Neurotransmitter

Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a presynaptic and a postsynaptic neuron. A chemical is classified as a neurotransmitter if it respects the following conditions:

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

Types of neurotransmitters

Neurotransmitters are 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 (ATP, GTP and their derivatives) are also generally admitted as neurotransmitters in autonomic neurons. 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.

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 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 receptor effects on ion channels are carried by second messenger systems.

Neuroactive peptides are synthesized 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 as a rapid or slow inhibitor, depending on whether an ionotropic or metabotropic receptor is the target of the molecule. Small molecule transmitters tend to have consistently inhibitory or excitatory action on their targets. Meanwhile, the same polypeptide may have inhibitory or excitatory effect on a cell, depending on the receptor.

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; GAB and glycine are well-known inhibitory neurotransmitters.

Many neurotransmitters are removed from the synaptic cleft by a process is 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.

Specific actions

While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others are only used in certain brain regions by particular classes of nerve cells. Serotonin is generally used as a neurotransmitter in cells involved in emotional regulation. Dopamine acts as the neurotransmitter of choice for cells in the hypothalamus which are effectively the brain's reward system.

Neurotransmitters which 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.

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. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.