a response in target cells or neurons.
3. Experimental response: Application of the chemical directly to the target cells should produce the same response observed when the chemical is naturally released from neurons.
4. Removal mechanism: There must be a mechanism in place to remove the neurotransmitter from its site of action once its signaling role is complete.^[15]

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that:

• Carry messages between neurons via influence on the postsynaptic membrane.
• Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
• Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, a neuron may release more than one transmitter from its synaptic terminal.^[16] Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.^[17]

Neurons communicate with each other through synapses, specialized contact points where neurotransmitters transmit signals. When an action potential reaches the presynaptic terminal, the action potential can trigger the release of neurotransmitters into the synaptic cleft. These neurotransmitters then bind to receptors on the postsynaptic membrane, influencing the receiving neuron in either an inhibitory or excitatory manner. If the overall excitatory influences outweigh the inhibitory influences, the receiving neuron may generate its own action potential, continuing the transmission of information to the next neuron in the network. This process allows for the flow of information and the formation of complex neural networks.^[18]

A neurotransmitter may have an excitatory, inhibitory or modulatory effect on the target cell. The effect is determined by the receptors the neurotransmitter interacts with at the post-synaptic membrane. Neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will produce an action potential. Synapses containing receptors with excitatory effects are called Type I synapses, while Type II synapses contain receptors with inhibitory effects.^[19] Thus, despite the wide variety of synapses, they all convey messages of only these two types. The two types are different appearance and are primarily located on different parts of the neurons under its influence.^[20] Receptors with modulatory effects are spread throughout all synaptic membranes and binding of neurotransmitters sets in motion signaling cascades that help the cell regulate its function.^[8] Binding of neurotransmitters to receptors with modulatory effects can have many results. For example, it may result in an increase or decrease in sensitivity to future stimulus by recruiting more or less receptors to the synaptic membrane.^{[citation needed]}

Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a Type II, and the Type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse.^{[citation needed]}

The different locations of Type I and Type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.^[21]

As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors.

• Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes.^[22] Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease.^[23]
• GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.^[24]
• Glycine is the primary inhibitory neurotransmitter in the spinal cord.^[25]
• Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems. It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system.^[17] It is the main neurotransmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain as neuromodulatory, but uses different types of receptors, including nicotinic and muscarinic receptors.^[26]
• Dopamine has a number of important functions in the brain. This includes critical role in the reward system, motivation and emotional arousal. It also plays an important role in fine motor control; Parkinson's disease has been linked to low levels of dopamine due to the loss of dopaminergic neurons in substantia nigra pars compacta.^[27] Schizophrenia, a highly heterogeneous and complicated disorder has been linked to high levels of dopamine.^[28]
• Serotonin is a monoamine neurotransmitter. Most of it is produced by the intestine (approximately 90%),^[29] and the remainder by central nervous system neurons at the raphe nuclei. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and the functions of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients have been reported to exhibit lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.^[30]
• Norepinephrine is a member of the catecholamine family of neurotransmitters. It is synthesized from the amino acid tyrosine. In the peripheral nervous system, one of the primary roles of norepinephrine is to stimulate the release of the stress hormone epinephrine (i.e. adrenaline) from the adrenal glands.^[31] Norepinephrine is involved in the fight-or-flight response^[32] and is also affected in anxiety disorders^[33] and depression.^[34]
• Epinephrine, a neurotransmitter and hormone is synthesized from tyrosine. It is released from the adrenal glands and also plays a role in the fight-or-flight response. Epinephrine has vasoconstrictive effects, which promote increased heart rate, blood pressure, energy mobilization. Vasoconstriction influences metabolism by promoting the breakdown of glucose released into the bloodstream. Epinephrine also has bronchodilation effects, which is the relaxing of airways.^[31]

There are many different ways to classify neurotransmitters. They are commonly classified into amino acids, monoamines and peptides.^[35]

Some of the major neurotransmitters are:

• Amino acids: glutamate,^[36] aspartate, D-serine, gamma-Aminobutyric acid (GABA),^{[nb 1]} glycine
• Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S)
• Monoamines:
  • Catecholamines: dopamine (DA), norepinephrine (noradrenaline, NE), epinephrine (adrenaline)
  • Indolamines: serotonin (5-HT, SER), melatonin
  • histamine
• Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc.
• Peptides: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides^[37]
• Purines: adenosine triphosphate (ATP), adenosine
• Others: acetylcholine (ACh), anandamide, etc.

In addition, over 100 neuroactive peptides have been found, and new ones are discovered regularly.^[38][39] Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.^{[citation needed]}

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some,^[40] as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S).^[41] The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.^{[citation needed]}

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.^[36] The next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.^{[citation needed]}

This list is incomplete; you can help by adding missing items. (January 2017)

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines have a modulatory effect on neurotransmission in monoamine pathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout the brain via signaling through trace amine-associated receptor 1.^[45][46] A brief comparison of these systems follows:

Understanding the effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of neuroscience. Most neuroscientists involved in this field of research believe that such efforts may further advance our understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and someday possibly prevent or cure such illnesses.^{[63][medical citation needed]}

Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are called receptor antagonists. For example, drugs used to treat patients with schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists. An example of a receptor agonist is morphine, an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous system. Drugs such as tetrodotoxin that block neural activity are typically lethal.^{[citation needed]}

Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin.^[64] 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.^{[citation needed]}

This section needs expansion with: coverage of full agonists and their distinction from partial agonist and inverse agonist.. You can help by adding to it. (August 2015)

An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor, and initiating the same reaction typically produced by the binding of the endogenous substance.^[68] An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists, inverse agonists.^[69][70]

Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic neuron, or both.^[71] Typically, neurotransmitter receptors are located on the postsynaptic neuron, while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for monoamine neurotransmitters;^[45] in some cases, a neurotransmitter utilizes retrograde neurotransmission, a type of feedback signaling in neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic neuron.^{[72][note 1]} Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons.^[67] Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties.^[67]

Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters.^[71] Some indirect agonists trigger neurotransmitter release and prevent neurotransmitter reuptake. Amphetamine, for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their respective neurons;^[45][46] it produces both neurotransmitter release into the presynaptic neuron and subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activating TAAR1, a presynaptic G protein-coupled receptor, and binding to a site on VMAT2, a type of monoamine transporter located on synaptic vesicles within monoamine neurons.^[45][46]

An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (such as an opiate); especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by combining with and blocking its nervous receptor.^[73]

There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:

1. Direct-acting antagonist- which takes up space present on receptors which are otherwise taken up by neurotransmitters themselves. This results in neurotransmitters being blocked from binding to the receptors. An example of one of the most common is called Atropine.
2. Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters (e.g., Reserpine).

An antagonist drug is one that attaches (or binds) to a site called a receptor without activating that receptor to produce a biological response. It is therefore said to have no intrinsic activity. An antagonist may also be called a receptor "blocker" because they block the effect of an agonist at the site. The pharmacological effects of an antagonist, therefore, result in preventing the corresponding receptor site's agonists (e.g., drugs, hormones, neurotransmitters) from binding to and activating it. Antagonists may be "competitive" or "irreversible".^{[citation needed]}

A competitive antagonist competes with an agonist for binding to the receptor. As the concentration of antagonist increases, the binding of the agonist is progressively inhibited, resulting in a decrease in the physiological response. High concentration of an antagonist can completely inhibit the response. This inhibition can be reversed, however, by an increase of the concentration of the agonist, since the agonist and antagonist compete for binding to the receptor. Competitive antagonists, therefore, can be characterized as shifting the dose–response relationship for the agonist to the right. In the presence of a competitive antagonist, it takes an increased concentration of the agonist to produce the same response observed in the absence of the antagonist.^{[citation needed]}

An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable for binding to the agonist. Irreversible antagonists may even form covalent chemical bonds with the receptor. In either case, if the concentration of the irreversible antagonist is high enough, the number of unbound receptors remaining for agonist binding may be so low that even high concentrations of the agonist do not produce the maximum biological response.^[74]

Biosynthetic pathways for catecholamines and trace amines in the human brain[75][76][77] L-Phenylalanine L-Tyrosine L-DOPA Epinephrine Phenethylamine p-Tyramine Dopamine Norepinephrine N-Methylphenethylamine N-Methyltyramine p-Octopamine Synephrine 3-Methoxytyramine AADC AADC AADC primary pathway PNMT PNMT PNMT PNMT AAAH AAAH brain CYP2D6 minor pathway COMT DBH DBH In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

The following sections describe how imbalances or dysfunction in specific neurotransmitters—dopamine, serotonin, and glutamate—have been tentatively linked to various mental or neurological disorders.

For example, problems in producing dopamine (mainly in the substantia nigra) can result in Parkinson's disease, a disorder that affects a person's ability to move as they want to, resulting in stiffness, tremors or shaking, and other symptoms. Some studies suggest that having too little or too much dopamine or problems using dopamine in the thinking and feeling regions of the brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD). Dopamine is also involved in addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especially opioid and methamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.^[78]

Similarly, after some research suggested that drugs that block the recycling, or reuptake, of serotonin seemed to help some people diagnosed with depression, it was theorized that people with depression might have lower-than-normal serotonin levels. Though widely popularized, this theory was not borne out in subsequent research.^[79] Therefore, selective serotonin reuptake inhibitors (SSRIs) are used to increase the amounts of serotonin in synapses.^{[citation needed]}

Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental disorders, including autism, obsessive–compulsive disorder (OCD), schizophrenia, and depression.^[80] Having too much glutamate has been linked to neurological diseases such as Parkinson's disease, multiple sclerosis, Alzheimer's disease, stroke, and ALS (amyotrophic lateral sclerosis).^[81]

Generally, there are no scientifically established "norms" for appropriate levels or "balances" of different neurotransmitters. In most cases, it is practically impossible to measure neurotransmitter levels in the brain or body at any given moment. Neurotransmitters regulate each other's release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people.^{[82][83][84][85][86]} However, significant imbalances or disruptions in neurotransmitter systems are associated with various diseases and mental disorders, including Parkinson's disease, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic weight changes, and addictions. Some of these conditions are also related to neurotransmitter switching, a phenomenon where neurons change the type of neurotransmitters they release.^[87][88][89] Chronic physical or emotional stress can be a contributor to neurotransmitter system changes. Genetics also plays a role in neurotransmitter activities.

Apart from recreational use, medications that directly and indirectly interact with one or more transmitter or its receptor are commonly prescribed for psychiatric and psychological issues. Notably, drugs interacting with serotonin and norepinephrine are prescribed to patients with problems such as depression and anxiety—though the notion that there is much solid medical evidence to support such interventions has been widely criticized.^[90] Studies shown that dopamine imbalance has an influence on multiple sclerosis and other neurological disorders.^[91]