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|Structure of a typical 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. 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. 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.
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.
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. 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.
There are four main criteria for identifying neurotransmitters:
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. Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.
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.
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, as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). 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. 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.
|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)||N-methyltryptamine||NMT||hTAAR1, various 5-HT receptors,|
|Neuropeptides||N-Acetylaspartylglutamate||NAAG||Metabotropic glutamate receptors; selective agonist of mGluR3||–|
|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|
|PP: Other||Gastrin releasing peptide||GRP||–||–|
|Gas||Nitric oxide||NO||Soluble guanylyl cyclase||–|
|Gas||Carbon monoxide||CO||–||Heme bound to potassium channels|
|Other||2-Arachidonyl glyceryl ether||2-AGE||Cannabinoid receptor||–|
|Other||N-Arachidonoyl dopamine||NADA||Cannabinoid receptor||TRPV1|
|Other||Adenosine triphosphate||ATP||P2Y12||P2X receptor|
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.
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.
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:
|System||Origin ||Regulated effects and processes|
|Noradernergic pathways: |
|Dopaminergic pathways: |
|Histaminergic pathways: |
|Serotonergic pathways: |
|GABAergic pathways: |
|Cholinergic pathways: |
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. 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.
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.
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.
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. 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.
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.
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 more effective than a placebo.
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.
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:
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 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. 
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