Neurotransmitter

Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets 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; and
• A biochemical mechanism for inactivation must be present.

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

Types of neurotransmitters

Neurotransmitters can be broadly classified into small-molecule transmitters and neuroactive peptides (neuropeptides).

Neuropeptides

Over 50 neuropeptides have been found, including hormones such as luteinizing hormone (LH) and insulin have that specific local actions in addition to their more commonly known long-range signalling properties. Other examples include vasopressin, somatostatin, and neurotensin.

Small-molecule transmitters

Around 10 small-molecule neurotransmitters are known.

Amino acids

3 or 4 amino acids are neurotransmitters depending on the exact definition used. Glutamic acid (glutamate) and GABA are the major "workhorse" neurotransmitters of the brain are. Examples are:

• Aspartate (aspartic acid)
• Glutamate (Glutamic acid) (Glu) is a principle excitory neurotransmitter in the brain.
• γ-Aminobutyric acid (GABA) is the principle inhibitory neurotransmitter in the brain.
• Glycine (Gly)

Biogenic amines

The biogenic amines are a "group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology."

Acetylcholine

See also Acetylcholine and Acetylcholine receptor

Acetylcholine (Ach) is synthesized by acetyltransferase from acetyl-CoA and the essential nutrient choline.

Biogenic monoamines

See also Biogenic amine receptor

The biogenic monoamines are derived from amino acids by enzymatic decarboxylation.

From phenylalanine and tyrosine (catecholamines, in the order of their synthesis):

• Dopamine (DA)
  • Norepinephrine (noradrenaline) (NE)
    • Epinephrine (adrenaline) (Epi)
• Octopamine
• Tyramine

From tryptophan:

• Serotonin (5-hydroxytryptamine, 5-HT)
  • Melatonin (Mel) (derived from serotonin, but not a monoamine)

From histidine:

• Histamine (H)

Purines

Examples of purines are adenosine, ATP, GTP and their derivatives.

Other proposed small-molecule neurotransmitters

• Carbon monoxide (CO)
• Nitric oxide (NO)
• Zinc. Single ions, such as synaptically-released zinc, are considered neurotransmitters by some.

Fatty acids

Fatty acids are receiving attention as the potential endogenous cannabinoid. An example is anandamide.

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. Glycine and glutamate also work in coordination to activate the NMDA receptor, a major excitatory receptor which is involved in learning.

Many neurotransmitters are removed from the synaptic cleft by neurotransmitter transporters in 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 often removed from the cleft by diffusion, and eventually 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 the action of others are regulated by distinct classes of nerve clusters which can be arranged in lamilar pathways around the brain. For example, serotonin is released specifically by cells in the brainstem, in an area called the raphe nuclei, but travels around the brain along the medial forebrain bundle activating the cortex, hippocampus, thalamus, hypothalamus and cerebellum. Also, it is released in the Caudal serotonin nuclei, so as to have effect on the spinal cord. In the peripherial nervous system (such as in the gut wall) serotonin regulates vascular tone. 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.

The neurotransmitter's effect is determined by its receptor. Other examples of neurotransmitter action:

• Acetylcholine - voluntary movement of the muscles
• Norepinephrine - wakefulness or arousal
• Dopamine - voluntary movement and emotional arousal
• Serotonin - memory, emotions, wakefulness, sleep and temperature regulation
• GABA (gamma aminobutyric acid) - motor behaviour
• Glycine - spinal reflexes and motor behaviour
• Neuromodulators - sensory transmission-especially pain