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Neurotransmitter

(Redirected fromNeurotransmitters)
For an introduction to concepts and terminology used in this article, seeChemical synapse.

Aneurotransmitteris asignaling moleculesecreted by aneuronto affect another cell across asynapse.The cell receiving the signal, or target cell, may be another neuron, but could also be aglandormuscle cell.[1]

Structure of a typicalchemical synapse

Neurotransmitters are released fromsynaptic vesiclesinto thesynaptic cleftwhere they are able to interact withneurotransmitter receptorson the target cell. Some neurotransmitters are also stored inlarge dense core vesicles.[2]The neurotransmitter's effect on the target cell is determined by the receptor it binds to. Many neurotransmitters are synthesized from simple and plentiful precursors such asamino acids,which are readily available and often require a small number ofbiosyntheticsteps for conversion.

Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in humans is unknown, but more than 100 have been identified.[3]Common neurotransmitters includeglutamate,GABA,acetylcholine,glycine,dopamineandnorepinephrine.

Mechanism and cycle

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See also:Neurotransmission

Synthesis

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Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found abundantly in the cell. Classes of neurotransmitters includeamino acids,monoamines,andpeptides.Monoamines are synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide neurotransmitters, orneuropeptides,are protein transmitters which are larger than the classical small-molecule neurotransmitters and are often released together to elicit a modulatory effect.[4]Purine neurotransmitters, likeATP,are derived from nucleic acids. Metabolic products such asnitric oxideandcarbon monoxidehave also been reported to act like neurotransmitters.[5]

Examples
Amino acids glycine,glutamate
Monoamines serotonin,epinephrine,dopamine
Peptides substance P,opioids
Purines ATP,GTP
Other nitric oxide,carbon monoxide

Storage

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Synaptic vesicles containing neurotransmitters

Neurotransmitters are generally stored insynaptic vesicles,clustered close to thecell membraneat theaxon terminalof the presynaptic neuron. However, some neurotransmitters, like the metabolic gases carbon monoxide and nitric oxide, are synthesized and released immediately following an action potential without ever being stored in vesicles.[6]

Release

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Generally, a neurotransmitter is released viaexocytosisat the presynaptic terminal in response to an electrical signal called anaction potentialin the presynaptic neuron. However, low-level "baseline" release also occurs without electrical stimulation. Neurotransmitters are released into and diffuse across thesynaptic cleft,where they bind to specificreceptorson the membrane of the postsynaptic neuron.[7]

Receptor interaction

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

Elimination

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Acetylcholine is cleaved in the synaptic cleft into acetic acid and choline.

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

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

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

Discovery

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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, throughhistologicalexaminations byRamón y Cajal,a 20 to 40 nm gap between neurons, known today as thesynaptic cleft,was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologistOtto Loewiconfirmed 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 discoveringacetylcholine(ACh) – the first known neurotransmitter.[14]

Identification

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To identify neurotransmitters, the following criteria are typically considered:

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

However, given advances inpharmacology,genetics,and chemicalneuroanatomy,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 orreuptakeof transmitters.

The anatomical localization of neurotransmitters is typically determined usingimmunocytochemicaltechniques, 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 theneuropeptides,are co-localized, that is, a neuron may release more than one transmitter from itssynaptic terminal.[16]Various techniques and experiments such asstaining,stimulating, and collecting can be used to identify neurotransmitters throughout thecentral nervous system.[17]

Actions

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

Modulation

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

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 theaxon hillockto trigger anaction potential.If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.[21]

Neurotransmitter actions

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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.

Types

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There are many different ways to classify neurotransmitters and are commonly classified intoamino acids,monoaminesandpeptides.[35]

Some of the major neurotransmitters are:

In addition, over 100 neuroactivepeptideshave been found, and new ones are discovered regularly.[38][39]Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse.Beta-Endorphinis a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions withopioid receptorsin thecentral nervous system.

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

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

List of neurotransmitters, peptides, and gaseous signaling molecules

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Neurotransmitters
Category Name Abbreviation Metabotropic Ionotropic
SmallTooltip Small molecule:Amino acids(Arg) Arginine Arg, R α2-Adrenergic receptors,imidazoline receptors NMDA receptors
Small: Amino acids Aspartate Asp, D – NMDA receptors
Small: Amino acids Glutamate Glu, E Metabotropic glutamate receptors NMDA receptors,kainate receptors,AMPARs
Small: Amino acids Gamma-aminobutyric acid GABA GABABreceptors GABAAreceptors,GABAA-ρ receptors
Small: Amino acids Glycine Gly, G – NMDA receptors,glycine receptors
Small: Amino acids D-serine Ser, S – NMDA receptors
Small: Acetylcholine Acetylcholine ACh Muscarinic acetylcholine receptors Nicotinic acetylcholine receptors
Small:Monoamine(Phe/Tyr) Dopamine DA Dopamine receptors,trace amine-associated receptor 1[42][43] –
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 Trace amine-associated receptorsTAAR1,TAAR2 –
Small: Trace amine (Phe) N-methylphenethylamine NMPEA TAAR1 –
Small: Trace amine (Phe/Tyr) Tyramine TYR TAAR1,TAAR2 –
Small: Trace amine (Phe/Tyr) octopamine Oct TAAR1 –
Small: Trace amine (Phe/Tyr) Synephrine Syn TAAR1 –
Small: Trace amine (Trp) Tryptamine TAAR1,variousserotonin receptors –
Small: Trace amine (Trp) N-methyltryptamine NMT TAAR1,variousserotonin 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
Small: Purine Nicotinamide adenine dinucleotide β-NAD P2Y receptors P2X receptors
Neuropeptides
Category Name Abbreviation Metabotropic Ionotropic
Bombesin-like peptides Bombesin BBR1-2-3 –
Bombesin-like peptide Gastrin releasing peptide GRP – –
Bombesin-like peptide Neuromedin B NMB Neuromedin B receptor –
Bradykinins Bradykinin B1,B2 –
Calcitonin/CGRP family Calcitonin Calcitonin receptor –
Calcitonin/CGRP family Calcitonin gene-related peptide CGRP CALCRL –
Corticotropin-releasing factors Corticotropin-releasing hormone CRH CRHR1 –
Corticotropin-releasing factors Urocortin CRHR1 –
Galanins Galanin GALR1,GALR2,GALR3 –
Galanins Galanin-like peptide GALR1,GALR2,GALR3 –
Gastrins Gastrin Cholecystokinin B receptor –
Gastrins Cholecystokinin CCK Cholecystokinin receptors –
Granins Chromogranin A ChgA – –
Melanocortins Adrenocorticotropic hormone ACTH ACTH receptor –
Melanocortins Proopiomelanocortin POMC Melanocortin 4 receptor –
Melanocortins Melanocyte-stimulating hormones MSH Melanocortin receptors –
Neurohypophyseals Vasopressin AVP Vasopressin receptors –
Neurohypophyseals Oxytocin OT Oxytocin receptor –
Neurohypophyseals Neurophysin I – –
Neurohypophyseals Neurophysin II – –
Neurohypophyseals Copeptin – –
Neuromedins Neuromedin U NmU NmUR1,NmUR2 –
Neuropeptide B/W Neuropeptide B NPB NPBW1,NPBW2 –
Neuropeptide B/W Neuropeptide S NPS Neuropeptide S receptors –
Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptors –
Neuropeptide Y Pancreatic polypeptide PP – –
Neuropeptide Y Peptide YY PYY – –
Opioids Enkephalins δ-Opioid receptor –
Opioids Dynorphins κ-Opioid receptor –
Opioids Neoendorphins κ-Opioid receptor –
Opioids Endorphins μ-Opioid receptors –
Opioids Endomorphins μ-Opioid receptors –
Opioids Morphine μ-Opioid receptors –
Opioids Nociceptin/orphanin FQ N/OFQ Nociceptin receptors –
Orexins Orexin A OX-A Orexin receptors –
Orexins Orexin B OX-B Orexin receptors –
Parathyroid hormone family Parathyroid hormone-related protein PTHrP – –
RFamides Kisspeptin KiSS GPR54 –
RFamides Neuropeptide FF NPFF NPFF1, NPFF2 –
RFamides Prolactin-releasing peptide PrRP PrRPR –
RFamides Pyroglutamylated RFamide peptide QRFP GPR103 –
Secretins Secretin Secretin receptor –
Secretins Motilin Motilin receptor –
Secretins Glucagon Glucagon receptor –
Secretins Glucagon-like peptide-1 GLP-1 Glucagon-like peptide 1 receptor –
Secretins Glucagon-like peptide-2 GLP-2 Glucagon-like peptide 2 receptor –
Secretins Vasoactive intestinal peptide VIP Vasoactive intestinal peptide receptors –
Secretins Growth hormone–releasing hormone GHRH Growth hormone–releasing hormone receptor –
Secretins Pituitary adenylate cyclase-activating peptide PACAP ADCYAP1R1 –
Somatostatins Somatostatin Somatostatin receptors –
Tachykinins Neurokinin A – –
Tachykinins Neurokinin B – –
Tachykinins Substance P – –
Tachykinins Neuropeptide K – –
Other Agouti-related peptide AgRP Melanocortin receptor–
Other N-Acetylaspartylglutamate NAAG Metabotropic glutamate receptor 3(mGluR3) –
Other Cocaine- and amphetamine-regulated transcript CART UnknownGi/Go-coupled receptor[44] –
Other Gonadotropin-releasing hormone GnRH GnRHR –
Other Thyrotropin-releasing hormone TRH TRHR –
Other Melanin-concentrating hormone MCH MCHR1,2 –
Gasotransmitters
Category Name Abbreviation Metabotropic Ionotropic
Gaseous signaling molecule Nitric oxide NO Solubleguanylyl cyclase –
Gaseous signaling molecule Carbon monoxide CO – Hemebound topotassium channels
Gaseous signaling molecule Hydrogen sulfide H2S – –

Neurotransmitter systems

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Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, calledvolume transmission.Major neurotransmitter systems include thenoradrenaline(norepinephrine) system, thedopaminesystem, theserotoninsystem, and thecholinergicsystem, among others.Trace amineshave a modulatory effect on neurotransmission inmonoaminepathways (i.e., dopamine, norepinephrine, and serotonin pathways) throughout the brain via signaling throughtrace amine-associated receptor 1.[45][46]A brief comparison of these systems follows:

Neurotransmitter systems in the brain
System Pathway origin and projections Regulated cognitive processes and behaviors
Noradrenaline system
[47][48][49][50][51][52] 		Noradrenergic pathways:
Dopamine system
[49][50][51][53][54][55] 		Dopaminergic pathways:
  • Hypothalamospinal projection
Histamine system
[50][51][56] 		Histaminergic pathways:
Serotonin system
[47][49][50][51][57][58][59] 		Serotonergic pathways:

Caudal nuclei(CN):
Raphe magnus,raphe pallidus,andraphe obscurus

  • Caudal projections

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

  • Rostral projections
Acetylcholine system
[47][49][50][51][60] 		Cholinergic pathways:

Forebrain cholinergic nuclei (FCN):
Nucleus basalis of Meynert,medial septal nucleus,anddiagonal band

  • Forebrain nuclei projections

Striatal tonically active cholinergic neurons (TAN)

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

  • Brainstem nuclei projections
Adrenaline system
[61][62] 		Adrenergic pathways:
Further information:Neural pathway,Neuromodulation,andList of regions in the human brain

Drug effects

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

Drugs can influence behavior by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are calledreceptor 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 receptoragonists.An example of a receptor agonist ismorphine,an opiate that mimics effects of the endogenous neurotransmitterβ-endorphinto 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 peripheralnervous system.Drugs such astetrodotoxinthat 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 ofdopamineback into thepresynapticneuron, leaving the neurotransmitter molecules in thesynaptic gapfor an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on thepostsynapticneuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to thedownregulationof 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.Fluoxetineis aselective serotonin re-uptake inhibitor(SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin.[64]AMPTprevents the conversion of tyrosine toL-DOPA,the precursor to dopamine;reserpineprevents dopamine storage withinvesicles;anddeprenylinhibitsmonoamine oxidase(MAO)-B and thus increases dopamine levels.

Drug–neurotransmitter interactions[65]
Drug Interacts with Receptor interaction Type Effects
Botulinum toxin(Botox) Acetylcholine – Antagonist Blocksacetylcholinerelease in PNS

Prevents muscle contractions

Black widow spider venom Acetylcholine – Agonist Promotes acetylcholine release in PNS

Stimulates muscle contractions

Neostigmine Acetylcholine – – Interferes with acetylcholinerase activity

Increases effects of ACh at receptors

Used to treat myasthenia gravis

Nicotine Acetylcholine Nicotinic(skeletal muscle) Agonist Increases ACh activity

Increases attention

Reinforcing effects

d-tubocurarine Acetylcholine Nicotinic(skeletal muscle) Antagonist Decreases activity at receptor site
Curare Acetylcholine Nicotinic(skeletal muscle) Antagonist Decreases ACh activity

Prevents muscle contractions

Muscarine Acetylcholine Muscarinic(heart and smooth muscle) Agonist Increases ACh activity

Toxic

Atropine Acetylcholine Muscarinic(heart and smooth muscle) Antagonist Blocks pupil constriction

Blocks saliva production

Scopolamine (hyoscine) Acetylcholine 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 vesicles

Causes sedation and depression

Apomorphine Dopamine D2 receptor(presynaptic autoreceptors/postsynaptic receptors) Antagonist (low dose) / direct agonist (high dose) Low dose: blocks autoreceptors

High dose: stimulates postsynaptic receptors

Amphetamine Dopamine/norepinephrine – Indirect agonist Releases dopamine, noradrenaline, and serotonin

Blocks reuptake[45][46]

Methamphetamine Dopamine/norepinephrine – – Releases dopamine and noradrenaline

Blocks reuptake

Methylphenidate Dopamine – – Blocks reuptake

Enhances attention and impulse control in ADHD

Cocaine Dopamine – Indirect agonist Blocks reuptake into presynapse

Blocks voltage-dependent sodium channels

Can be used as a topical anesthetic (eye drops)

Deprenyl Dopamine – Agonist Inhibits MAO-B

Prevents destruction of dopamine

Chlorpromazine Dopamine D2 Receptors Antagonist Blocks D2 receptors

Alleviates hallucinations

MPTP Dopamine – – Results in Parkinson-like symptoms
PCPA Serotonin (5-HT) – Antagonist Disrupts serotonin synthesis by blocking the activity oftryptophan hydroxylase
Ondansetron Serotonin (5-HT) 5-HT3receptors Antagonist Reduces side effects of chemotherapy and radiation

Reduces nausea and vomiting

Buspirone Serotonin (5-HT) 5-HT1Areceptors Partial agonist Treats symptoms of anxiety and depression
Fluoxetine Serotonin (5-HT) supports5-HTreuptake SSRI Inhibits reuptake of serotonin

Treats depression, some anxiety disorders, and OCD[64]Common examples:ProzacandSarafem

Fenfluramine Serotonin (5-HT) – – Causes release of serotonin

Inhibits reuptake of serotonin

Used as an appetite suppressant

Lysergic acid diethylamide Serotonin (5-HT) Post-synaptic 5-HT2Areceptors Direct agonist Produces visual perception distortions

Stimulates 5-HT2Areceptors in forebrain

Methylenedioxy­methamphetamine (MDMA) Serotonin (5-HT)/norepinphrine – – Stimulates release of serotonin and norepinephrine and inhibits the reuptake

Causes excitatory and hallucinogenic effects

Strychnine Glycine – Antagonist Causes severe muscle spasms[66]
Diphenhydramine Histamine Crosses blood–brain barrier to cause drowsiness
Tetrahydrocannabinol(THC) Endocannabinoids Cannabinoid (CB) receptors Agonist Produces analgesia and sedation

Increases appetite

Cognitive effects

Rimonabant Endocannabinoids Cannabinoid (CB) receptors Antagonist Suppresses appetite

Used in smoking cessation

MAFP Endocannabinoids – – Inhibits FAAH

Used in research to increase cannabinoid system activity

AM1172 Endocannabinoids – – Blocks cannabinoid reuptake

Used in research to increase cannabinoid system activity

Anandamide (endogenous) – Cannabinoid (CB) receptors; 5-HT3receptors – Reduce nausea and vomiting
Caffeine Adenosine Adenosine receptors Antagonist Blocks adenosine receptors

Increases wakefulness

PCP Glutamate NMDA receptor Indirect antagonist Blocks PCP binding site

Prevents calcium ions from entering neurons

Impairs learning

AP5 Glutamate NMDA receptor Antagonist Blocks glutamate binding site on NMDA receptor

Impairs synaptic plasticity and certain forms of learning

Ketamine Glutamate NMDA receptor Antagonist Used as anesthesia

Induces trance-like state, helps with pain relief and sedation

NMDA Glutamate NMDA receptor Agonist Used in research to study NMDA receptor

Ionotropic receptor

AMPA Glutamate AMPA receptor Agonist Used in research to study AMPA receptor

Ionotropic receptor

Allyglycine GABA – – Inhibits GABA synthesis

Causes seizures

Muscimol GABA GABA receptor Agonist Causes sedation
Bicuculine GABA GABA receptor Antagonist Causes Seizures
Benzodiazepines GABA GABAAreceptor Indirect agonists Anxiolytic, sedation, memory impairment, muscle relaxation
Barbiturates GABA GABAAreceptor Indirect agonists Sedation, memory impairment, muscle relaxation
Alcohol GABA GABA receptor Indirect agonist Sedation, memory impairment, muscle relaxation
Picrotoxin GABA GABAAreceptor Indirect antagonist High doses cause seizures
Tiagabine GABA – Antagonist GABA transporter antagonist

Increase availability of GABA

Reduces the likelihood of seizures

Moclobemide Norepinephrine – Agonist Blocks MAO-A to treat depression
Idazoxan Norepinephrine alpha-2 adrenergic autoreceptors Agonist Blocks alpha-2 autoreceptors

Used to study norepinephrine system

Fusaric acid Norepinephrine – – Inhibits activity of dopamine beta-hydroxylase which blocks the production of norepinephrine

Used to study norepinephrine system without affecting dopamine system

Opiates (opium,morphine,heroin,andoxycodone) Opioids Opioid receptor[67] Agonists Analgesia, sedation, and reinforcing effects
Naloxone Opioids – Antagonist Reverses opiate intoxication or overdose symptoms (i.e. problems with breathing)

Agonists

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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 substance.[68]An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or indirectly. Direct-binding agonists can be further characterized asfull agonists,partial agonists,inverse agonists.[69][70]

Direct agonistsact similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic neuron, or both.[71]Typically, neurotransmitter receptors are located on the postsynaptic neuron, while neurotransmitterautoreceptorsare located on the presynaptic neuron, as is the case formonoamine neurotransmitters;[45]in some cases, a neurotransmitter utilizesretrograde neurotransmission,a type of feedback signaling in neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic neuron.[72][note 1]Nicotine,a compound found intobacco,is a direct agonist of mostnicotinic acetylcholine receptors,mainly located incholinergic neurons.[67]Opiates,such asmorphine,heroin,hydrocodone,oxycodone,codeine,andmethadone,areμ-opioid receptoragonists; this action mediates theireuphoriantandpain relievingproperties.[67]

Indirect agonistsincrease the binding of neurotransmitters at their target receptors by stimulating the release or preventing thereuptakeof neurotransmitters.[71]Some indirect agoniststrigger neurotransmitter releaseandprevent neurotransmitter reuptake.Amphetamine,for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their respective neurons;[45][46]it produces both neurotransmitter release into the presynaptic neuron and subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activatingTAAR1,a presynapticG protein-coupled receptor,and binding to a site onVMAT2,a type ofmonoamine transporterlocated onsynaptic vesicleswithinmonoamine neurons.[45][46]

Antagonists

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Main article:Receptor antagonist

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

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

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

Drug antagonists

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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 thedose–response relationshipfor 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.[74]

Precursors

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Biosynthetic pathways forcatecholaminesandtrace aminesin thehuman brain[75][76][77]
In humans,catecholaminesand phenethylaminergictrace aminesare derived from theamino acidL-phenylalanine.

While intake of neurotransmitterprecursorsdoes increase neurotransmitter synthesis, evidence is mixed as to whetherneurotransmitter releaseand 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.[78][unreliable medical source?]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.[78][unreliable medical source?][79]

Catecholamine and trace amine precursors

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L-DOPA,a precursor ofdopaminethat crosses theblood–brain barrier,is used in the treatment ofParkinson's disease.For depressed patients where low activity of the neurotransmitternorepinephrineis implicated, there is only little evidence for benefit of neurotransmitter precursor administration.L-phenylalanineandL-tyrosineare both precursors fordopamine,norepinephrine,andepinephrine.These conversions requirevitamin B6,vitamin C,andS-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.[78][unreliable medical source?]

Serotonin precursors

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Administration ofL-tryptophan,a precursor forserotonin,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.[78][unreliable medical source?]This conversion requiresvitamin C.[30]5-hydroxytryptophan(5-HTP), also a precursor forserotonin,is more effective than a placebo.[78][unreliable medical source?]

Diseases and disorders

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Diseases and disorders may also affect specific neurotransmitter systems. The following are disorders involved in either an increase, decrease, or imbalance of certain neurotransmitters.

Dopamine

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For example, problems in producing dopamine (mainly in thesubstantia nigra) can result inParkinson'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 likeschizophreniaorattention deficit hyperactivity disorder(ADHD). Dopamine is also involved in addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especiallyopioidandmethamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.

Serotonin

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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 withdepressionmight have lower-than-normal serotonin levels. Though widely popularized, this theory was not borne out in subsequent research.[80]Therefore,selective serotonin reuptake inhibitors (SSRIs)are used to increase the amounts of serotonin in synapses.

Glutamate

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CAPON binds nitric oxide synthase, regulating NMDA receptor–mediated glutamate neurotransmission

Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental disorders, includingautism,obsessive–compulsive disorder(OCD),schizophrenia,anddepression.[81]Having too much glutamate has been linked to neurological diseases such asParkinson's disease,multiple sclerosis,Alzheimer's disease,stroke,andALS(amyotrophic lateral sclerosis).[82]

Neurotransmitter imbalance

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Generally, there are no scientifically established "norms" for appropriate levels or "balances" of different neurotransmitters. In most cases, it is practically impossible to measure neurotransmitter levels in the brain or body at any given moment. Neurotransmitters regulate each other's release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people.[83][84][85][86][87]However, significant imbalances or disruptions in neurotransmitter systems are associated with various diseases and mental disorders, including Parkinson's disease, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic weight changes, and addictions. Some of these conditions are also related to neurotransmitter switching, a phenomenon where neurons change the type of neurotransmitters they release.[88][89][90]Chronic physical or emotional stress can be a contributor to neurotransmitter system changes. Genetics also plays a role in neurotransmitter activities.

Apart from recreational use, medications that directly and indirectly interact with one or more transmitter or its receptor are commonly prescribed for psychiatric and psychological issues. Notably, drugs interacting withserotoninandnorepinephrineare 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.[91]Studies shown that dopamine imbalance has an influence on multiple sclerosis and other neurological disorders.[92]

See also

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Notes

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  1. ^In the central nervous system,anandamideotherendocannabinoidsutilize retrograde neurotransmission, since their release is postsynaptic, while their target receptor,cannabinoid receptor 1(CB1), is presynaptic.[72]Thecannabisplant containsΔ9-tetrahydrocannabinol,which is a direct agonist at CB1.[72]
  1. ^GABA is anon-proteinogenicamino acid

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  47. ^abcMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. p. 155.ISBN9780071481274.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.
  48. ^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 145, 156–157.ISBN9780071481274.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.
  49. ^abcdRang HP (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.ISBN978-0-443-07145-4.
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  51. ^abcdeMalenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York, USA: McGraw-Hill Medical. p. 295.ISBN9780071481274.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.
  52. ^Rinaman L (February 2011)."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.doi:10.1152/ajpregu.00556.2010.PMC3043801.PMID20962208.
  53. ^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157.ISBN9780071481274.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....
  54. ^Calipari ES, Bagot RC, Purushothaman I, Davidson TJ, Yorgason JT, Peña CJ, et al. (March 2016)."In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward".Proceedings of the National Academy of Sciences of the United States of America.113(10): 2726–31.Bibcode:2016PNAS..113.2726C.doi:10.1073/pnas.1521238113.PMC4791010.PMID26831103.Previous work has demonstrated that optogenetically stimulating D1 MSNs promotes reward, whereas stimulating D2 MSNs produces aversion.
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    Figure 3: The ventral striatum and self-administration of amphetamine
  56. ^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 175–176.ISBN9780071481274.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.
  57. ^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience(2nd ed.). New York: McGraw-Hill Medical. pp. 158–160.ISBN9780071481274.[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.
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