Neurotransmitter

Neurotransmitters are endogenous chemicals 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 acids, which are readily available from the diet and which require only a small number of biosynthetic steps to convert.

Discovery
Until the early 20th century, scientists assumed that synaptic communication 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. This discovery cast doubt on the existence of electrical transmission. In 1921, German pharmacologist Otto Loewi (1873–1961) confirmed that neurons 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 neurons do not communicate with electric signals but rather through the change in chemical concentrations. Furthermore, Otto Loewi is accredited with discovering acetylcholine—the first known neurotransmitter.

Identifying neurotransmitters
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:
 * 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 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:


 * Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine
 * Monoamines (a.k.a. Biogenic amines): dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT), melatonin
 * Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.

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.

Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, 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
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:
 * Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength.  Modifiable synapses are thought to be the main memory-storage elements in the brain.
 * GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine  is the inhibitory transmitter in the spinal cord.
 * Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses.  Acetylcholine also operates in many regions of the brain, but using different types of receptors.
 * Dopamine has a number of important functions in the brain. It plays a critical role in the reward system, but dysfunction of the dopamine system is also implicated in Parkinson's disease and schizophrenia.
 * Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.
 * Substance P is an undecapeptide responsible for transmission of pain from certain sensory neurons to the central nervous system.

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, causing the body to down-regulate 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.

A brief comparison of the major neurotransmitter systems follows:

Precursors of neurotransmitters
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.

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.