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|Structure of a typical chemical synapse|
|Structure of a typical chemical synapse|
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane in the axon terminal, on the presynaptic side of a synapse. They 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. Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may also follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation. 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.
Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations of 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. 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.
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The chemical identity of neurotransmitters is often difficult to determine experimentally. For example, it is easy using an electron microscope to recognize vesicles on the presynaptic side of a synapse, but it may not be easy to determine directly what chemical is packed into them. The difficulties led to many historical controversies over whether a given chemical was or was not clearly established as a transmitter. In an effort to give some structure to the arguments, neurochemists worked out a set of experimentally tractable rules. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:
Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of these rules. A series of experiments that may have taken several years in the 1960s can now be done, with much better precision, in a few months. Thus, it is unusual nowadays for the identification of a chemical as a neurotransmitter to remain controversial for very long periods of time.
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, as are some gaseous molecules such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO). 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. 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.
|This section does not cite any references or sources. (November 2012)|
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.
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.
Drugs targeting the neurotransmitter of such 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. Prozac 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. 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.
A brief comparison of the major neurotransmitter systems follows:
|Noradrenaline system||locus coeruleus|
|Lateral tegmental field|
|Dopamine system||dopamine pathways:||motor system, reward, cognition, endocrine, nausea|
|Serotonin system||caudal dorsal raphe nucleus||Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.|
|rostral dorsal raphe nucleus|
|Cholinergic system||pontomesencephalotegmental complex|
|basal optic nucleus of Meynert|
|medial septal nucleus|
|Small: Amino acids||Aspartate||-||-|
|Neuropeptides||N-Acetylaspartylglutamate||NAAG||Metabotropic glutamate receptors; selective agonist of mGluR3||-|
|Small: Amino acids||Glutamate (glutamic acid)||Glu||Metabotropic glutamate receptor||NMDA receptor, Kainate receptor, AMPA receptor|
|Small: Amino acids||Gamma-aminobutyric acid||GABA||GABAB receptor||GABAA, GABAA-ρ receptor|
|Small: Amino acids||Glycine||Gly||-||Glycine receptor|
|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 (Phe/Tyr)||Octopamine||-||-|
|Small: Monoamine (Phe/Tyr)||Tyramine||-|
|Small: Monoamine (Trp)||Serotonin (5-hydroxytryptamine)||5-HT||Serotonin receptor, all but 5-HT3||5-HT3|
|Small: Monoamine (Trp)||Melatonin||Mel||Melatonin receptor||-|
|Small: Diamine (His)||Histamine||H||Histamine receptor||-|
|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: 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||Gastrin releasing peptide||GRP||-||-|
|Gas||Nitric oxide||NO||Soluble guanylyl cyclase||-|
|Gas||Carbon monoxide||CO||-||Heme bound to potassium channels|
|Other||Adenosine triphosphate||ATP||P2Y12||P2X receptor|
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. 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.
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.
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. This conversion requires vitamin C. 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo.
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 the target of the body's own regulatory system or recreational drugs.
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. An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter.
Nicotine, found in tobacco, is an agonist for acetylcholine at nicotinic receptors. 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.
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