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Neurotransmitter

neurotransmitters, neurotransmitters and their functions
Neurotransmitters, also known as chemical messengers, are endogenous chemicals that enable neurotransmission They transmit signals across a chemical synapse, such as a neuromuscular junction, from one neuron nerve cell to another "target" neuron, muscle cell, or gland cell1 Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by receptors on the target cells Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available from the diet and only require a small number of biosynthetic steps for conversion Neurotransmitters play a major role in shaping everyday life and functions Their exact numbers are unknown, but more than 100 chemical messengers have been uniquely identified2

Contents

  • 1 Mechanism
  • 2 Discovery
  • 3 Identification
  • 4 Types
    • 41 List of neurotransmitters, peptides, and gasotransmitters
  • 5 Actions
    • 51 Excitatory and inhibitory
    • 52 Examples of important neurotransmitter actions
  • 6 Brain neurotransmitter systems
  • 7 Drug effects
    • 71 Agonists
    • 72 Antagonists
      • 721 Drug antagonists
    • 73 Precursors
      • 731 Catecholamine and trace amine precursors
      • 732 Serotonin precursors
  • 8 Diseases and disorders
  • 9 Neurotransmitter imbalance
  • 10 Elimination of neurotransmitters
  • 11 See also
  • 12 Notes
  • 13 References
  • 14 External links

Mechanismedit

Neurotransmitters are stored in a synapse in synaptic vesicles, clustered beneath the membrane in the axon terminal located at the presynaptic side of the synapse Neurotransmitters are released into and diffused across the synaptic cleft, where they bind to specific receptors in the membrane on the postsynaptic side of the synapse3

Most neurotransmitters are about the size of a single amino acid, however, some neurotransmitters may be the size of larger proteins or peptides A released neurotransmitter is typically available in the synaptic cleft for a short time before it is metabolized by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor Nevertheless, short-term exposure of the receptor to a neurotransmitter is typically sufficient for causing a postsynaptic response by way of synaptic transmission

In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal Low level "baseline" release also occurs without electrical stimulation The released neurotransmitter may then move across the synapse to be detected by and bind with receptors in the postsynaptic neuron Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way This neuron may be connected to many more neurons, and if the total of excitatory influences are greater than those of inhibitory influences, the neuron will also "fire" Ultimately it will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron4

Discoveryedit

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical However, through the careful histological examinations by Ramón y Cajal 1852–1934, 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 1873–1961 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 neurotransmitter5 Some neurons do, however, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another6

Identificationedit

There are four main criteria for identifying neurotransmitters:

  1. The chemical must be synthesized in the neuron or otherwise be present in it
  2. When the neuron is active, the chemical must be released and produce a response in some target
  3. The same response must be obtained when the chemical is experimentally placed on the target
  4. A mechanism must exist for removing the chemical from its site of activation after its work is done

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 either 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, one neuron may release more than one transmitter from its synaptic terminal7 Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system8

Typesedit

There are many different ways to classify neurotransmitters Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes

Major neurotransmitters:

  • Amino acids: glutamate,4 aspartate, D-serine, γ-aminobutyric acid GABA, glycine
  • Gasotransmitters: nitric oxide NO, carbon monoxide CO, hydrogen sulfide H2S
  • Monoamines: dopamine DA, norepinephrine noradrenaline; NE, NA, epinephrine adrenaline, histamine, serotonin SER, 5-HT
  • Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc
  • Peptides: somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides9
  • Purines: adenosine triphosphate ATP, adenosine
  • Others: acetylcholine ACh, anandamide, etc

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly 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 β-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

Single ions such as synaptically released zinc are also considered neurotransmitters by some,10 as well as some gaseous molecules such as nitric oxide NO, carbon monoxide CO, and hydrogen sulfide H2S11 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

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain4 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

List of neurotransmitters, peptides, and gasotransmittersedit

This list is incomplete; you can help by expanding it
Category Name Abbreviation Metabotropic Ionotropic
Small: Amino acids Arg Arginine α2-Adrenergic receptors, imidazoline receptors NMDA receptors
Small: Amino acids Asparagine Asp NMDA receptors
Small: Amino acids Glutamine Glu Metabotropic glutamate receptors NMDA receptors, kainate receptors, AMPARs
Small: Amino acids Gamma-aminobutyric acid GABA GABAB receptors GABAA receptors, GABAA-ρ receptors
Small: Amino acids Glycine Gly NMDA receptors, glycine receptors
Small: Amino acids D-serine Ser NMDA receptors
Small: Acetylcholine Acetylcholine Ach Muscarinic acetylcholine receptors Nicotinic acetylcholine receptors
Small: Monoamine Phe/Tyr Dopamine DA Dopamine receptors, trace amine-associated receptor 11213
Small: Monoamine Phe/Tyr Norepinephrine noradrenaline NE, NAd Adrenergic receptors
Small: Monoamine Phe/Tyr Epinephrine adrenaline Epi, Ad Adrenergic receptors
Small: Monoamine Trp Serotonin 5-hydroxytryptamine 5-HT Serotonin receptors all except 5-HT3 5-HT3
Small: Monoamine His Histamine H Histamine receptors
Small: Trace amine Phe Phenethylamine PEA Human trace amine-associated receptors: hTAAR1, hTAAR2
Small: Trace amine Phe N-methylphenethylamine NMPEA hTAAR1
Small: Trace amine Phe/Tyr Tyramine TYR hTAAR1, hTAAR2
Small: Trace amine Phe/Tyr Octopamine Oct hTAAR1
Small: Trace amine Phe/Tyr Synephrine Syn hTAAR1
Small: Trace amine Trp Tryptamine hTAAR1, various serotonin receptors
Small: Trace amine Trp N-methyltryptamine NMT hTAAR1, various serotonin receptors
Lipid Anandamide AEA Cannabinoid receptors
Lipid 2-Arachidonoylglycerol 2-AG Cannabinoid receptors
Lipid 2-Arachidonyl glyceryl ether 2-AGE Cannabinoid receptors
Lipid N-Arachidonoyl dopamine NADA Cannabinoid receptors TRPV1
Lipid Virodhamine Cannabinoid receptors
Small: Purine Adenosine Ado Adenosine receptors
Small: Purine Adenosine triphosphate ATP P2Y receptors P2X receptors
PP: Galanins Galanin GALR1, GALR2, GALR3
PP: Galanins Galanin-like peptide GALR1, GALR2, GALR3
PP: Gastrins Gastrin Cholecystokinin B receptor
PP: Gastrins Cholecystokinin CCK Cholecystokinin receptors
PP: Neurohypophyseals Vasopressin AVP Vasopressin receptors
PP: Neurohypophyseals Oxytocin OT Oxytocin receptor
PP: Neurohypophyseals Neurophysin I
PP: Neurohypophyseals Neurophysin II
PP: Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptors
PP: Neuropeptide Y Pancreatic polypeptide PP
PP: Neuropeptide Y Peptide YY PYY
PP: Opioids Enkephalin δ-Opioid receptor
PP: Opioids Dynorphin κ-Opioid receptor
PP: Opioids Endorphin μ-Opioid receptors
PP: Opioids Endomorphin μ-Opioid receptors
PP: Orexins Orexin A OX-A Orexin receptors
PP: Orexins Orexin B OX-B Orexin receptors
PP: Secretins Secretin Secretin receptor
PP: Secretins Motilin Motilin receptor
PP: Secretins Glucagon Glucagon receptor
PP: Secretins Vasoactive intestinal peptide VIP Vasoactive intestinal peptide receptors
PP: Secretins Growth hormone–releasing hormone GHRH Growth hormone–releasing hormone receptor
PP: Somatostatins Somatostatin Somatostatin receptors
PP: Tachykinins Neurokinin A
PP: Tachykinins Neurokinin B
PP: Tachykinins Substance P
PP: Tachykinins Neuropeptide K
PP: Other Adrenocorticotropic hormone ACTH ACTH receptor
PP: Other N-Acetylaspartylglutamate NAAG Metabotropic glutamate receptor 3 mGluR3
PP: Other Cocaine- and amphetamine-regulated transcript CART Unknown Gi/Go-coupled receptor14
PP: Other Bombesin
PP: Other Gastrin releasing peptide GRP
PP: Other Kisspeptin GPR54
Gasotransmitter Nitric oxide NO Soluble guanylyl cyclase
Gasotransmitter Carbon monoxide CO Heme bound to potassium channels
Gasotransmitter Hydrogen sulfide H2S

Actionsedit

Neurons form elaborate networks through which nerve impulses—action potentials—travel Each neuron has as many as 15,000 connections with neighboring neurons

Neurons do not touch each other except in the case of an electrical synapse through a gap junction; instead, neurons interact at contact points called synapses: a junction within two nerve cells, consisting of a miniature gap which impulses pass by a neurotransmitter A neuron transports its information by way of a nerve impulse called an action potential When an action potential arrives at the synapse's presynaptic terminal button, it may stimulate the release of neurotransmitters These neurotransmitters are released into the synaptic cleft to bind onto the receptors of the postsynaptic membrane and influence another cell, either in an inhibitory or excitatory way The next neuron may be connected to many more neurons, and if the total of excitatory influences minus inhibitory influences is great enough, it will also "fire" That is to say, it will create a new action potential at its axon hillock, releasing neurotransmitters and passing on the information to yet another neighboring neuron

Excitatory and inhibitoryedit

A neurotransmitter can influence the function of a neuron through a remarkable number of mechanisms In its direct actions in influencing a neuron’s electrical excitability, however, a neurotransmitter acts in only one of two ways: excitatory or inhibitory A 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 Thus, despite the wide variety of synapses, they all convey messages of only these two types, and they are labeled as such Type I synapses are excitatory in their actions, whereas type II synapses are inhibitory Each type has a different appearance and is located on different parts of the neurons under its influence Each neuron receives thousands of excitatory and inhibitory signals every secondcitation 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

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 removed15

Examples of important neurotransmitter actionsedit

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 that the transmitter binds to

Here are a few examples of important neurotransmitter actions:

  • 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", ie 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 strokes16 Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, Amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease17
  • 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 GABA18 Correspondingly, glycine is the inhibitory transmitter in the spinal cord
  • 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 system8 It is distinguished as the transmitter 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, but using different types of receptors, including nicotinic and muscarinic receptors19
  • Dopamine has a number of important functions in the brain; this includes regulation of motor behavior, pleasures related to motivation and also emotional arousal It plays a critical role in the reward system; people with Parkinson's disease have been linked to low levels of dopamine and people with schizophrenia have been linked to high levels of dopamine20
  • Serotonin is a monoamine neurotransmitter Most is produced by and found in the intestine approximately 90%, and the remainder in central nervous system neurons It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue21
  • Norepinephrine which focuses on the central nervous system, based on patients sleep patterns, focus and alertness It is synthesized from tyrosine
  • Epinephrine which is also synthesized from tyrosine takes part in controlling the adrenal glands It plays a role in sleep, with ones ability to become and stay alert, and the fight-or-flight response
  • Histamine works with the central nervous system CNS, specifically the hypothalamus tuberomammillary nucleus and CNS mast cells

Brain neurotransmitter systemsedit

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 It should be noted that trace amines, primarily via TAAR1 activation, have a very significant effect on neurotransmission in monoamine pathways ie, dopamine, histamine, norepinephrine, and serotonin pathways throughout the brain2223 A brief comparison of these systems follows:

Neurotransmitter systems in the brain
System Pathway origin and projections Regulated cognitive processes and behaviors
Noradrenaline system
242526
Noradrenergic pathways:
  • Locus coeruleus LC projections
  • LC → Amygdala and Hippocampus
  • LC → Brain stem and Spinal cord
  • LC → Cerebellum
  • LC → Cerebral cortex
  • LC → Hypothalamus
  • LC → Tectum
  • LC → Thalamus
  • LC → Ventral tegmental area
  • Lateral tegmental field LTF projections
  • LTF → Brain stem and Spinal cord
  • LTF → Olfactory bulb
  • anxiety
  • arousal wakefulness and attention
  • circadian rhythm
  • cognitive control and working memory co-regulated by dopamine
  • hunger
  • medullary control of respiration
  • negative emotional memory
  • reward perception minor role
Dopamine system
262728
Dopaminergic pathways:
  • Ventral tegmental area VTA projections
  • VTA → Amygdala
  • VTA → Cingulate cortex
  • VTA → Hippocampus
  • VTA → Nucleus accumbens Mesolimbic pathway
  • VTA → Olfactory bulb
  • VTA → Prefrontal cortex Mesocortical pathway
  • Nigrostriatal pathway
  • Substantia nigra → Caudate nucleus and putamen
  • Tuberoinfundibular pathway
  • Arcuate nucleus → Median eminence
  • aversion
  • cognitive control and working memory co-regulated by norepinephrine
  • mood
  • reward perception primary mediator
  • positive reinforcement
  • motivation incentive salience
  • motor system function
  • sexual arousal, orgasm, and refractory period via neuroendocrine regulation
Histamine system
29
Histaminergic pathways:
  • Tuberomammillary nucleus TMN projections
  • TMN → Cerebral cortex
  • TMN → Hippocampus
  • TMN → Neostriatum
  • TMN → Nucleus accumbens
  • TMN → Amygdala
  • TMN → Hypothalamus
  • arousal wakefulness and attention
  • feeding and energy balance
  • learning
  • memory
  • sleep
Serotonin system
24263031
Serotonergic pathways:

Caudal nuclei CN:
Raphe magnus, raphe pallidus, and raphe obscurus

  • Caudal projections
  • CN → Cerebral cortex
  • CN → Thalamus
  • CN → Caudate-putamen and nucleus accumbens
  • CN → Substantia nigra and ventral tegmental area

Rostral nuclei RN:
Nucleus linearis, dorsal raphe, medial raphe, and raphe pontis

  • Rostral projections
  • RN → Amygdala
  • RN → Cingulate cortex
  • RN → Hippocampus
  • RN → Hypothalamus
  • RN → Neocortex
  • RN → Septum
  • RN → Thalamus
  • RN → Ventral tegmental area
  • appetite satiety
  • arousal wakefulness and attention
  • body temperature regulation
  • emotion and mood, potentially including aggression
  • reward perception minor role
  • sensory perception
  • sleep
Acetylcholine system
242632
Cholinergic pathways:

Forebrain cholinergic nuclei FCN:
Nucleus basalis of Meynert, medial septal nucleus, and diagonal band

  • Forebrain nuclei projections
  • FCN → Hippocampus
  • FCN → Cerebral cortex
  • FCN → Limbic cortex and sensory cortex

Brainstem cholinergic nuclei BCN:
Pedunculopontine nucleus, laterodorsal tegmentum, medial habenula, and
parabigeminal nucleus

  • Brainstem nuclei projections
  • BCN → Ventral tegmental area
  • BCN → Thalamus
  • arousal wakefulness and attention
  • emotion
  • learning
  • motor system function
  • short-term memory
  • reward perception minor role

Drug effectsedit

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 illnesses33

Drugs can influence behavior by altering neurotransmitter activity For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzymes 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 Valium, a benzodiazepine that mimics effects of the endogenous neurotransmitter gamma-aminobutyric acid GABA to decrease anxiety 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

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 serotonin34 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

Agonistsedit

Main article: Agonist

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 substance35 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 agonistscitation needed

Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor sites, which may be located on the presynaptic neuron or postsynaptic neuron, or both36 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;22 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 neuron37note 1 Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons38 Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties38

Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters36 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;2223 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 neurons2223

Antagonistsedit

Main article: Receptor antagonist

An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance 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 receptor39

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 The most common is called Atropine
  2. Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters eg, Reserpine

Drug antagonistsedit

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 eg, drugs, hormones, neurotransmitters from binding to and activating it Antagonists may be "competitive" or "irreversible"

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

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 response40

Precursorsedit

Biosynthetic pathways for catecholamines and trace amines in the human brain414243 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

While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release and postsynaptic receptor firing is increased Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing44 Some neurotransmitters may have a role in depression and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression4445

Catecholamine and trace amine precursorsedit

L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine These conversions require vitamin B6, vitamin C, and S-adenosylmethionine A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area44

Serotonin precursorsedit

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain It is significantly more effective than a placebo in the treatment of mild and moderate depression44 This conversion requires vitamin C21 5-hydroxytryptophan 5-HTP, also a precursor for serotonin, is more effective than a placebo44

Diseases and disordersedit

Diseases and disorders may also affect specific neurotransmitter systems For example, problems in producing dopamine 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 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 research46 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 depression47

CAPON Binds Nitric Oxide Synthase, Regulating NMDA Receptor–Mediated Glutamate Neurotransmission

Neurotransmitter imbalanceedit

Generally, there are no scientifically established "norms" for appropriate levels or "balances" of different neurotransmitters It is in most cases pragmatically impossible to even measure levels of neurotransmitters in a brain or body at any distinct moments in time Neurotransmitters regulate each other's release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people 4849505152 Strong imbalances or disruptions to neurotransmitter systems have been associated with many diseases and mental disorders These include Parkinson's, depression, insomnia, Attention Deficit Hyperactivity Disorder ADHD, anxiety, memory loss, dramatic changes in weight and addictions Chronic physical or emotional stress can be a contributor to neurotransmitter system changes Genetics also plays a role in neurotransmitter activities Medications that directly react 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 criticized53

Elimination of neurotransmittersedit

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction This allows new signals to be produced from the adjacent nerve cells When the neurotransmitter has been secreted into the synaptic cleft, it binds to specific receptors on the postsynaptic cell, thereby generating a postsynaptic electrical signal The transmitter must then be removed rapidly to enable the postsynaptic cell to engage in another cycle of neurotransmitter release, binding, and signal generation Neurotransmitters are terminated in three different ways:

  1. Diffusion – the neurotransmitter detaches from receptor, drifting out of the synaptic cleft, here it becomes absorbed by glial cells
  2. Enzyme degradation – special chemicals called enzymes break it down
  3. Reuptake – re-absorption of a neurotransmitter into the neuron Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals the presynaptic neuron where they are stored54

For example, choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh Other neurotransmitters such as dopamine 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 by recreational drugs

See alsoedit

  • Neuroscience portal
  • Neurotransmission
  • Neurotransmitter receptor
  • Neurotransmitter release
  • Gasotransmitters
  • Kiss-and-run fusion
  • Neuromuscular transmission
  • Neuropsychopharmacology
  • Neuroendocrine
  • Neuroendocrinology
  • Natural neuroactive substance

Notesedit

  1. ^ In the central nervous system, anandamide other endocannabinoids utilize retrograde neurotransmission, since their release is postsynaptic, while their target receptor, cannabinoid receptor 1 CB1, is presynaptic37 The cannabis plant contains Δ9-tetrahydrocannabinol, which is a direct agonist at CB137

Referencesedit

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  10. ^ Kodirov,Sodikdjon A, Shuichi Takizawa, Jamie Joseph, Eric R Kandel, Gleb P Shumyatsky, and Vadim Y Bolshakov Synaptically released zinc gates long-term potentiation in fear conditioning pathways PNAS, 10 October 2006 10341: 15218-23 doi:101073/pnas0607131103
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  25. ^ Malenka RC, Nestler EJ, Hyman SE 2009 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin" In Sydor A, Brown RY Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed New York: McGraw-Hill Medical pp 156–157 ISBN 9780071481274 The locus ceruleus LC, which is located on the floor of the fourth ventricle in the rostral pons, contains more than 50% of all noradrenergic neurons in the brain; it innervates both the forebrain eg, it provides virtually all the NE to the cerebral cortex and regions of the brainstem and spinal cord  The other noradrenergic neurons in the brain occur in loose collections of cells in the brainstem, including the lateral tegmental regions These neurons project largely within the brainstem and spinal cord NE, along with 5HT, ACh, histamine, and orexin, is a critical regulator of the sleep-wake cycle and of levels of arousal  LC firing may also increase anxiety Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion  Epinephrine occurs in only a small number of central neurons, all located in the medulla Epinephrine is involved in visceral functions, such as control of respiration 
  26. ^ a b c d 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 
  27. ^ Malenka RC, Nestler EJ, Hyman SE 2009 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin" In Sydor A, Brown RY Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed New York: McGraw-Hill Medical pp 147–148, 154–157 ISBN 9780071481274 Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs Neurons from the VTA innervate the ventral striatum nucleus accumbens, olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory  Thus, acting in diverse terminal fields, dopamine confers motivational salience "wanting" on the reward itself or associated cues nucleus accumbens shell region, updates the value placed on different goals in light of this new experience orbital prefrontal cortex, helps consolidate multiple forms of memory amygdala and hippocampus, and encodes new motor programs that will facilitate obtaining this reward in the future nucleus accumbens core region and dorsal striatum  DA has multiple actions in the prefrontal cortex It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions  Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control  
  28. ^ Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, Walker DM, Pirpinias ST, Guise KG, Ramakrishnan C, Deisseroth K, Nestler EJ February 2016 "In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward" Proc Natl Acad Sci USA 113: 2726–31 doi:101073/pnas1521238113 PMID 26831103 Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion 
  29. ^ Malenka RC, Nestler EJ, Hyman SE 2009 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin" In Sydor A, Brown RY Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed New York: McGraw-Hill Medical pp 175–176 ISBN 9780071481274 Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus TMN that lies within the posterior hypothalamus There are approximately 64000 histaminergic neurons per side in humans These cells project throughout the brain and spinal cord Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus   While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory It also appears that histamine is involved in the regulation of feeding and energy balance 
  30. ^ Malenka RC, Nestler EJ, Hyman SE 2009 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin" In Sydor A, Brown RY Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed New York: McGraw-Hill Medical pp 158–160 ISBN 9780071481274 The dorsal raphe preferentially innervates the cerebral cortex, thalamus, striatal regions caudate-putamen and nucleus accumbens, and dopaminergic nuclei of the midbrain eg, the substantia nigra and ventral tegmental area, while the median raphe innervates the hippocampus, septum, and other structures of the limbic forebrain  it is clear that 5HT influences sleep, arousal, attention, processing of sensory information in the cerebral cortex, and important aspects of emotion likely including aggression and mood regulation The rostral nuclei, which include the nucleus linearis, dorsal raphe, medial raphe, and raphe pontis, innervate most of the brain, including the cerebellum The caudal nuclei, which comprise the raphe magnus, raphe pallidus, and raphe obscuris, have more limited projections that terminate in the cerebellum, brainstem, and spinal cord 
  31. ^ Nestler, Eric J "BRAIN REWARD PATHWAYS" Icahn School of Medicine at Mount Sinai Nestler Lab Retrieved 16 August 2014 The dorsal raphe is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism 
  32. ^ Malenka RC, Nestler EJ, Hyman SE 2009 "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin" In Sydor A, Brown RY Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed New York: McGraw-Hill Medical pp 167–175 ISBN 9780071481274 The basal forebrain cholinergic nuclei are comprised the medial septal nucleus Ch1, the vertical nucleus of the diagonal band Ch2, the horizontal limb of the diagonal band Ch3, and the nucleus basalis of Meynert Ch4 Brainstem cholinergic nuclei include the pedunculopontine nucleus Ch5, the laterodorsal tegmental nucleus Ch6, the medial habenula Ch7, and the parabigeminal nucleus Ch8 
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      Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
      Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
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External linksedit

  • Molecular Cell Biology 4th edition Section 214: Neurotransmitters, Synapses, and Impulse Transmission
  • Molecular Expressions Photo Gallery: The Neurotransmitter Collection
  • Brain Neurotransmitters
  • Endogenous Neuroactive Extracellular Signal Transducers
  • Neurotransmitter at the US National Library of Medicine Medical Subject Headings MeSH
  • neuroscience for kids website
  • brain explorer website
  • wikibooks cellular neurobiology

neurotransmitter acetylcholine, neurotransmitter dopamine, neurotransmitter imbalance, neurotransmitter receptors, neurotransmitter release, neurotransmitter serotonin, neurotransmitter testing, neurotransmitters, neurotransmitters and their functions, neurotransmitters in the brain


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