Neurotransmitter

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Structure of a typical chemical synapse
 
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For an introduction to concepts and terminology used in this article, see Chemical synapse.
Structure of a typical chemical synapse

Neurotransmitters are endogenous chemicals that transmit signals across a synapse from one neuron (brain cell) to another 'target' neuron.[1] Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane in the axon terminal located at the presynaptic side of a synapse. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors in the membrane on the postsynaptic side of the synapse.[2] Many neurotransmitters are synthesized from plentiful and simple precursors (such as amino acids), which are readily available from the diet and only require a small number of biosynthetic steps to convert them. Neurotransmitters play a major role in shaping everyday life and functions. Scientists do not yet know exactly how many neurotransmitters exist, but more than 100 chemical messengers have been identified.[3]

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

In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal. Low level "baseline" release also occurs without electrical stimulation. The released neurotransmitter may then move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way. This neuron may be connected to many more neurons, and if the total of excitatory influences are greater than those of inhibitory influences, the neuron will also "fire". Ultimately it will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron.[4]

Discovery[edit]

Until the early 20th century, scientists assumed that the majority of synaptic communications within the brain were electrical. However, careful histological examinations by Ramón y Cajal (1852–1934), led to the discovery of what is presently known as the synaptic cleft, a 20 to 40 nm gap between neurons. The presence of synaptic clefts suggested communications via chemical messengers traversing the synaptic cleft. Furthermore, in 1921, German pharmacologist Otto Loewi (1873–1961) confirmed that neurons can communicate by releasing chemicals. Loewi led a series of experiments involving the vagus nerves of frogs and 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 regulations of cardiac function can be mediated through changes in chemical concentrations. Otto Loewi is now accredited with discovering acetylcholine (ACh)—the first known neurotransmitter.[5] Some neurons, nevertheless, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another.[6]

Identification[edit]

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:

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify either the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal.[7] Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.[8]

Types[edit]

There are numerous ways to classify neurotransmitters. However, for classification purposes, the main neurotransmitters are: amino acids, amines (monoamines and other biogenic amines), peptides, and certain soluble gases.

Major neurotransmitters:

In addition, over 50 neuroactive peptides have been discovered and more recent peptides are found regularly. Many of these are "co-released" along with a small-molecule transmitter. Nevertheless, in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some,[10] as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).[11] 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.[4] Next 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 gasotransmitters[edit]

CategoryNameAbbreviationMetabotropicIonotropic
Small: Amino acids (Arg)Agmatineα2 adrenergic receptor Imidazoline receptorNMDA receptor
Small: Amino acidsAspartateAspNMDA receptor
Small: Amino acidsGlutamate (glutamic acid)GluMetabotropic glutamate receptorNMDA receptor (co-agonist), Kainate receptor, AMPA receptor
Small: Amino acidsGamma-aminobutyric acidGABAGABAB receptorGABAA, GABAA-ρ receptor
Small: Amino acidsGlycineGlyGlycine receptor, NMDA receptor (co-agonist)
Small: Amino acidsD-serineSerNMDA receptor (co-agonist)
Small: AcetylcholineAcetylcholineAchMuscarinic acetylcholine receptorNicotinic acetylcholine receptor
Small: Monoamine (Phe/Tyr)DopamineDADopamine receptor
Small: Monoamine (Phe/Tyr)Norepinephrine (noradrenaline)NEAdrenergic receptor
Small: Monoamine (Phe/Tyr)Epinephrine (adrenaline)EpiAdrenergic receptor
Small: Monoamine (Trp)Serotonin (5-hydroxytryptamine)5-HTSerotonin receptor, all but 5-HT35-HT3
Small: Monoamine (Trp)MelatoninMelMelatonin receptor
Small: Monoamine (His)HistamineHHistamine receptor
Small: Trace amine (Phe)PhenethylaminePEATrace amine-associated receptors: hTAAR1, hTAAR2
Small: Trace amine (Phe)N-methylphenethylamineNMPEAhTAAR1
Small: Trace amine (Phe/Tyr)TyramineTYRhTAAR1, hTAAR2
Small: Trace amine (Phe/Tyr)OctopamineOcthTAAR1
Small: Trace amine (Phe/Tyr)SynephrineSynhTAAR1
Small: Trace amine (Phe/Tyr)3-methoxytyramine3-MThTAAR1
Small: Trace amine (Trp)TryptaminehTAAR1, various 5-HT receptors
Small: Trace amine (Trp)N-methyltryptamineNMThTAAR1, various 5-HT receptors,
NeuropeptidesN-AcetylaspartylglutamateNAAGMetabotropic glutamate receptors; selective agonist of mGluR3
PP: GastrinsGastrin
PP: GastrinsCholecystokininCCKCholecystokinin receptor
PP: NeurohypophysealsVasopressinAVPVasopressin receptor
PP: NeurohypophysealsOxytocinOTOxytocin receptor
PP: NeurohypophysealsNeurophysin I
PP: NeurohypophysealsNeurophysin II
PP: Neuropeptide YNeuropeptide YNYNeuropeptide Y receptor
PP: Neuropeptide YPancreatic polypeptidePP
PP: Neuropeptide YPeptide YYPYY
PP: OpioidsCorticotropin (adrenocorticotropic hormone)ACTHCorticotropin receptor
PP: OpioidsEnkephalineδ-opioid receptor
PP: OpioidsDynorphinκ-opioid receptor
PP: OpioidsEndorphinμ-opioid receptor
PP: SecretinsSecretinSecretin receptor
PP: SecretinsMotilinMotilin receptor
PP: SecretinsGlucagonGlucagon receptor
PP: SecretinsVasoactive intestinal peptideVIPVasoactive intestinal peptide receptor
PP: SecretinsGrowth hormone-releasing factorGRF
PP: SomatostatinsSomatostatinSomatostatin receptor
SS: TachykininsNeurokinin A
SS: TachykininsNeurokinin B
SS: TachykininsSubstance P
PP: OtherCocaine and amphetamine regulated transcriptCARTUnknown Gi/Go-coupled receptor[12]
PP: OtherBombesin
PP: OtherGastrin releasing peptideGRP
GasNitric oxideNOSoluble guanylyl cyclase
GasCarbon monoxideCOHeme bound to potassium channels
OtherAnandamideAEACannabinoid receptor
Other2-Arachidonoylglycerol2-AGCannabinoid receptor
Other2-Arachidonyl glyceryl ether2-AGECannabinoid receptor
OtherN-Arachidonoyl dopamineNADACannabinoid receptorTRPV1
OtherVirodhamineCannabinoid receptor
OtherAdenosine triphosphateATPP2Y12P2X receptor
OtherAdenosineAdoAdenosine receptor

Actions[edit]

Neurons form elaborate networks through which nerve impulses—action potentials—travel. Each neuron has 15,000 connections with neighboring neurons. Neurons do not make physical contact with one another (except in the case of an electrical synapse through a gap junction); instead, neurons interact at synapses- a junction within two nerve cells, consisting of a miniature gap which impulses pass by a neurotransmitter. A neuron transports information through an action potential. When an action potential arrives at the presynaptic terminal button, it stimulates the release of a neurotransmitter that is then released into the synaptic cleft to bind onto the receptors of the postsynaptic membrane.

Excitatory and inhibitory[edit]

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. It influences trans-membrane ion flow either to increase or to decrease 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, excitatory or inhibitory, 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.

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. You can think of excitatory and inhibitory messages as interacting from these two different perspectives.

From an inhibitory perspective, you can picture excitation coming in over the dendrites and spreading 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.[13]

Examples of important neurotransmitter actions[edit]

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:

Major neurotransmitter systems[edit]

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.

A brief comparison of the major neurotransmitter systems follows:

Neurotransmitter systems
SystemOrigin [20]Regulated effects and processes[20]
Noradrenaline system
[21][22]
Noradernergic pathways:
Dopamine system
[23]
Dopaminergic pathways:
Histamine system
[24]
Histaminergic pathways:
  • Arousal
  • feeding and energy balance
  • learning
  • memory
  • sleep
Serotonin system
[21][25][26]
Serotonergic pathways:

Caudal nuclei (CN):
Raphe magnus, raphe pallidus, raphe obscuris

  • Caudal projections

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

  • Rostral projections
GABA system
[27]
GABAergic pathways:
  •  
  • (coming soon)
Acetylcholine system
[21][28]
Cholinergic pathways:

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

  • Brainstem nuclei projections

Forebrain cholinergic nuclei (FCN):
Medial septal nucleus & diagonal band

  • Forebrain nuclei projections

Drug effects[edit]

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 Valium, a benzodiazepine that mimics effects of the endogenous neurotransmitter gamma-aminobutyric acid (GABA) to decrease anxiety. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous system. Drugs such as tetrodotoxin that block neural activity are typically lethal.

Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin.[29] 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.

Agonists[edit]

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.[30] An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter.[31]

Nicotine, found in tobacco, is an agonist for acetylcholine at nicotinic receptors.[32] Opiate agonists include morphine, heroin, hydrocodone, oxycodone, codeine, and methadone. These drugs activate mu opioid receptors that typically respond to endogenous transmitters such as enkephalins. When these receptors are activated, individuals experience euphoria, pain relief, and drowsiness.[32]

Antagonists[edit]

Main article: Receptor antagonist

An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (as an opiate); especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by combining with and blocking its nervous receptor.[33]

Precursors[edit]

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.[37] 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.[37][38]

Catecholamine and trace amine precursors[edit]

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.[37]

Serotonin precursors[edit]

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.[37] This conversion requires vitamin C.[19] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo.[37]

Diseases and disorders[edit]

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 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). Moreover, research shows that people diagnosed with depression often have lower than normal levels of serotonin. The types of medications most commonly prescribed to treat depression act by blocking the recycling, or reuptake, of serotonin by the sending neuron. As a result, more serotonin stays in the synapse for the receiving neuron to bind onto, leading to more normal mood functioning. Furthermore, problems in making or using glutamate have been linked to many mental disorders, including autism, obsessive compulsive disorder (OCD), schizophrenia, and depression.[39]

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

Elimination of neurotransmitters[edit]

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. 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.[40]

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.

Neurotransmitter Imbalances[edit]

Neurotransmitter imbalances have been connected to the cause of many diseases. These include Parkinson's, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic changes in weight and addictions. They all involve amino acids which form neurotransmitters. The acids are made up of protein and without a sufficient amount of this then our cells are not structured properly; therefore not functioning properly. Scientists are trying to supplement medication by changing the diets of some patients instead; adding amino acids into the body. Diseases such as depression and anxiety disorders prescribe patients with medications such as Celexa, and Effexor. These medications directly react with neurotransmitter serotonin and norepinephrine which bind to receptors creating stabilization for the patients. [41]

See also[edit]

References[edit]

  1. ^ "Neurotransmitter" at Dorland's Medical Dictionary
  2. ^ Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental Foundations. Boston: Pearson
  3. ^ Cherry, Kendra. "What is a Nuerotransmitter?". Retrieved 6 October 2014. 
  4. ^ a b c Robert Sapolsky (2005). "Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition". The Teaching Company. "see pages 13 & 14 of Guide Book" 
  5. ^ Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 ISBN 0-07-727620-5
  6. ^ "Junctions Between Cells". Retrieved 22 November 2010. 
  7. ^ University, S. Marc Breedlove, Michigan State University, Neil V. Watson, Simon Fraser (2013). Biological psychology : an introduction to behavioral, cognitive, and clinical neuroscience (Seventh edition. ed.). Sunderland, MA: Sinauer Associates. ISBN 978-0878939275. 
  8. ^ a b Whishaw, Bryan Kolb, Ian Q. (2014). An introduction to brain and behavior (4th ed.). New York, NY: Worth Publishers. pp. 150–151. ISBN 978-1429242288. 
  9. ^ Snyder SH, Innis RB (1979). "Peptide neurotransmitters". Annu. Rev. Biochem. 48: 755–82. doi:10.1146/annurev.bi.48.070179.003543. PMID 38738. 
  10. ^ Kodirov,Sodikdjon A., Shuichi Takizawa, Jamie Joseph, Eric R. Kandel, Gleb P. Shumyatsky, and Vadim Y. Bolshakov. Synaptically released zinc gates long-term potentiation in fear conditioning pathways. PNAS, 10 October 2006. 103(41): 15218-23. doi:10.1073/pnas.0607131103
  11. ^ Nitric oxide and other gaseous neurotransmitters
  12. ^ Lin Y, Hall RA, Kuhar MJ; Hall; Kuhar (October 2011). "CART peptide stimulation of G protein-mediated signaling in differentiated PC12 cells: identification of PACAP 6–38 as a CART receptor antagonist". Neuropeptides 45 (5): 351–358. doi:10.1016/j.npep.2011.07.006. PMC 3170513. PMID 21855138. 
  13. ^ Whishaw, Bryan Kolb, Ian Q. (2014). An introduction to brain and behavior (4th ed. ed.). New York, NY: Worth Publishers. ISBN 978-1429242288. 
  14. ^ Glutamate: Seizures and strokes- PLoS Biol. 2006 November; 4(11): e371. Published online 2006 October 17. doi: 10.1371/journal.pbio.0040371 by author Liza Gross- Courtesy Public Library of Science (2006); PubMed (PMC) of NCBI, Retrieved 2013-16-13
  15. ^ Yang JL, Sykora P, Wilson DM, Mattson MP, Bohr VA (August 2011). "The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency". Mech. Ageing Dev. 132 (8–9): 405–11. doi:10.1016/j.mad.2011.06.005. PMC 3367503. PMID 21729715. 
  16. ^ Orexin receptor antagonists a new class of sleeping pill, National Sleep Foundation.
  17. ^ "Acetylcholine Receptors". Ebi.ac.uk. Retrieved 25 August 2014. 
  18. ^ Schacter, Gilbert and Weger. Psychology.United States of America.2009.Print.
  19. ^ a b University of Bristol. "Introduction to Serotonin". Retrieved 15 October 2009. 
  20. ^ a b Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. pp. 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system. ISBN 0-443-07145-4. 
  21. ^ a b c Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 155. ISBN 9780071481274. "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." 
  22. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 156–157. ISBN 9780071481274. "The locus ceruleus (LC), which is located on the floor of the fourth ventricle in the rostral pons, contains more than 50% of all noradrenergic neurons in the brain; it innervates both the forebrain (eg, it provides virtually all the NE to the cerebral cortex) and regions of the brainstem and spinal cord. ... The other noradrenergic neurons in the brain occur in loose collections of cells in the brainstem, including the lateral tegmental regions. These neurons project largely within the brainstem and spinal cord. NE, along with 5HT, ACh, histamine, and orexin, is a critical regulator of the sleep-wake cycle and of levels of arousal. ... LC firing may also increase anxiety ...Stimulation of β-adrenergic receptors in the amygdala results in enhanced memory for stimuli encoded under strong negative emotion ... Epinephrine occurs in only a small number of central neurons, all located in the medulla. Epinephrine is involved in visceral functions, such as control of respiration." 
  23. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274. "Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. ..." 
  24. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 175–176. ISBN 9780071481274. "Within the brain, histamine is synthesized exclusively by neurons with their cell bodies in the tuberomammillary nucleus (TMN) that lies within the posterior hypothalamus. There are approximately 64000 histaminergic neurons per side in humans. These cells project throughout the brain and spinal cord. Areas that receive especially dense projections include the cerebral cortex, hippocampus, neostriatum, nucleus accumbens, amygdala, and hypothalamus.  ... While the best characterized function of the histamine system in the brain is regulation of sleep and arousal, histamine is also involved in learning and memory ...It also appears that histamine is involved in the regulation of feeding and energy balance." 
  25. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 158–160. ISBN 9780071481274. "[The] dorsal raphe preferentially innervates the cerebral cortex, thalamus, striatal regions (caudate-putamen and nucleus accumbens), and dopaminergic nuclei of the midbrain (eg, the substantia nigra and ventral tegmental area), while the median raphe innervates the hippocampus, septum, and other structures of the limbic forebrain. ... it is clear that 5HT influences sleep, arousal, attention, processing of sensory information in the cerebral cortex, and important aspects of emotion (likely including aggression) and mood regulation. ...The rostral nuclei, which include the nucleus linearis, dorsal raphe, medial raphe, and raphe pontis, innervate most of the brain, including the cerebellum. The caudal nuclei, which comprise the raphe magnus, raphe pallidus, and raphe obscuris, have more limited projections that terminate in the cerebellum, brainstem, and spinal cord." 
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