Neurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell.[1] Neurotransmitters are packaged into vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and released into the synaptic cleft, where they bind to receptors located in the membrane on the postsynaptic side of the synapse. Release of neurotransmitters is most commonly driven by arrival of an action potential at the synapse, but may also be driven by graded electrical potentials. Also, there is often a low level of "baseline" release even in the absence of electrical stimulation.
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Some of the properties that define a chemical as a neurotransmitter are difficult to test 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.
There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some purposes.
Approximately ten "small-molecule neurotransmitters" are known:
In addition, over 50 neuroactive peptides have been found, and new ones are discovered on a regular basis. 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.
Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, as are a few gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). These are not neurotransmitters by the strict definition, however, because although they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way, they are not packaged into vesicles.
Not all neurotransmitters are equally important. By far the most prevalent transmitter is glutamate, which is used at well over 90% of the synapses in the human brain. The next most prevalent is GABA, which is used at more than 90% of the synapses that don't use glutamate. Note, however, that 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 system, and the great majority of these act through transmitters other than glutamate or GABA. Addictive drugs such as cocaine, amphetamine, and heroin, for example, exert their effects primarily on the dopamine system.
Some neurotransmitters are commonly described as "excitatory" or "inhibitory". It is important to understand what these terms mean. The only thing that a neurotransmitter does directly is to activate one or more types of receptors. The effect on the postsynaptic cell depends entirely on the properties of the receptors. It so 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. There are, however, other important 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 widely understood to be an abuse of language to call a neurotransmitter excitatory or inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very 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. The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system.
Drugs targeting the neurotransmitter of such systems affects the whole system; this fact explains the mode of action of many drugs. Cocaine, for example, blocks the reentering of dopamine back into the presynaptic neuron, leaving these neurotransmitters in the synaptic gap longer. Since the dopamine is in the synapse longer, the neurotransmitter rapidly hit the receptors on the postsynaptic neuron cell, and therefore causing happiness. Excess intake of cocaine can lead to physical addiction. The physical addiction of cocaine is when the neurotransmitters stay in the synapse so long , the body removes some receptors from the postsynaptic neuron. After the effects of the drug wear off, the person usually feels unhappy, because now the neurotransmitters are less likely to hit the receptor since the body removed many of them during the drug intake. Prozac is a selective serotonin reuptake inhibitor (SSRI), 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. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
A brief comparison of the major neurotransmitter systems follows:
System | Origin [2] | Effects[2] |
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Noradrenaline system | locus coeruleus |
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Lateral tegmental field | ||
Dopamine system | dopamine pathways:
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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 |
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basal optic nucleus of Meynert | ||
medial septal nucleus |
Category | Name | Abbreviation | Metabotropic | Ionotropic |
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, GABAC |
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: Monoamine (His) | Histamine | H | Histamine receptor | - |
PP: Gastrins | Gastrin | - | - | |
PP: Gastrins | Cholecystokinin | CCK | Cholecystokinin receptor | - |
PP: Neurohypophyseals | Vasopressin | Vasopressin receptor | - | |
PP: Neurohypophyseals | Oxytocin | 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 | Dynorphin | - | - | |
PP: Opioids | Endorphin | - | - | |
PP: Opioids | Enkephaline | - | - | |
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: Somtostatins | Somatostatin | Somatostatin receptor | - | |
SS: Tachykinins | Neurokinin A | - | - | |
SS: Tachykinins | Neurokinin B | - | - | |
SS: Tachykinins | Substance P | - | - | |
PP: Other | Bombesin | - | - | |
PP: Other | Gastrin releasing peptide | GRP | - | - |
Gas | Nitric oxide | NO | - | - |
Gas | Carbon monoxide | CO | - | - |
Other | Anandamide | AEA | Cannabinoid receptor | - |
Other | Adenosine triphosphate | ATP | P2Y12 | P2X receptor |
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.
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