Neurotransmitter

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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, on 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 which require only a small number of biosynthetic steps to convert.

Most neurotransmitters are about the size of a single amino acid, but some neurotransmitters may be the size of larger proteins or peptides. A neurotransmitter is available only briefly – before rapid deactivation – to bind to the postsynaptic receptors. Deactivation may occur due to: the removal of neurotransmitter by re-uptake into the presynaptic terminal; or degradative enzymes in the synaptic cleft. Nevertheless, short-term exposure of the receptor to 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 is greater than that of inhibitory influences, it will also "fire". That is to say, it will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron.[3]

Discovery[edit]

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 accredited with discovering acetylcholine (ACh)—the first known neurotransmitter.[4] 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.[5]

Neurons form elaborate networks through which nerve impulses (action potentials) travel. Each neuron has as many as 15,000 connections with other 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 neuron transports its information by way of a nerve impulse. When a nerve impulse arrives at the synapse, it may release neurotransmitters, which 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 is greater than that of inhibitory influences, 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.

Identification[edit]

The chemical identity of neurotransmitters is often difficult to determine experimentally. Imaging technologies such as electron microscopy can visually identify vesicles on the presynaptic side of a synapse. A lack of experimental methodology to identify the chemical identity of neurotransmitters in the vesicles led to many historical controversies over what endogenous chemicals act as transmitters. In the 1960s, neurochemists worked out a set of experimentally tractable rules. Per those rules, a chemical could be classified as a neurotransmitter if it meets the following conditions:

  • There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.
  • The chemical is present in the presynaptic element.
  • It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron.
  • There are postsynaptic receptors and the chemical is able to bind to them.
  • A biochemical mechanism for inactivation is present.

Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of these rules.

A series of experiments can now be done, with much better precision, in a few months.

Types[edit]

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

Major neurotransmitters:

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, but in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known example of a peptide neurotransmitter; 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,[7] as are some gaseous molecules such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO).[8] Because they are not packaged into vesicles they are not classical neurotransmitters by the strictest definition, however they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way.

By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.[3] The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Even though other transmitters are used in far 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 amphetamine 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.

Excitatory and inhibitory[edit]

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential. For other neurotransmitters, such as GABA, the most important receptors all have inhibitory effects (although there is evidence that GABA is excitatory during early brain development). There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or inhibitory—nevertheless it is convenient to call glutamate excitatory and GABA inhibitory so this usage is seen frequently.

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:

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
System Origin [15] Regulated effects and processes[15]
Noradrenaline system
[16][17]
Noradernergic pathways:
Dopamine system
[18]
Dopaminergic pathways:
Histamine system
[19]
Histaminergic pathways:
  • Arousal
  • learning
  • memory
  • sleep
Serotonin system
[16][20][21]
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
[22]
GABAergic pathways:
  •  
  • (coming soon)
Acetylcholine system
[16][23]
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 & nucleus of diagonal band

  • Forebrain nuclei projections

Drug effects[edit]

Drugs can influence an animal's behavior by altering neurotransmitter activity. For example, drugs can decrease the rate of synthesis of neurotransmitter by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter synthesis is blocked, the amount of neurotransmitter available for release is lowered, 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 the effect 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 reuptake 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; this fact explains the complexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap longer. 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 postsynaptic receptors. After the effects of the drug wear off, one might feel depressed because of the decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse and allows it to remain there longer, hence potentiating the effect of naturally released serotonin.[24] 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.

Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Levodopa is a precursor of dopamine, and is the most widely used drug to treat Parkinson's disease.

List of neurotransmitters, peptides, and gasotransmitters[edit]

Category Name Abbreviation Metabotropic Ionotropic
Small: Amino acids (Arg) Agmatine α2 adrenergic receptor Imidazoline receptor NMDA receptor
Small: Amino acids Aspartate Asp NMDA receptor
Small: Amino acids Glutamate (glutamic acid) Glu Metabotropic glutamate receptor NMDA receptor (co-agonist), Kainate receptor, AMPA receptor
Small: Amino acids Gamma-aminobutyric acid GABA GABAB receptor GABAA, GABAA-ρ receptor
Small: Amino acids Glycine Gly Glycine receptor, NMDA receptor (co-agonist)
Small: Amino acids D-serine Ser NMDA receptor (co-agonist)
Small: Acetylcholine Acetylcholine Ach Muscarinic acetylcholine receptor Nicotinic acetylcholine receptor
Small: Monoamine (Phe/Tyr) Dopamine DA Dopamine receptor
Small: Monoamine (Phe/Tyr) Norepinephrine (noradrenaline) NE Adrenergic receptor
Small: Monoamine (Phe/Tyr) Epinephrine (adrenaline) Epi Adrenergic receptor
Small: Monoamine (Trp) Serotonin (5-hydroxytryptamine) 5-HT Serotonin receptor, all but 5-HT3 5-HT3
Small: Monoamine (Trp) Melatonin Mel Melatonin receptor
Small: Monoamine (His) Histamine H Histamine receptor
Small: Trace amine (Phe) Phenethylamine PEA Trace amine-associated receptors: hTAAR1, hTAAR2
Small: Trace amine (Phe) N-methylphenethylamine NMPEA hTAAR1
Small: Trace amine (Phe/Tyr) Tyramine TYR hTAAR1, hTAAR2
Small: Trace amine (Phe/Tyr) Octopamine Oct hTAAR1
Small: Trace amine (Phe/Tyr) Synephrine Syn hTAAR1
Small: Trace amine (Phe/Tyr) 3-methoxytyramine 3-MT hTAAR1
Small: Trace amine (Trp) Tryptamine hTAAR1, various 5-HT receptors
Small: Trace amine (Trp) Dimethyltryptamine DMT hTAAR1, various 5-HT receptors,
Neuropeptides N-Acetylaspartylglutamate NAAG Metabotropic glutamate receptors; selective agonist of mGluR3
PP: Gastrins Gastrin
PP: Gastrins Cholecystokinin CCK Cholecystokinin receptor
PP: Neurohypophyseals Vasopressin AVP Vasopressin receptor
PP: Neurohypophyseals Oxytocin OT Oxytocin receptor
PP: Neurohypophyseals Neurophysin I
PP: Neurohypophyseals Neurophysin II
PP: Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptor
PP: Neuropeptide Y Pancreatic polypeptide PP
PP: Neuropeptide Y Peptide YY PYY
PP: Opioids Corticotropin (adrenocorticotropic hormone) ACTH Corticotropin receptor
PP: Opioids Enkephaline δ-opioid receptor
PP: Opioids Dynorphin κ-opioid receptor
PP: Opioids Endorphin μ-opioid receptor
PP: Secretins Secretin Secretin receptor
PP: Secretins Motilin Motilin receptor
PP: Secretins Glucagon Glucagon receptor
PP: Secretins Vasoactive intestinal peptide VIP Vasoactive intestinal peptide receptor
PP: Secretins Growth hormone-releasing factor GRF
PP: Somatostatins Somatostatin Somatostatin receptor
SS: Tachykinins Neurokinin A
SS: Tachykinins Neurokinin B
SS: Tachykinins Substance P
PP: Other Cocaine and amphetamine regulated transcript CART Unknown Gi/Go-coupled receptor[25]
PP: Other Bombesin
PP: Other Gastrin releasing peptide GRP
Gas Nitric oxide NO Soluble guanylyl cyclase
Gas Carbon monoxide CO Heme bound to potassium channels
Other Anandamide AEA Cannabinoid receptor
Other 2-Arachidonoylglycerol 2-AG Cannabinoid receptor
Other 2-Arachidonyl glyceryl ether 2-AGE Cannabinoid receptor
Other ''N''-Arachidonoyl dopamine NADA Cannabinoid receptor TRPV1
Other Virodhamine Cannabinoid receptor
Other Adenosine triphosphate ATP P2Y12 P2X receptor
Other Adenosine Ado Adenosine receptor

Precursors[edit]

While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release (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.[26] 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.[26][27]

Dopamine precursors[edit]

L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease.

Norepinephrine precursors[edit]

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.[26]

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.[26] This conversion requires vitamin C.[14] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo.[26]

Degradation and elimination[edit]

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory neurotransmitter, is broken down by acetylcholinesterase (AChE). 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.

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.[28] An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter.[29]

Nicotine, found in tobacco, is an agonist for acetylcholine at nicotinic receptors.[30] 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.[30]

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. ^ 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" 
  4. ^ Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 ISBN 0-07-727620-5
  5. ^ "Junctions Between Cells". Retrieved 22 November 2010. 
  6. ^ Snyder, S. H.; Innis, R. B. (1979). "Peptide Neurotransmitters". Annual Review of Biochemistry 48: 755–782. doi:10.1146/annurev.bi.48.070179.003543. PMID 38738.  edit
  7. ^ 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
  8. ^ Nitric oxide and other gaseous neurotransmitters
  9. ^ 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
  10. ^ Yang, J. L.; Sykora, P.; Wilson Dm, D. M.; Mattson, M. P.; Bohr, V. A. (2011). "The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency". Mechanisms of Ageing and Development 132 (8–9): 405–411. doi:10.1016/j.mad.2011.06.005. PMC 3367503. PMID 21729715.  edit
  11. ^ Orexin receptor antagonists a new class of sleeping pill, National Sleep Foundation.
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  14. ^ a b University of Bristol. "Introduction to Serotonin". Retrieved 15 October 2009. 
  15. ^ 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. 
  16. ^ 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." 
  17. ^ 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." 
  18. ^ 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. ..." 
  19. ^ 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. 
  20. ^ 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." 
  21. ^ Nestler, Eric J. "BRAIN REWARD PATHWAYS". Icahn School of Medicine at Mount Sinai. Nestler Lab. Retrieved 16 August 2014. "The dorsal raphe is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism." 
  22. ^ Barrot M, Sesack SR, Georges F, Pistis M, Hong S, Jhou TC (October 2012). "Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions". J. Neurosci. 32 (41): 14094–101. doi:10.1523/JNEUROSCI.3370-12.2012. PMC 3513755. PMID 23055478. 
  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. 167–175. ISBN 9780071481274. "The basal forebrain cholinergic nuclei are comprised of 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)." 
  24. ^ Yadav, V. et al; Ryu, Je-Hwang; Suda, Nina; Tanaka, Kenji F.; Gingrich, Jay A.; Schütz, Günther; Glorieux, Francis H.; Chiang, Cherie Y. et al. (2008). "Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum". Cell 135 (5): 825–837. doi:10.1016/j.cell.2008.09.059. PMC 2614332. PMID 19041748. 
  25. ^ Lin Y, Hall RA, Kuhar MJ (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. 
  26. ^ a b c d e Meyers, Stephen (2000). "Use of Neurotransmitter Precursors for Treatment of Depression". Alternative Medicine Review 5 (1): 64–71. PMID 10696120. 
  27. ^ Van Praag, HM (1981). "Management of depression with serotonin precursors". Biol Psychiatry 16 (3): 291–310. PMID 6164407. 
  28. ^ . Merriam-Webster http://www.merriam-webster.com/dictionary/agonist.  Missing or empty |title= (help)
  29. ^ "Drug Receptor Interactions". Virtual Chembook, Elmhurst College. 
  30. ^ a b Fallows, Zak. MIT MedLinks. Center for Health Promotion and Wellness at MIT Medical http://ocw.mit.edu/ans7870/SP/SP.236/S09/lecturenotes/drugchart.htm |url= missing title (help). 

External links[edit]