NEUROTRANSMITTERS:
Neurotransmitters are endogenous chemical which transmit signals from a neuron to a target cell across a synapse.Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to 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. Neurotransmitters are synthesized from plentiful and simple precursors, such as amino acid, which are readily available from the diet and which require only a small number of biosynthetic steps to convert.
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Discovery: 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 control 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. 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. Types of neurotransmitters: 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 , as are some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). These are not classical neurotransmitters by the strictest 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. 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. Excitatory and inhibitory: 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. 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 so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently. Actions: 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. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
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Precursors of neurotransmitters:
Norepinephrine precursors:
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.
Serotonin precursors:
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 and nearly as effective or of equal effectiveness to some antidepressants. Interestingly, it takes less than 2 weeks for an antidepressant response to occur, while antidepressant drugs generally take 2–4 weeks. 5-HTP also has no significant side effects.
Administration of 5-HTP bypasses the rate-limiting step in the synthesis of serotonin from tryptophan. Also, 5-HTP readily passes through the blood-brain barrier, and enters the central nervous system without need of a transport molecule. Note, however, that there is some evidence to suggest that a postsynaptic defect in serotonin utilization may be an important factor in depression, not only insufficient serotonin.
It is important to note that not all cases of depression are caused by low levels of serotonin. However, in the subgroup of depressed patients that are serotonin-deficient, there is strong evidence to suggest that 5-HTP is therapeutically useful in treating depression, and more useful than L-tryptophan.
Depression does not have one cause; not all cases of depression are due to low levels of serotonin or norepinephrine. Blood tests for the ratio of tryptophan to other amino acids, as well as red blood cell membrane transport of these amino acids, can be predictive of whether serotonin or norepinephrine would be of therapeutic benefit. Overall, there is evidence to suggest that neurotransmitter precursors may be useful in the treatment of mild and moderate depression.
Degradation and elimination:
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.
NEUROMUSCULAR JUNCTION:
A neuromuscular junction (NMJ) is the synapse or junction of the axon terminal of a motoneuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract. In vertebrates, the signal passes through the neuromuscular junction via the neurotransmitter acetylcholine.
Mechanism of action
Detailed view of a neuromuscular junction:1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion
1.Upon the arrival of an action potential at the presynaptic neuron terminal, voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
2.This influx of Ca2+ causes neurotransmitter-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane. Fusion of the vesicular membrane with the presynaptic cell membrane results in the emptying of the vesicle's contents (acetylcholine) into the synaptic cleft, a process known as exocytosis.
3.Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptors bound to the motor end plate.
4.These receptors are ligand-gated ion channels, and when they bind acetylcholine, they open, allowing sodium ions to flow in and potassium ions to flow out of the muscle's cytosol.
5.Because of the differences in electrochemical gradients across the plasma membrane, more sodium moves in than potassium out, producing a local depolarization of the motor end plate known as an end-plate potential (EPP).
6.This depolarization spreads across the surface of the muscle fiber into transverse tubules, eliciting the release of calcium from the sarcoplasmic reticulum, thus initiating muscle contraction.
7.The action of acetylcholine is terminated when the enzyme acetylcholinesterase degrades part of the neurotransmitter (producing choline and an acetate group) and the rest of it diffuses away.
8. The choline produced by the action of acetylcholinesterase is recycled — it is transported, through reuptake, back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.
Acetylcholine is a neurotransmitter synthesized in the human body from dietary choline and acetyl coenzyme A. One of the first neurotransmitters discovered, the substance was originally referred to as "vagusstoff" because it was found to be released by the stimulation of the vagus nerve. Later, it was established that acetylcholine is, in fact, important in the stimulation of all muscle tissue and that its action may be either excitatory or inhibitory, depending on a number of factors. Within the body, the synaptic action of acetylcholine usually quickly comes to a halt, the neurotransmitter naturally breaking down soon after its release. However, some nerve gases are designed to thwart this breakdown, causing prolonged stimulation of the receptor cells and resulting in severe muscle spasms.
Development of the neuromuscular junction:
During development, the growing end of motor neuron axons secrete a protein known as agrin.
This protein binds to several receptors on the surface of skeletal muscle.
The receptor which seems to be required for formation of the neuromuscular junction is the MuSK protein (Muscle specific kinase).
MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the release of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.
Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors (AChR).
In addition to the AChR and MuSK, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the NMJ.
Knockout studies:
These findings were demonstrated in part by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the neuromuscular junction does not form. Further, mice deficient in Dok-7 did not form either acetylcholine receptor clusters or neuromuscular synapses.
Many other proteins also comprise the NMJ, and are required to maintain its integrity.
Neuromuscular block:
Further information:
Neuromuscular junction disease and Neuromuscular blocking drugs
A block or decrease in the transmission across the neuromuscular junction can cause a complete or relative loss of muscle function. It can result from neuromuscular junction diseases or be intentionally induced with neuromuscular blocking drugs. It can also be a side effect of other drugs that are generally not classified as neuromuscular blocking drugs, such as some anesthetic drugs.
The degree of neuromuscular block may be estimated by Bromage score, which originally had four grades designate with the Roman numerals I until IV, but later complemented by Breen et al with an inverse grading with Hindu-Arabic numerals:
Bromage score | |||
Grade | Criteria | Approximate degree of block | |
IV | 1 | Complete block, inability to move feet or knees | 100% |
III | 2 | Almost complete block, ability to move feet only, with inability to flex knees | 66% |
II | 3 | Partial block, ability to flex knees | 33% |
4 | Detectable weakness of hip flexion while supine, ability of full flexion of knees | ||
5 | No detectable weakness of hip flexion while supine | ||
I | 6 | Free movement of legs and feet, ability to perform partial knee bend | 0% |
In unconscious patients, such as during anesthesia, neural block can be assessed by a "train-of-four" by stimulating musclesfrom surface electrodes.
Neurotransmitters, mental disorders, and medications
Schizophrenia:
Impairment of dopamine-containing neurons in the brain is implicated in schizophrenia , a mental disease marked by disturbances in thinking and emotional reactions. Medications that block dopamine receptors in the brain, such as chlorpromazine and clozapine , have been used to alleviate the symptoms and help patients return to a normal social setting.
Depression:
In depression, which afflicts about 3.5% of the population, there appears to be abnormal excess or inhibition of signals that control mood, thoughts, pain, and other sensations. Depression is treated with antidepressants that affect norepinephrine and serotonin in the brain. The antidepressants help correct the abnormal neurotransmitter activity. A newer drug, fluoxetine (Prozac), is a selective serotonin reuptake inhibitor (SSRI) that appears to establish the level of serotonin required to function at a normal level. As the name implies, the drug inhibits the re-uptake of serotonin neurotransmitter from synaptic gaps, thus increasing neurotransmitter action. In the brain, then, the increased serotonin activity alleviates depressive symptoms.
Alzheimer's disease:
Alzheimer's disease , which affects an estimated four million Americans, is characterized by memory loss and the eventual inability for self-care. The disease seems to be caused by a loss of cells that secrete acetylcholine in the basal forebrain (region of brain that is the control center for sensory and associative information processing and motor activities). Some medications to alleviate the symptoms have been developed, but presently there is no known treatment for the disease.
Generalized anxiety disorder:
People with generalized anxiety disorder (GAD) experience excessive worry that causes problems at work and in the maintenance of daily responsibilities. Evidence suggests that GAD involves several neurotransmitter systems in the brain, including norepinephrine and serotonin.
Attention-deficit/hyperactivity disorder:
People affected by attention-deficit/hyperactivity disorder (ADHD) experience difficulties in the areas of attention, overactivity, impulse control, and distractibility. Research shows that dopamine and norepinephrine imbalances are strongly implicated in causing ADHD.
Others
Substantial research evidence also suggests a correlation of neurotransmitter imbalance with disorders such as borderline personality disorders ,schizotypal personality disorder , avoidant personality disorder , social phobia , histrionic personality disorder , and somatization disorder .
Drug addictions:
Cocaine and crack cocaine are psychostimulants that affect neurons containing dopamine in the areas of the brain known as the limbic and frontal cortex. When cocaine is used, it generates a feeling of confidence and power. However, when large amounts are taken, people "crash" and suffer from physical and emotional exhaustion as well as depression.
Opiates, such as heroin and morphine, appear to mimic naturally occurring peptide substances in the brain that act as neurotransmitters with opiate activity called endorphins. Natural endorphins of the brain act to kill pain, cause sensations of pleasure, and cause sleepiness. Endorphins released with extensive aerobic exercise, for example, are responsible for the "rush" that long-distance runners experience. It is believed that morphine and heroin combine with the endorphin receptors in the brain, resulting in reduced natural endorphin production. As a result, the drugs are needed to replace the naturally produced endorphins and addiction occurs. Attempts to counteract the effects of the drugs involve using medications that mimic them, such as nalorphine, naloxone, and naltrexone .
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