Chemical substances used for signalling between neurons in the nervous system. Transmitters are released at the SYNAPSE by the PRESYNAPTIC neuron into the SYNAPTIC CLEFT. They then bind to RECEPTORS on the POSTSYNAPTIC neuron or an effector organ such as muscle, to evoke a variety of postsynaptic effects. The nature of this response depends on the properties of the receptor activated, rather than the transmitter itself. Thus, the same neurotransmitter can have different effects depending on the receptor present on the postsynaptic neuron, and by the same token, different transmitters can have similar effects if the properties of the activated receptors are similar. Transmitters also bind to presynaptic receptors to modulate further release from the axon terminal. A substance is accepted as a transmitter when the following four criteria are met: synthesis and presence in the presynaptic terminal, release from the presynaptic terminal, mimicking of the post-synaptic action by exogenous administration, and inactivation mechanisms to terminate its action.
Neurotransmitters are classified into two categories: small-molecule transmitters, and peptide transmitters. Small-molecule transmitters are relatively few in number, and include, among others, ACETYLCHOLINE, BIOGENIC AMINES (the CATECHOLAMINES, DOPAMINE, NORADRENALINE and ADRENALINE; and the INDOLEAMINES, SEROTONIN and HISTAMINE), and AMINO ACIDS (GLUTAMATE (or glutamic acid), GABA (gamma aminobutyric acid) and GLYCINE). More than 50 peptide transmitters are known to date, although only several of them have so far satisfied all four criteria as a neurotransmitter. Peptide transmitters usually contain 3 to 36 amino acids. They include hypothalamic releasing HORMONES such as SOMATOSTATIN, pituitary hormones such as VASOPRESSIN, OXYTOCIN and BETA ENDORPHIN, and gastrointestinal peptides such as CHOLECYSTOKININ, SUBSTANCE P and ENKEPHALINS (see GUT-BRAIN PEPTIDES). Small-molecule transmitters and peptide transmitters differ in several ways. Small-molecule transmitters are usually synthesized at the TERMINAL. Their precursors are supplied locally, while their synthesizing enzymes are transported from the CELL BODY. At the terminal, small-molecule transmitters are packaged into SYNAPTIC VESICLES by VESICULAR TRANSPORTERS. In contrast, peptide transmitters are not synthesized at the terminal, but rather derive from precursor proteins that are synthesized in the cell body. The precursors are packaged into vesicles along with the cleaving enzymes and transported along the axon to terminals. The final processing of neuropeptides occurs during the transport. Therefore, once a neuropeptide is depleted at the terminal, further release requires a new supply of the peptide from the cell body.
The mechanism of release is the same for all transmitters. The arrival of action potentials at the axon terminal causes an increase in the intracellular CALCIUM (Ca2+) concentration. This causes synaptic vesicles to fuse with the cell membrane, and transmitters are released into the synaptic cleft. This process is called EXOCYTOSIS. Once transmitters are released, timely removal or inactivation is crucial for terminating their action. Amino acids and biogenic amines are removed from the synaptic cleft by high-affinity REUPTAKE transporters located at the presynaptic terminal or in GLIAL CELLS, whereas acetylcholine is degraded enzymatically by ACETYLCHOLINESTERASE. Neuroactive peptides are removed more slowly, by diffusion and degradation by peptidases in the extracellular space. Transmitters internalized by the high-affinity reuptake mechanisms are recycled for subsequent release.
Small-molecule transmitters and peptide transmitters can coexist in the same neuron, and be co-released. Numerous examples of such co-localization have been reported in the nervous system. For example, vasoactive intestinal polypeptide is present in the cholinergic presynaptic terminals in the parasympathetic ganglia (see GANGLION). The release of colocalized neuropeptides appears to be activity-dependent in that they are released only when the neuron is highly active, as during bursts, whereas the release of small-molecule transmitters is usually proportional to the activity of the neuron. Certain small-molecule transmitters and neuropeptides also interact at the presynaptic terminal to regulate transmitter release. These presynaptic and postsynaptic actions of co-localized transmitters permit an extraordinary diversity of information transfer at one synapse. In addition to these classical neurotransmitters, non-classical transmitters have been identified. These include ATP and NITRIC OXIDE (NO). Although ATP has an important role in energy metabolism, it is also packaged into synaptic vesicles and released synaptically in a Ca2+-dependent manner. Nitric oxide is a gaseous neurotransmitter that diffuses across the cell membrane. Because of this diffusibility, nitric oxide has been sug-gested to play a role as a retrograde messenger (a messenger that is released by the postsynaptic neuron to act on the presynaptic terminal) during LONG-TERM POTENTIATION. Carbon monoxide (CO) may act in a similar manner to NO.
Many drugs work by influencing the synthesis, release, reuptake and receptor binding of neurotransmitters. For example, stimulants such as AMPHETAMINE and COCAINE are known to enhance dopamine release in the MESOLIMBIC DOPAMINE SYSTEM. MORPHINE works by acting at endogenous OPIOID RECEPTORS. Biogenic amines and acetylcholine are also implicated in neurological disorders such as PARKINSON’S DISEASE and ALZHEIMER'S DEMENTIA, as well as SCHIZOPHRENIA and AFFECTIVE DISORDERS. Drugs that affect the action of these transmitters at various strategic sites have been developed for therapeutic purposes. The L-DOPA therapy for Parkinson’s disease is well known in which L-DOPA acts as a precursor for dopamine.
