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A neuron generates and propagates an action potential along its axon, then transmits this signal across a synapse by releasing neurotransmitters, which trigger a reaction in another neuron or an effector cell (eg, muscle cells; most exocrine and endocrine cells). The signal may stimulate or inhibit the receiving cell, depending on the neurotransmitter and receptor involved.
In the CNS, interconnections are complex. An impulse from one neuron to another may pass from axon to cell body, axon to dendrite (a neuron's receiving branches), cell body to cell body, or dendrite to dendrite. A neuron simultaneously receives many impulses—excitatory and inhibitory—from other neurons and integrates them into various patterns of firing.
Propagation:
Action potential propagation along an axon is electrical, caused by the exchanges of Na+ and K+ ions across the axonal membrane. A particular neuron generates an identical action potential after each stimulus, conducting it at a fixed velocity along the axon. Velocity depends on axonal diameter and degree of myelination and ranges from 1 to 4 m/sec in small, unmyelinated fibers to 75 m/sec in large myelinated ones. Propagation speed is higher in myelinated fibers because the myelin cover has regular gaps (nodes of Ranvier) where the axon is exposed. The electrical impulse jumps from one node to the next, skipping the myelinated section of the axon. Thus, disorders that alter the myelin cover (eg, multiple sclerosis) interfere with impulse propagation, causing various neurologic symptoms.
Transmission:
Impulse transmission is chemical, caused by release of specific neurotransmitters from the nerve ending (terminal). Neurotransmitters diffuse across the synaptic cleft and bind briefly to specific receptors on the adjoining neuron or effector cell. Depending on the receptor, the response may be excitatory or inhibitory.
One type of synapse, the electrical synapse, does not involve neurotransmitters; ion channels directly connect the cytoplasm of the presynaptic and postsynaptic neurons. This type of transmission is the fastest.
The nerve cell body produces enzymes that synthesize most neurotransmitters, which are stored in vesicles at the nerve terminal (see Fig. 1: Neurotransmission: Neurotransmission. ). The amount in one vesicle (usually several thousand molecules) is a quantum. An action potential arriving at the terminal opens axonal Ca channels; Ca inflow releases neurotransmitter molecules from many vesicles by fusing the vesicle membranes to the nerve terminal membrane. Membrane fusion generates an opening through which the molecules are expelled into the synaptic cleft via exocytosis.
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Fig. 1
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Neurotransmission.
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Action potentials open the axonal Ca channels (not shown). Ca++ activates release of neurotransmitters (NT) from vesicles where they are stored. NT molecules fill the synaptic cleft. Some bind to postsynaptic receptors, initiating a response. The others are pumped back into the axon and stored or diffuse into the surrounding tissues.
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The amount of neurotransmitters in the terminal is typically independent of nerve activity and kept relatively constant by modifying uptake of neurotransmitter precursors or the activity of enzymes involved in neurotransmitter synthesis or destruction. Stimulation of presynaptic receptors can decrease presynaptic neurotransmitter synthesis, and blockade can increase it.
The neurotransmitter-receptor interaction must be terminated quickly to allow rapid, repeated activation of receptors. The neurotransmitter is quickly pumped back into the presynaptic nerve terminals by active, ATP-dependent processes (reuptake), is destroyed by enzymes near the receptors, or diffuses into the surrounding area and is removed. Neurotransmitters taken up by the nerve terminals are repackaged in vesicles for reuse.
Disorders or substances that alter the production, release, reception, breakdown, or reuptake of neurotransmitters or that change the number and affinity of receptors can cause neurologic or psychiatric symptoms and disorders (see Table 1: Neurotransmission: Examples of Disorders Associated With Defects in Neurotransmission  ). Drugs that modify neurotransmission can alleviate many of these disorders (eg, Parkinson's disease, depression).
Receptors:
Neurotransmitter receptors are protein complexes that span the cell membrane. Their nature determines whether a given neurotransmitter is excitatory or inhibitory. Receptors that are continuously stimulated by neurotransmitters or drugs become desensitized (downregulated); those that are not stimulated by their neurotransmitter or are chronically blocked by drugs become supersensitive (upregulated). Downregulation or upregulation of receptors strongly influences the development of tolerance and physical dependence. These concepts are particularly important in organ or tissue transplantation, in which denervation deprives receptors of their neurotransmitter. Withdrawal symptoms can be explained at least in part by a rebound phenomenon due to altered receptor affinity or density.
Most neurotransmitters interact primarily with postsynaptic receptors, but some receptors are located on presynaptic neurons, providing fine control of neurotransmitter release.
In one family of receptors (eg, N-methyl-d-glutamate, kinate-quisqualate, nicotinic acetylcholine, glycine, and γ-aminobutyric acid [GABA] receptors), the neurotransmitter recognition site is directly associated with an ion channel, thus providing a rapid response. In the other family (eg, serotonin, α- and β-adrenergic, and dopaminergic receptors), receptor activation causes another molecule (2nd messenger) to carry the message to the effector. The 2nd messenger is commonly an enzyme that catalyzes a chain of events resulting in protein phosphorylation or Ca mobilization; responses mediated by a 2nd messenger system are slower. Far more neurotransmitters activate specific receptors than 2nd messengers.
Major
Neurotransmitters
and Receptors
At least 100 substances can act as neurotransmitters; about 18 are of major importance. Several occur in slightly different forms.
Glutamate and aspartate:
These amino acids are the major excitatory neurotransmitters in the CNS. They occur in the cortex, cerebellum, and spinal cord. In neurons, synthesis of nitric oxide (NO) increases in response to glutamate. Excess glutamate can be toxic, increasing intracellular Ca, free radicals, and proteinase activity. These neurotransmitters may contribute to tolerance to opioid therapy and mediate hyperalgesia.
Glutamate receptors are classified as NMDA (N-methyl-d-aspartate) receptors and non-NMDA receptors. Phencyclidine (PCP, also known as angel dust) and memantine (used to treat Alzheimer's disease) bind to NMDA receptors.
GABA:
GABA is the major inhibitory neurotransmitter in the brain. It is an amino acid derived from glutamic acid, which is decarboxylated by glutamate decarboxylase. After interaction with its receptors, GABA is actively pumped back into nerve terminals and metabolized. Glycine, which resembles GABA in its action, occurs principally in interneurons (Renshaw cells) of the spinal cord and in circuits that relax antagonist muscles.
GABA receptors are classified as GABAA (activating chloride channels) and GABAB (potentiating cAMP formation). GABAA receptors are the site of action for several neuroactive drugs, including benzodiazepines, newer anticonvulsants (eg, lamotrigine ), barbiturates, picrotoxin, and muscimol. GABAB receptors are activated by baclofen , used to treat muscle spasms.
Serotonin:
Serotonin (5-hydroxytryptamine, or 5-HT) is generated by the raphe nucleus and midline neurons of the pons and upper brain stem. Tryptophan is hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan, then decarboxylated to serotonin. Serotonin levels are controlled by the uptake of tryptophan and intraneuronal monoamine oxidase (MAO).
Serotoninergic (5-HT) receptors (with at least 15 subtypes) are classified as 5-HT1 (with 4 subtypes), 5-HT2, and 5-HT3. Selective serotonin receptor agonists (eg, sumatriptan ) can abort migraines.
Acetylcholine:
Acetylcholine is the major neurotransmitter of the bulbospinal motor neurons, autonomic preganglionic fibers, postganglionic cholinergic (parasympathetic) fibers, and many neurons in the CNS (eg, basal ganglia, motor cortex). It is synthesized from choline and acetyl coenzyme A by choline acetyltransferase, and its action is rapidly terminated via local hydrolysis to choline and acetate by acetylcholinesterase. Acetylcholine levels are regulated by choline acetyltransferase and by choline uptake. Levels of this neurotransmitter are decreased in patients with Alzheimer's disease.
Cholinergic receptors are classified as nicotinic N1 (in the adrenal medulla and autonomic ganglia) or N2 (in skeletal muscle) or muscarinic M1 through M5 (widely distributed in the CNS). M1 occurs in the autonomic nervous system, striatum, cortex, and hippocampus; M2 occurs in the autonomic nervous system, heart, intestinal smooth muscle, hindbrain, and cerebellum.
Dopamine:
Dopamine interacts with receptors on some peripheral nerve fibers and many central neurons (eg, in the substantia nigra, midbrain, ventral tegmental area, and hypothalamus). The amino acid tyrosine is taken up by dopaminergic neurons and converted by tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (dopa), which is decarboxylated by aromatic-l-amino-acid decarboxylase to dopamine . After release and interaction with receptors, dopamine is actively pumped back (reuptake) into the nerve terminal. Tyrosine hydroxylase and MAO regulate dopamine levels in nerve terminals.
Dopaminergic receptors are classified as D1 through D5. D3 and D4 receptors play a role in thought control (limiting the negative symptoms of schizophrenia); D2 receptor activation controls the extrapyramidal system.
Norepinephrine:
Norepinephrine is the neurotransmitter of most postganglionic sympathetic fibers and many central neurons (eg, in the locus caeruleus and hypothalamus). The precursor tyrosine is converted to dopamine , which is hydroxylated by dopamine β-hydroxylase to norepinephrine . After release and interaction with receptors, some norepinephrine is degraded by catechol O-methyltransferase (COMT), and the remainder is actively taken back into the nerve terminal, where it is degraded by MAO. Tyrosine hydroxylase and MAO regulate intraneuronal norepinephrine levels.
Adrenergic receptors are classified as α1 (postsynaptic in the sympathetic system), α2 (presynaptic in the sympathetic system and postsynaptic in the brain), β1 (in the heart), or β2 (in other sympathetically innervated structures).
Endorphins and enkephalins:
Endorphins are polypeptides that activate many central neurons (eg, in the hypothalamus, amygdala, thalamus, and locus caeruleus). The cell body contains a large polypeptide called pro-opiomelanocortin, the precursor of α-, β-, and γ-endorphins. This polypeptide is transported down the axon and cleaved into fragments; one is β-endorphin, contained in neurons that project to the periaqueductal gray matter, limbic structures, and major catecholamine-containing neurons in the brain. After release and interaction with receptors, β-endorphin is hydrolyzed by peptidases.
Met-enkephalin and leu-enkephalin are small peptides present in many central neurons (eg, in the globus pallidus, thalamus, caudate, and central gray matter). Their precursor, proenkephalin, is formed in the cell body, then split by specific peptidases into the active peptides. These substances are also localized in the spinal cord, where they act as neuromodulators of pain signals. The neurotransmitters of pain signals in the posterior horn of the spinal cord are glutamate and substance P. Enkephalins decrease the amount of neurotransmitter released and hyperpolarize (make more negative) the postsynaptic membrane, reducing the generation of action potentials and pain perception at the level of the postcentral gyrus. After release and interaction with peptidergic receptors, enkephalins are hydrolyzed into smaller, inactive peptides and amino acids. Rapid inactivation prevents these substances from being clinically useful. More stable molecules (eg, morphine ) are used as analgesics instead.
Endorphin-enkephalin (opioid) receptors are classified as μ1 and μ2 (affecting sensorimotor integration and analgesia), δ1 and δ2 (affecting motor integration, cognitive function, and analgesia), and κ1, κ2, and κ3 (affecting water balance regulation, analgesia, and food intake). σ-Receptors, currently classified as nonopioid and mostly localized in the hippocampus, bind PCP. New data suggest the presence of many more receptor subtypes, with pharmacologic implications. Components of the molecular precursor to the receptor protein can be rearranged during receptor synthesis to produce several receptor variants (eg, 19 splice variants of the μ opioid receptor). Also, 2 receptors can combine (dimerize) to form a new receptor.
Other neurotransmitters:
Dynorphins are a group of 7 peptides with similar amino acid sequences. They coexist with enkephalins.
Substance P, a peptide, occurs in central neurons (habenula, substantia nigra, basal ganglia, medulla, and hypothalamus) and is highly concentrated in the dorsal root ganglia. Its release is triggered by intense afferent painful stimuli.
Nitric oxide (NO) is a labile gas that mediates many neuronal processes. It is generated from arginine by NO synthase, an enzyme that activates soluble guanylate cyclase by binding to Ca/calmodulin complexes. Thus, neurotransmitters that increase intracellular Ca (eg, substance P, glutamate, acetylcholine) stimulate NO synthesis in neurons that express NO synthetase. NO may be an intracellular messenger; it may diffuse out of a cell into a 2nd neuron and produce physiologic responses (eg, long-term potentiation [a form of learning], neurotransmitter release and reuptake) or enhance glutamate (NMDA) receptor-mediated neurotoxicity.
Substances with less firmly established roles in neurotransmission include histamine, vasopressin , vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin, bombesin, somatostatin, corticotropin releasing factor, neurotensin, and possibly adenosine .
Last full review/revision November 2005
Content last modified November 2005
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