Neurotransmitters

Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. According to the dogma of the 1960s, a chemical can be classified as a neurotransmitter if it respects the following conditions:


 * It is synthesized endogenously, that is, within the presynaptic neuron
 * It is available in sufficient quantity in the presynaptic neuron to exert an effect on the postsynaptic neuron
 * Externally administered, it must mimic the endogenously-released substance
 * A biochemical mechanism for inactivation must be present

However, there are other materials, such as the zinc ion, that are neither synthesized nor cataboloized (i.e., degraded. see Anabolism) and are considered neurotransmitters by some. Thus, the old definitions are being revised.

Types of neurotransmitters
Substances that act as Neurotransmitters can be categorized into three major  groups: (1) amino acids (primarily glutamic acid, GABA, aspartic acid & glycine), (2) peptides (vasopressin, somatostatin, neurotensin, etc.) and (3) monoamines (norepinephrine, dopamine & serotonin) plus acetylcholine. The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA. Neurotransmitters can be broadly classified into small-molecule transmitters and neuroactive peptides. Around 10 small-molecule neurotransmitters are generally admitted: acetylcholine, 5 amines, and 3 or 4 amino acids (depending on exact definition used), Purines, (Adenosine, ATP, GTP and their derivatives) are neurotransmitters. Fatty acids are also receiving attention as the potential endogenous cannabinoid. Over 50 neuroactive peptides have been found, among them hormones such as LH or insulin that have specific local actions in addition to their long-range signalling properties. Single ions, such as synaptically-released zinc, are also considered neurotransmitters by some.

It is important to appreciate that it is the receptor that dictates the neurotransmitter's effect.

Mechanism of action
Within the cells, small-molecule neurotransmitter molecules are usually packaged in vesicles. When an action potential travels to the synapse, the rapid depolarization causes calcium ion channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane; the vesicle and cell membrane fuse, leading to the release of the packaged neurotransmitter, a mechanism called exocytosis.

The neurotransmitters then diffuse across the synaptic cleft to bind to receptors. The receptors are broadly classified into ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels that open or close through neurotransmitter binding. Metabotropic receptors, which can have a diverse range of effects on a cell, transduct the signal by secondary messenger systems, or G-proteins.

Neuroactive peptides are made in the neuron's soma and are transported through the axon to the synapse. They are usually packaged into dense-core vesicles and are released through a similar, but metabolically distinct, form of exocytosis used for small-molecule synaptic vesicles.

Post-synaptic effect
A neurotransmitter's effect is determined by its receptor. For example, GABA can act on both rapid or slow inhibitory receptors (the GABA-A and GABA-B receptor respectively). Many other neurotransmitters, however, may have excitatory or inhibitory actions depending on which receptor they bind to.

Neurotransmitters may cause either excitatory or inhibitory post-synaptic potentials. That is, they may help the initiation of a nerve impulse in the receiving neuron, or they may discourage such an impulse by modifying the local membrane voltage potential. In the central nervous system, combined input from several synapses is usually required to trigger an action potential. Glutamate is the most prominent of excitatory transmitters; GABA and glycine are well-known inhibitory neurotransmitters.

Many neurotransmitters are removed from the synaptic cleft by a process called reuptake (or often simply uptake). Without reuptake, the molecules might continue to stimulate or inhibit the firing of the postsynaptic neuron. Another mechanism for removal of a neurotransmitter is digestion by an enzyme. For example, at cholinergic synapses (where acetylcholine is the neurotransmitter), the enzyme acetylcholinesterase breaks down the acetylcholine. Neuroactive peptides are usually removed from the cleft by diffusion, and eventual broken down by proteases.

Specific actions
While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others can have more specific effects, such as on the Autonomic nervous system, by both pathways in the sympathetic nervous system and the parasympathetic nervous system, and others are used only in certain brain regions by particular classes of nerve cells. Serotonin is released specifically by cells in the brainstem, in an area called the raphe nuclei. Dopamine classically modulates two systems: the brain's reward mechanism, and movement control.

Neurotransmitters that have these types of specific actions are often targeted by drugs. Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer. Prozac is a serotonin reuptake inhibitor, hence potentiating its effect. 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.

Some neurotransmitter/neuromodulators like zinc not only can modulate the sensitivity of a receptor to other neurotransmitters (allosteric modulation) but can even penetrate specific, gated channels in post-synaptic neurons, thus entering the post-synaptic cells. This "translocation" is another mechanism by which synaptic transmitters can affect postsynaptic cells.

Diseases may affect specific neurotransmitter pathways. 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.

Amino acids

 * Aspartate
 * Glutamate (Glu)
 * &gamma;-Aminobutyric acid (GABA)
 * Glycine (Gly)

Biogenic amines

 * Acetylcholine (Ach)

Monoamines

 * From phenylalanine and tyrosine (catecholamines, in the order of their synthesis):
 * Dopamine (DA)
 * Norepinephrine (noradrenaline) (NE)
 * Epinephrine (adrenaline) (Epi)
 *  From tryptophan:
 * Serotonin (5-hydroxytryptamine, 5-HT)
 * Melatonin (Mel) (derived from serotonin, but not a monoamine)
 *  From histidine:
 * Histamine (H)

Polypeptides (neuropeptides)

 * Bombesin
 * Gastrin releasing peptide (GRP)


 * Gastrins
 * Gastrin
 * Cholecystokinin (CCK)


 * Neurohypophyseals
 * Vasopressin
 * Oxytocin
 * Neurophysin I
 * Neurophysin II


 * Neuropeptide Y
 * Neuropeptide Y (NY)
 * Pancreatic polypeptide (PP)
 * Peptide YY (PYY)


 * Opioids
 * Corticotropin (adrenocorticotropic hormone, ACTH)
 * Beta-lipotropin
 * Dynorphin
 * Endorphin
 * Enkephaline
 * Leumorphin


 * Secretins
 * Secretin
 * Motilin
 * Glucagon
 * Vasoactive intestinal peptide (VIP)
 * Growth hormone-releasing factor (GRF)


 * Somatostatins
 * Somatostatin


 * Tachykinins
 * Neurokinin A
 * Neurokinin B
 * Neuropeptide A
 * Neuropeptide gamma
 * Substance P


 * Other neurotransmitters
 * Nitric oxide (NO)
 * Carbon monoxide (CO)
 * Anandamide