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{{For|an introduction to concepts and terminology used in this article|Chemical synapse}}{{Use dmy dates|date=June 2018}}{{Synapse map}}Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron (nerve cell) to another "target" neuron, muscle cell, or gland cell.BOOK, Lodish, H., Berk, A., Zipursky, S.L., Molecular Cell Biology: Section 21.4Neurotransmitters, Synapses, and Impulse Transmission, 2000, W. H. Freeman, New York, 4th,weblink Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter 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 200 chemical messengers have been uniquely identified.WEB, Cherry, Kendra, What is a Neurotransmitter?,weblink 6 October 2014, WEB,weblink Neuropeptide database, 23 May 2018, WEB,weblink Neuropeptides. IUPHAR/BPS Guide to pharmacology, 23 May 2018,

Mechanism

(File:Neurotransmitters.jpg|thumb|Synaptic vesicles containing neurotransmitters)Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental Foundations. Boston: PearsonMost 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 neuron.NEWS, Robert Sapolsky, Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition, The Teaching Company, see pages 13 & 14 of Guide Book, 2005,

Discovery

{{see also|History of catecholamine research}}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 neurotransmitter.Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 {{ISBN|0-07-727620-5}} 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 another.WEB,weblink Junctions Between Cells, 22 November 2010,

Identification

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 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 terminal.BOOK, University, S. Marc Breedlove, Michigan State University, Neil V. Watson, Simon Fraser, Biological psychology : an introduction to behavioral, cognitive, and clinical neuroscience, 2013, Sinauer Associates, Sunderland, MA, 978-0878939275, Seventh, Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.BOOK, Whishaw, Bryan Kolb, Ian Q., An introduction to brain and behavior, 2014, Worth Publishers, New York, NY, 978-1429242288, 150–151, 4th,

Types

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, 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: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptidesJOURNAL, Snyder SH, Innis RB, Peptide neurotransmitters, Annu. Rev. Biochem., 48, 755–82, 1979, 38738, 10.1146/annurev.bi.48.070179.003543,
• 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,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. 103(41): 15218-23. {{doi|10.1073/pnas.0607131103}} as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).WEB,weblink International Symposium on Nitric Oxide – Dr. John Andrews – MaRS, MaRS, yes,weblink" title="web.archive.org/web/20141014083429weblink">weblink 14 October 2014, 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 brain. 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 gaseous signaling molecules

{{expand list|date=January 2017}}{| class="sortable wikitable"! scope="col" style="width: 15%;" | Category! scope="col" style="width: 24%;" | Name! scope="col" style="width: 6%;" class="unsortable" | Abbreviation! scope="col" style="width: 31%;" | Metabotropic! scope="col" style="width: 24%;" | Ionotropic

Small

Amino acids (Arginine>Arg)

Arginine

Alpha-2 adrenergic receptor

s, imidazoline receptors >| NMDA receptors |-

Aspartate >

| NMDA receptors |-

Glutamate >

Metabotropic glutamate receptors >| NMDA receptors, kainate receptors, AMPARs |-

Gamma-aminobutyric acid >

GABAB receptor>GABAB receptors

GABAA receptor

s, GABAA-rho receptor>GABAA-ρ receptors |-

Glycine >

| NMDA receptors, glycine receptors |-

D-serine>D-serine

Ser

–

NMDA receptors |-

Acetylcholine >

Muscarinic acetylcholine receptors >| Nicotinic acetylcholine receptors |-

Monoamine neurotransmitter>Monoamine (Phenylalanine

/Tyrosine>Tyr)

Dopamine

DA

Dopamine receptors, trace amine-associated receptor 1DOPAMINE: BIOLOGICAL ACTIVITY > URL=HTTP://WWW.GUIDETOPHARMACOLOGY.ORG/GRAC/LIGANDDISPLAYFORWARD?TAB=BIOLOGY&LIGANDID=940

PUBLISHER=INTERNATIONAL UNION OF BASIC AND CLINICAL PHARMACOLOGY

JOURNAL = DRUG ALCOHOL DEPEND.

ISSUE =

DATE = FEBRUARY 2016

DOI = 10.1016/J.DRUGALCDEP.2015.11.014

PMC = 4724540,

– |-

Phenylalanine>Phe/Tyrosine

) >

Norepinephrine (noradrenaline) >

Adrenergic receptors >| – |-

Phenylalanine>Phe/Tyrosine

) >

Epinephrine (adrenaline) >

Adrenergic receptors >| – |-

Tryptophan>Trp)

Serotonin (5-hydroxytryptamine)

5-HT

Serotonin receptors (all except 5-HT3)

5-HT3 |-

Histidine>His)

Histamine

H

Histamine receptors

– |-

Trace amine (Phenylalanine>Phe)

Phenethylamine

PEA

Human trace amine-associated receptors: {{abbrlink

human trace amine associated receptor 1}}, {{abbrlink

human trace amine associated receptor 2}}

– |-

Phenylalanine>Phe)

N-methylphenethylamine

N-methylphenethylamine >

hTAAR1 >| – |-

Phenylalanine>Phe/Tyrosine

) >

Tyramine >

hTAAR1, hTAAR2 >| – |-

Phenylalanine>Phe/Tyrosine

) >

octopamine (neurotransmitter)>Octopamine

Oct

hTAAR1

– |-

Phenylalanine>Phe/Tyrosine

) >

Synephrine >

hTAAR1 >| – |-

Small: Trace amine (Tryptophan

) >

Tryptamine >

hTAAR1, various serotonin receptors >| – |-

Small: Trace amine (Tryptophan

) >

N-methyltryptamine>N-methyltryptamine

NMT

hTAAR1, various serotonin receptors

– |-|Lipid

Anandamide >

Cannabinoid receptors >| – |-|Lipid

2-Arachidonoylglycerol >

Cannabinoid receptors >| – |-|Lipid

2-Arachidonyl glyceryl ether >

Cannabinoid receptors >| – |-|Lipid

N-Arachidonoyl dopamine>N-Arachidonoyl dopamine

NADA

Cannabinoid receptors

TRPV1 |-|Lipid

Virodhamine >

Cannabinoid receptors >| – |-

Purine >

Adenosine >

Adenosine receptors >| – |-

Adenosine triphosphate >

P2Y receptors >| P2X receptors |-

PP

Bradykinin >

Bradykinin receptor B1>B1, Bradykinin receptor B2

>| –

Corticotropin-releasing factor family>Corticotropin-releasing factors

Corticotropin-releasing hormone

CRH

Corticotropin-releasing hormone receptor 1

>| – |-

Urocortin >

Corticotropin-releasing hormone receptor 1>CRHR1

– |-

Galanin >

GALR1, GALR2, GALR3 >| –

	Galanin-like peptide >		GALR1, GALR2, GALR3 >| –

Gastrin >

Cholecystokinin B receptor >| – |-

Cholecystokinin >

Cholecystokinin receptors >| – |-

Melanocortins >

Adrenocorticotropic hormone >

ACTH receptor >| – |-

Proopiomelanocortin >

Melanocortin 4 receptor >| – |-

Melanocyte-stimulating hormones >

Melanocortin receptors >| – |-

Neurohypophyseals >

Vasopressin >

Vasopressin receptors >| – |-

Oxytocin >

Oxytocin receptor >| – |-

Neurophysin I >

| – |-

Neurophysin II >

| – |-

Neuromedin U >

Neuromedin U receptor 1>NmUR1, Neuromedin U receptor 2

>| – |-

Neuropeptide B >

NPBWR1>NPBW1, Neuropeptides B/W receptor 2

>| –

Neuropeptide S >

Neuropeptide S receptors >| – |-

Neuropeptide Y >

Neuropeptide Y receptors >| – |-

Pancreatic polypeptide >

| – |-

Peptide YY >

| – |-

Opioids >

Enkephalin >

Delta opioid receptor>δ-Opioid receptor

– |-

Dynorphin >

Kappa opioid receptor>κ-Opioid receptor

– |-

Endorphin >

Mu opioid receptor>μ-Opioid receptors

– |-

Endomorphin >

Mu opioid receptor>μ-Opioid receptors

–

Nociceptin>Nociceptin/orphanin FQ

N/OFQ

Nociceptin receptors

– |-

Orexins >

Orexin A >

Orexin receptors >| – |-

Orexin B >

Orexin receptors >| – |-

RFamide peptide family>RFamides

Kisspeptin

KiSS

GPR54

– |-

Neuropeptide FF >

| – |-

Prolactin-releasing peptide >

Prolactin-releasing peptide receptor>PrRPR

–

Pyroglutamylated RFamide peptide >

Pyroglutamylated RFamide peptide receptor>GPR103

– |-

Secretin family>Secretins

Secretin

Secretin receptor

– |-

Motilin >

Motilin receptor >| – |-

Glucagon >

Glucagon receptor >| – |-

Glucagon-like peptide-1 >

Glucagon-like peptide 1 receptor >| –

Glucagon-like peptide-2 >

Glucagon-like peptide 2 receptor >| – |-

Vasoactive intestinal peptide >

Vasoactive intestinal peptide receptors >| – |-

Growth hormone–releasing hormone >

Growth-hormone-releasing hormone receptor>Growth hormone–releasing hormone receptor

– |-

Pituitary adenylate cyclase-activating peptide >

ADCYAP1R1 >| – |-

Somatostatin >

Somatostatin receptors >| – |-

Tachykinin peptides>Tachykinins

Neurokinin A

–

– |-

Neurokinin B >

| – |-

Substance P >

| – |-

Neuropeptide K >

| – |-

Agouti-related peptide >

| Melanocortin receptor – |-

N-Acetylaspartylglutamate>N-Acetylaspartylglutamate

NAAG

Metabotropic glutamate receptor 3 (mGluR3)

– |-

Cocaine- and amphetamine-regulated transcript >

Gi alpha subunit>Gi/Go-coupled receptorLIN Y, HALL RA, KUHAR MJ > TITLE = CART PEPTIDE STIMULATION OF G PROTEIN-MEDIATED SIGNALING IN DIFFERENTIATED PC12 CELLS: IDENTIFICATION OF PACAP 6–38 AS A CART RECEPTOR ANTAGONIST

VOLUME = 45

PAGES = 351–358

PMID = 21855138

DOI = 10.1016/J.NPEP.2011.07.006,

– |-

Bombesin >

| – |-

Gastrin releasing peptide >

| – |-

Gonadotropin-releasing hormone >

gonadotropin-releasing hormone receptor>GnRHR

– |-

Melanin-concentrating hormone >

Melanin-concentrating hormone receptor>MCHR 1,2

– |-

Gaseous signaling molecule >

Nitric oxide >

guanylyl cyclase >| – |-

Carbon monoxide >

| Heme bound to potassium channels |-

Hydrogen sulfide >

| – |-

Actions

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 within which impulses are carried 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 inhibitory

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 second.{{Citation needed|date=November 2016}}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 removed.BOOK, Whishaw, Bryan Kolb, Ian Q., An introduction to brain and behavior, 2014, Worth Publishers, New York, NY, 978-1429242288, 4th,

Examples of important neurotransmitter actions

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", 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.JOURNAL, 1609133, 20076484, 10.1371/journal.pbio.0040371, 4, "Supporting" players take the lead in protecting the overstimulated brain, Gross L, PLoS Biol, e371, 2006, Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease.JOURNAL, Yang JL, Sykora P, Wilson DM, Mattson MP, Bohr VA, The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency, Mech. Ageing Dev., 132, 8–9, 405–11, August 2011, 21729715, 3367503, 10.1016/j.mad.2011.06.005,
• 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.Orexin receptor antagonists a new class of sleeping pill, National Sleep Foundation. 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 system. 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 receptors.WEB,weblink Acetylcholine Receptors, Ebi.ac.uk, 25 August 2014,
• 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; Parkinson's disease has been linked to low levels of dopamine and schizophrenia has been linked to high levels of dopamine.Schacter, Gilbert and Weger. Psychology.United States of America.2009.Print.
• 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 tissue.WEB,weblink University of Bristol, Introduction to Serotonin, 15 October 2009,
• Norepinephrine which is synthesized in the central nervous system and sympathetic nerves, modulates the responses of the autonomic nervous system, the sleep patterns, focus and alertness. It is synthesized from tyrosine.
• Epinephrine which is also synthesized from tyrosine is released in the adrenal glands and the brainstem. 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 systems {{anchor|table}}

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.JOURNAL, Miller GM, The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity, J. Neurochem., 116, 2, 164–176, January 2011, 21073468, 3005101, 10.1111/j.1471-4159.2010.07109.x, JOURNAL, Eiden LE, Weihe E, VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse, Ann. N. Y. Acad. Sci., 1216, 86–98, January 2011, 21272013, 10.1111/j.1749-6632.2010.05906.x, VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC)., 4183197, A brief comparison of these systems follows:{| class="wikitable" style="width:92%"|+Neurotransmitter systems in the brain! System !! Pathway origin and projections !! Regulated cognitive processes and behaviors!id=Noradrenaline|Noradrenaline systemBOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 155, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, Different subregions of the VTA receive glutamatergic inputs from the prefrontal cortex, orexinergic inputs from the lateral hypothalamus, cholinergic and also glutamatergic and GABAergic inputs from the laterodorsal tegmental nucleus and pedunculopontine nucleus, noradrenergic inputs from the locus ceruleus, serotonergic inputs from the raphe nuclei, and GABAergic inputs from the nucleus accumbens and ventral pallidum., BOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 145, 156–157, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, Descending NE fibers modulate afferent pain signals. ... 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., BOOK, Rang, H. P., Pharmacology, Churchill Livingstone, Edinburgh, 2003, 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system., 0-443-07145-4, JOURNAL, Rinaman L, Hindbrain noradrenergic A2 neurons: diverse roles in autonomic, endocrine, cognitive, and behavioral functions, American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 300, 2, R222-35, February 2011, 20962208, 3043801, 10.1152/ajpregu.00556.2010, | Noradrenergic pathways:

• Locus coeruleus (LC) projections

• Lateral tegmental field (LTF) projections

• anxiety
• arousal (wakefulness)
• circadian rhythm
• cognitive control and working memory (co-regulated by dopamine)
• feeding and energy homeostasis
• medullary control of respiration
• negative emotional memory
• nociception (perception of pain)
• reward (minor role)

!id=Dopamine|Dopamine systemBOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 147–148, 154–157, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, 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. ..., JOURNAL, Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, Walker DM, Pirpinias ST, Guise KG, Ramakrishnan C, Deisseroth K, Nestler EJ, In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward, Proc. Natl. Acad. Sci. U.S.A., 113, 2726–31, February 2016, 26831103, 10.1073/pnas.1521238113, Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion., 4791010, JOURNAL, Ikemoto S, Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory, Neurosci Biobehav Rev, 35, 2, 129–50, 2010, 20149820, 2894302, 10.1016/j.neubiorev.2010.02.001, Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens, Figure 3: The ventral striatum and self-administration of amphetamine| Dopaminergic pathways:

• Ventral tegmental area (VTA) projections

• Nigrostriatal pathway

• Tuberoinfundibular pathway

• arousal (wakefulness)
• aversion
• cognitive control and working memory (co-regulated by norepinephrine)
• emotion and mood
• motivation (motivational salience)
• motor function
• positive reinforcement
• reward (primary mediator)
• sexual arousal, orgasm, and refractory period (via neuroendocrine regulation)

!id=Histamine|Histamine systemJOURNAL, IwaÅ„czuk W, Guźniczak P, Neurophysiological foundations of sleep, arousal, awareness and consciousness phenomena. Part 1, Anaesthesiol Intensive Ther, 47, 2, 162–167, 2015, 25940332, 10.5603/AIT.2015.0015, The ascending reticular activating system (ARAS) is responsible for a sustained wakefulness state. ... The thalamic projection is dominated by cholinergic neurons originating from the pedunculopontine tegmental nucleus of pons and midbrain (PPT) and laterodorsal tegmental nucleus of pons and midbrain (LDT) nuclei [17, 18]. The hypothalamic projection involves noradrenergic neurons of the locus coeruleus (LC) and serotoninergic neurons of the dorsal and median raphe nuclei (DR), which pass through the lateral hypothalamus and reach axons of the histaminergic tubero-mamillary nucleus (TMN), together forming a pathway extending into the forebrain, cortex and hippocampus. Cortical arousal also takes advantage of dopaminergic neurons of the substantia nigra (SN), ventral tegmenti area (VTA) and the periaqueductal grey area (PAG). Fewer cholinergic neurons of the pons and midbrain send projections to the forebrain along the ventral pathway, bypassing the thalamus [19, 20]., BOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, USA, 9780071481274, 295, 2nd, Chapter 12: Sleep and Arousal, The ARAS is a complex structure consisting of several different circuits including the four monoaminergic pathways ... The norepinephrine pathway originates from the locus ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells., BOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 175–176, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, 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., |Histaminergic pathways:

• Tuberomammillary nucleus (TMN) projections

• arousal (wakefulness)
• feeding and energy homeostasis
• learning
• memory

!id=Serotonin|Serotonin systemBOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 158–160, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, [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., WEB, Nestler, Eric J., BRAIN REWARD PATHWAYS,weblink Icahn School of Medicine at Mount Sinai, Nestler Lab, 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., JOURNAL, Marston OJ, Garfield AS, Heisler LK, Role of central serotonin and melanocortin systems in the control of energy balance, European Journal of Pharmacology, 660, 1, 70–79, June 2011, 21216242, 10.1016/j.ejphar.2010.12.024, |Serotonergic pathways:Caudal nuclei (CN):Raphe magnus, raphe pallidus, and raphe obscurus

• Caudal projections

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

• Rostral projections

• arousal (wakefulness)
• body temperature regulation
• emotion and mood, potentially including aggression
• feeding and energy homeostasis
• reward (minor role)
• sensory perception

!id=Acetylcholine|Acetylcholine systemBOOK, Malenka RC, Nestler EJ, Hyman SE, Sydor A, Brown RY, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2009, McGraw-Hill Medical, New York, 9780071481274, 167–175, 2nd, Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin, 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)., |Cholinergic pathways:Forebrain cholinergic nuclei (FCN):Nucleus basalis of Meynert, medial septal nucleus, and diagonal band

• Forebrain nuclei projections

Brainstem cholinergic nuclei (BCN):Pedunculopontine nucleus, laterodorsal tegmentum, medial habenula, andparabigeminal nucleus

• Brainstem nuclei projections

|

• arousal (wakefulness)
• emotion and mood
• learning
• motor function
• motivation (motivational salience)
• short-term memory
• reward (minor role)

Drug effects

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.WEB, Neuron Conversations: How Brain Cells Communicate,weblink Brainfacts.org, 2 December 2014, {{mcn|date=December 2017}}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.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.JOURNAL, Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G, Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum, Cell, 135, 5, 825–37, November 2008, 19041748, 2614332, 10.1016/j.cell.2008.09.059, 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.{| class="wikitable sortable"978-0134080918}}!Drug!Interacts with:!Receptor Interaction:!Type!Effects

Botulinum toxin>Botulinum Toxin (Botox)|Acetylcholine| –|Antagonist|Blocks acetylcholine release in PNSPrevents muscle contractions

|Black Widow Spider Venom|Acetylcholine| –|Agonist|Promotes acetylcholine release in PNSStimulates muscle contractions|Neostigmine|Acetylcholine | –| –|Interferes with acetylcholinerase activityIncreases effects of ACh at receptorsUsed to treat myasthenia gravis|Nicotine|Acetylcholine

Nicotinic acetylcholine receptor>Nicotinic (skeletal muscle)|Agonist|Increases ACh activityIncreases attentionReinforcing effects

|d-tubocurarine|Acetylcholine

Nicotinic acetylcholine receptor>Nicotinic (skeletal muscle) |Antagonist|Decreases activity at receptor site

|Curare|Acetylcholine

Nicotinic acetylcholine receptor>Nicotinic (skeletal muscle)|Antagonist|Decreases ACh activityPrevents muscle contractions

|Muscarine|Acetylcholine

Muscarinic acetylcholine receptor>Muscarinic (heart and smooth muscle) |Agonist|Increases ACh activityToxic

|Atropine|Acetylcholine

Muscarinic acetylcholine receptor>Muscarinic (heart and smooth muscle)|Antagonist|Blocks pupil constrictionBlocks saliva production

|Scopolamine (Hyoscine)|Acetylcholine

Muscarinic acetylcholine receptor>Muscarinic (heart and smooth muscle)|Antagonist|Treats motion sickness and postoperative nausea and vomiting

|AMPT|Dopamine/norepinephrine| –| –|Inactivates tyrosine hydroxylase and inhibits dopamine production|Reserpine|Dopamine| –| –|Prevents storage of dopamine and other monoamines in synaptic vesiclesCauses sedation and depression|Apomorphine|Dopamine

Dopamine receptor D2>D2 Receptor (presynaptic autoreceptors/postsynaptic receptors)|Antagonist (low dose)/Direct agonist (high dose)|Low dose: blocks autoreceptorsHigh dose: stimulates postsynaptic receptors

|Amphetamine|Dopamine/norepinephrine| –|Indirect agonist|Releases dopamine, noradrenaline, and serotoninBlocks reuptake|Methamphetamine|Dopamine/norepinephrine| –| –|Releases dopamine and noradrenalineBlocks reuptake|Methylphenidate|Dopamine| –| –|Blocks reuptakeEnhances attention and impulse control in ADHD|Cocaine|Dopamine| –|Indirect Agonist|Blocks reuptake into presynapseBlocks voltage-dependent sodium channelsCan be used as a topical anesthetic (eye drops)|Deprenyl|Dopamine| –|Agonist|Inhibits MAO-BPrevents destruction of dopamine|Chlorpromazine|Dopamine

Dopamine receptor D2>D2 Receptors|Antagonist|Blocks D2 receptorsAlleviates hallucinations

|MPTP|Dopamine| –| –|Results in Parkinson like symptoms|PCPA|Serotonin (5-HT)| –|Antagonist|Disrupts serotonin synthesis by blocking the activity of tryptophan hydroxylase|Ondanestron|Serotonin (5-HT)

5-HT receptor>5-HT3 receptors|Antagonist|Reduces side effects of chemotherapy and radiationReduces nausea and vomiting

|Buspirone|Serotonin (5-HT)

5-HT1A receptor>5-HT1A receptors|Partial Agonist|Treats symptoms of anxiety and depression

|Fluoxetine|Serotonin (5-HT)| –|SSRI|Inhibits reuptake of serotoninTreats depression, some anxiety disorders, and OCD|Fenfluramine|Serotonin (5-HT)| –| –|Causes release of serotonin Inhibits reuptake of serotoninUsed as an appetite suppressant|Lysergic acid diethylamide|Serotonin (5-HT)|Post-synaptic 5-HT2A receptors|Direct Agonist|Produces visual perception distortionsStimulates 5-HT2A receptors in forebrain|Methylenedioxymethamphetamine (MDMA)|Serotonin (5-HT)/ norepinphrine| –| –|Stimulates release of serotonin and norepinephrine and inhibits the reuptakeCauses excitatory and hallucinogenic effects|Strychnine|Glycine| –|Antagonist

	website=emergency.cdc.gov	access-date=7 May 2018}}

|Diphenyldramine|Histamine|||Crosses blood brain barrier to cause drowsiness |Tetrahydrocannabinol (THC)|Endocannabinoids|Cannabinoid (CB) receptors |Agonist|Produces analgesia and sedationIncreases appetiteCognitive effects|Rimonabant|Endocannabinoids|Cannabinoid (CB) receptors |Antagonist|Suppresses appetiteUsed in smoking cessation|MAFP|Endocannabinoids| –| –|Inhibits FAAHUsed in research to increase cannabinoid system activity|AM1172|Endocannabinoids| –| –|Blocks cannabinoid reuptakeUsed in research to increase cannabinoid system activity|Anandamide (endogenous)| –|Cannabinoid (CB) receptors; 5-HT3 receptors| –|Reduce nausea and vomiting |Caffeine|Adenosine|Adenosine receptors |Antagonist|Blocks adenosine receptorsIncreases wakefullness

PCP (drug)>PCP|Glutamate|NMDA receptor|Indirect Antagonist|Blocks PCP binding sitePrevents calcium ions from entering neuronsImpairs learning

|AP5|Glutamate|NMDA receptor|Antagonist|Blocks glutamate binding site on NMDA receptorImpairs synaptic plasticity and certain forms of learning

N-Methyl-D-aspartic acid>NMDA|Glutamate|NMDA receptor|Agonist|Used in research to study NMDA receptor

|AMPA|Glutamate|AMPA receptor|Agonist|Used in research to study AMPA receptor|Ketamine|Glutamate|Kainate receptor|Antagonist|Used in research to study Kainate receptor|Allyglycine|GABA| –| –|Inhibits GABA synthesisCauses seizures|Muscimol|GABA|GABA receptor|Agonist|Causes sedation

Bicuculline>Bicuculine|GABA|GABA receptor|Antagonist|Causes Seizures

|Benzodiazepines|GABA

GABAA receptor>GABAA receptor|Indirect agonists|Anxiolytic, sedation, memory impairment, muscle relaxation

|Barbiturates|GABA

GABAA receptor>GABAA receptor|Indirect agonists|Sedation, memory impairment, muscle relaxation

Alcohol (drug)>Alcohol|GABA|GABA receptor|Indirect agonist|Sedation, memory impairment, muscle relaxation

|Picrotoxin|GABA

GABAA receptor>GABAA receptor|Indirect antagonist|High doses cause seizures

|Tiagabine|GABA| –|Antagonist|GABA transporter antagonistIncrease availability of GABAReduces the likelihood of seizures|Moclobemide|Norepinephrine| –|Agonist|Blocks MAO-A to treat depression|Idazoxan|Norepinephrine |alpha-2 adrenergic autoreceptors|Agonist|Blocks alpha-2 autoreceptorsUsed to study norepinephrine system|Fusaric acid|Norepinephrine| –| –|Inhibits activity of dopamine beta-hydroxylase which blocks the production of norepinephrineUsed to study norepinephrine system without affecting dopamine system|Opiates (Opium, morphine, heroin,and oxycodone)|Opioids|Opioid receptor|Agonists|Analgesia, sedation, and reinforcing effects|Naloxone|Opioids| –|Antagonist|Reverses opiate intoxication or overdo

Agonists

{{expand section|coverage of full agonists and their distinction from partial agonist and inverse agonist.|date=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.WEB,weblink Agonist – Definition and More from the Free Merriam-Webster Dictionary, Merriam-webster.com, 25 August 2014, 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.{{citation needed|date=August 2015}}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. 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; 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.{{#tag:ref|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 presynaptic.JOURNAL, Flores A, Maldonado R, Berrendero F, Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far, Front Neurosci, 7, 256, 2013, 24391536, 3868890, 10.3389/fnins.2013.00256, {{bull}}Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2{{bull}}Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems The cannabis plant contains Δ9-tetrahydrocannabinol, which is a direct agonist at CB1.|group="note"|name="retrograde"}} Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons.WEB,weblink Neurotransmitters and Drugs Chart, Ocw.mit.edu, 25 August 2014, Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties.Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters.BOOK, Richard K. Ries, David A. Fiellin, Shannon C. Miller, Principles of addiction medicine., 2009, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, 9780781774772, 709–710, 4th,weblink 16 August 2015, 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; 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.

Antagonists

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 receptor.WEB, Antagonist,weblink Medical definition of Antagonist, 5 November 2014, 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 (e.g., Reserpine).

Drug antagonists

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".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 response.WEB, Goeders, Nick E., Antagonist,weblink 2 December 2014, Encyclopedia of Drugs, Alcohol, and Addictive Behavior, 2001,

Precursors

{{Phenylalanine biosynthesis|align=right}}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 firing.JOURNAL, Meyers, Stephen, Use of Neurotransmitter Precursors for Treatment of Depression, Alternative Medicine Review, 5, 64–71, 2000, 10696120,weblink 1, yes,weblink" title="web.archive.org/web/20040805114256weblink">weblink 5 August 2004, dmy-all, {{ums|date=December 2017}} 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 depression.{{ums|date=December 2017}}JOURNAL, Management of depression with serotonin precursors, Biol Psychiatry, 16, 291–310, 1981, 6164407, 3, Van Praag, HM,

Catecholamine and trace amine precursors

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 area.{{ums|date=December 2017}}

Serotonin precursors

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 depression.{{ums|date=December 2017}} This conversion requires vitamin C. 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo.{{ums|date=December 2017}}

Diseases and disorders

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 research.JOURNAL, Healy, David, 21 April 2015, Serotonin and depression,weblink BMJ, en, 350, h1771, 10.1136/bmj.h1771, 1756-1833, 25900074, 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.WEB, NIMH Brain Basics,weblink U.S. National Institutes of Health, 29 October 2014, (File:CAPON Binds Nitric Oxide Synthase, Regulating NMDA Receptor–Mediated Glutamate Neurotransmission.png|thumb|CAPON Binds Nitric Oxide Synthase, Regulating NMDA Receptor–Mediated Glutamate Neurotransmission)

Neurotransmitter imbalance

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 .Netter, P. (1991) Biochemical variables in the study of temperament. In Strelau, J. & Angleitner, A. (Eds.), Explorations in temperament: International perspectives on theory and measurement 147–161. New York: Plenum Press.JOURNAL, Trofimova I, Robbins TW, 2016, Temperament and arousal systems: a new synthesis of differential psychology and functional neurochemistry, Neuroscience and Biobehavioral Reviews, 64, 382–402, 10.1016/j.neubiorev.2016.03.008, Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament and character" Arch Gen Psychiatry 1993; 50:975-990.JOURNAL, 2016, Trofimova, IN, The interlocking between functional aspects of activities and a neurochemical model of adult temperament., In: Arnold, M.C. (Ed.) Temperaments: Individual Differences, Social and Environmental Influences and Impact on Quality of Life. New York: Nova Science Publishers, Inc., 77–147, JOURNAL, Depue RA, Morrone-Strupinsky JV, 2005, A neurobehavioural model of affiliate bonding: implications for conceptualizing a human trait of affiliation, Behavioral and Brain Sciences, 28, 3, 313–350, 10.1017/s0140525x05000063, 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. Apart from recreational use, medications that directly and indirectly interact 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.Leo, J., & Lacasse, J. (10 October 2007). The Media and the Chemical Imbalance Theory of Depression. Retrieved 1 December 2014, fromweblink

Elimination of neurotransmitters

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 stored."General, Organic and Biological Chemistry Structures of Life" by Karen C. Timberlake p.661

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 also

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• Kiss-and-run fusion
• Natural neuroactive substance
• Neuroendocrine
• Neuroendocrinology
• Neuropsychopharmacology
• Neurotransmitter release

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Notes

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References

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External links

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• Molecular Cell Biology. 4th edition. Section 21.4: Neurotransmitters, Synapses, and Impulse Transmission
• Molecular Expressions Photo Gallery: The Neurotransmitter Collection
• Brain Neurotransmitters
• Endogenous Neuroactive Extracellular Signal Transducers
• {{MeshName|Neurotransmitter}}
• neuroscience for kids website
• brain explorer website

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