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At one time it was believed that neurons signalled each other or their cellular targets by electrical means. However, with an accumulation of experimental evidence it became clear that although electrical transmission does occur, by far the major mode of synaptic transmission was due to the release of chemicals, referred to as neurotransmitters.
1. Chemical Neurotransmitters In The Nervous System
Although suggestions of chemical transmitters were made by DuBois-Raymond, Elliott Dixon, and Langley, it remained for Otto Loewi in 1921 to directly demonstrate the release of neurotransmitters from nerve endings. Loewi’s inhibitory chemical, which was released following vagal stimulation of the heart, was called agusstoff and subsequently shown to be acetylcholine. Later, acetylcholine (ACh) was identiﬁed as the neurotransmitter at a variety of peripheral synapses such as the neuromuscular junction of skeletal muscle, cardiac muscle, visceral smooth muscle, and at preganglionic synapses in the autonomic nervous system. However, to identify ACh or any other neurotransmitter in the central nervous system (CNS) was considerably more difficult since one could not stimulate a speciﬁc neuron and collect the exudate. Eventually, with the development of electrophysiological and neurochemical techniques and the designation of a set of criteria to deﬁne a neurotransmitter molecule, a number of these chemicals have now been identiﬁed. These will be individually discussed after we examine the rigid criteria for a neurotransmitter.
(a) The transmitter must be synthesized and stored in the presynaptic terminal. Experimental evidence that satisﬁes this criterion include cytochemical and subcellular biochemical evidence and a demonstration of the loss of the suspected transmitter following surgical or chemical lesioning of the presynaptic neuron.
(b) Stimulation of the presynaptic neuron should release the transmitter. With current sophisticated techniques, it is possible to collect and identify the released transmitter.
(c) Application of the putative transmitter to the synapse should mimic the response of electrical stimulation of presynaptic nerve tracts. Conversely, drugs that block the response of the electrically stimulated release of the transmitter should also block the response of the applied suspected transmitter.
(d) A mechanism must exist for the rapid termination of transmitter activity. This would be either enzymatic catabolism or a high affinity reuptake system for the transmitter either in the presynaptic terminal or adjacent glial cells.
Before discussing the certiﬁed neurotransmitters, it is appropriate to clarify some confusion in the literature on the deﬁnitions of neurotransmitters, neuromodulators, and neurohormones. The criteria for classifying a compound as a neurotransmitter have already been discussed. Neuromodulators, as the name implies, do not have intrinsic activity but modulate ongoing synaptic activity. Thus, if transmitter release at a synapse was prevented, the addition of a neuromodulator to the preparation would have no effect. Neuromodulators may affect synaptic transmission, by acting on presynaptic receptors, or the synthesis, release, reuptake, or metabolism of transmitters. In contrast to neuromodulators, neurohormones do have intrinsic activity but differ from neurotransmitters in that following release from either a neuronal or glial source, they travel in some circulation to produce their effects at a distance from their release site.
Having deﬁned these terms it is necessary to point out that it is a futile exercise to classify a neuroactive agent as a transmitter, modulator, or hormone until one knows its activity and its site of action, since these agents can play different roles. Thus, for example, dopamine is a certiﬁed transmitter in the striatum, yet it can also be released from the hypothalamus, and travel in the hypophyseal–portal circulation to act on the pituitary to inhibit the release of prolactin. In this case dopamine is obviously acting as a neurohormone. Similar examples exist amongst the other transmitters to be discussed such as norepinephrine, serotonin, and acetylcholine.
Another class of agents that causes confusion in the literature are the neuroactive peptides. These compounds, often referred to as co-transmitters, can be released from nerve terminals to affect synaptic transmission. For example, vasoactive intestinal polypeptide (VIP) is released from the salivary gland along with ACh and increases secretion while simultaneously increasing the affinity of ACh for the cholinergic receptor in the salivary gland. Another peptide, substance P, is currently thought to be the actual neurotransmitter in the spinal cord rather than just being a modulatory agent.
As noted earlier, the ﬁrst neurotransmitter to be identiﬁed was acetylcholine (ACh). ACh is synthesized from acetyl CoA and choline, catalyzed by the enzyme choline acetyltransferase (Fig. 1). The transmitter activity of ACh is terminated by hydrolysis of ACh to acetate and choline, catalyzed by the enzyme acetylcholinesterase. (This is the enzyme, incidentally, that is inhibited by the so-called ‘nerve gases’.)
In contrast to the other neurotransmitters to be discussed, the rate-limiting step in the synthesis of ACh is the uptake of choline into the presynaptic terminal. In the terminals, ACh, like the other transmitters, is stored in small sacs, referred to as synaptic vesicles, from which it is released by an exocytotic mechanism (see below).
In the peripheral nervous system, ACh is the transmitter at autonomic ganglia, at parasympathetic postganglionic synapses, and at the neuromuscular junction. In the CNS, experimentally a more difficult area in which to localize neurotransmitter activity, major cholinergic tracts originate in the medial septal nucleus, the vertical limbus nucleus of the diagonal band, the horizontal nucleus of the diagonal band, and the nucleus basalis of the substantia inominata. These tracts respectively innervate the hippocampus, the olfactory bulb, and the cerebral cortex and amygdala. Cholinergic interneurons are found in the striatum. The ﬁrst cholinergic tracts that were identiﬁed were the motoneuron collaterals to the Renshaw cells in the spinal cord.
When ACh is released from nerve terminals, it exerts its physiological effects by acting on two different types of receptor, muscarinic and nicotinic. (Each of these exist in multiple sub-types which when activated produce different responses.)
The major disease associated with ACh is myasthenia gravis, an autoimmune disease whereby circulating antibodies affect the ACh receptor at the neuromuscular junction. Circumstantial evidence implicates ACh in cognitive functions, particularly in the early stages of Alzheimer’s Disease.
2. Biogenic Amines
Four neurotransmitters come under the chemical classiﬁcation of biogenic amines. These are epinephrine, norepinephrine, dopamine, and serotonin. Although epinephrine is the transmitter in frogs, in mammals its role has been supplanted by norepinephrine. Epinephrine’s function in the mammalian brain is still unclear and may be limited to a hormonal role.
Starting with tyrosine, the catecholamines (norepinephrine and dopamine) are synthesized in a cascade of reactions beginning with the rate-limiting enzyme, tyrosine hydroxylase. Figure 2 depicts the enzymes and cofactors involved. The catecholamines are catabolized by two enzymatic pathways (Fig. 3) involving monamine oxidase, a neuronal mitochondrial enzyme, and catechol-o-methyltransferase, a cytoplasmic enzyme, found primarily in the kidney and the liver. However, as noted earlier, when norepinephrine and dopamine are released into the synapse, their activity is terminated by reuptake into the presynaptic terminal rather than by enzymatic catabolism. The reuptake is inhibited by a number of antidepressant drugs.
Noradrenergic neurons arise from the locus coeruleus, the lateral tegmental system, and a dorsal medullary group and innervate virtually all areas of the brain and spinal cord. Central effects of noradrenaline stimulation are not clear but appear to involve behavioral attention and reactivity.
Peripherally where noradrenaline is released from postganglionic sympathetic neurons of the autonomic nervous system, the major effects are to regulate blood pressure, relax bronchi, and relieve nasal congestion. These effects are mediated by the major receptors, α and β, each again with multiple subtypes.
At one time dopamine was thought to be just an intermediate in the conversion of tyrosine to noradrenaline. It is now clear, however, that dopamine is a major player in the CNS with its implication in Parkinson’s disease and in schizophrenia. Dopamine cells originate in the substantia nigra, ventral tegmental area, caudal thalamus, periventricular hypothalamus, and olfactory bulb. Dopaminergic terminals are found in the basal ganglia, the nucleus acumbens, the olfactory tubercle, the amygdala, and the frontal cortex. The nigrostriatal pathway is particularly important since its degeneration is involved in Parkinson’s disease. Initially, dopamine receptors were classiﬁed as D1 or D2. Currently the subtypes consist of D1 through D5 with the possibility of a D6. All the receptors are coupled to G proteins as their second messenger. Arising from the observation that a correlation existed between therapeutic doses of antipsychotic drugs and inhibition of binding of dopamine receptor antagonists, the D2 receptor has been ﬁngered in the pathophysiology of schizophrenia. The atypical neuroleptic drug clozapine, however, exhibits a greater affinity for the D4 receptor, dopaminergic transmission in the nucleus accumbens, involving both D1 and D4 receptors, is believed to be involved in the reward activity of abused drugs such as cocaine. The catabolism of dopamine is shown in Fig. 4.
The last of the biogenic amine neurotransmitters to be discussed is serotonin (5-hydroxytryptamine). Its synthesis and its catabolism are depicted in Figs. 5 and 6. In addition to its presence in the CNS, serotonin is found in the GI tract and in blood platelets. It is also localized in the pineal gland where it serves as a precursor to the hormone melatonin. Serotinergic neurons innervate the limbic system, the neostriatum, cerebral and cerebellar cortex and the thalamus. Currently, 18 serotonin receptor subtypes have been identiﬁed. Most are G-protein linked except for the 5-HT3 receptor which is ligand gated. Hallucinogen drugs have been shown to act on the 5-HT2A receptors. Serotonin receptor antagonists that are relatively speciﬁc have been used to treat migraine headaches, body-weight regulation and obsessive–compulsive disorders.
Decarboxylation of the amino acid histidine results in the formation of histamine, a still questionable neurotransmitter. This amine does not qualify as a transmitter according to the rigid deﬁnitions outlined earlier, since no evidence exists for either its release on stimulation of a neuronal tract, nor is there a rapid reuptake mechanism or enzymatic catabolism to terminate its activity. Histaminergic neurons are located almost exclusively in the ventral posterior hypothalamus and project throughout the entire CNS. Three histamine receptors have been described, H1, H2 and H3. Antagonists of H1 are the well-known antihistamine drugs which exhibit a sedative action. H2 antagonists are used to block gastric acid secretion. H3 receptors are autoreceptors which, when activated, inhibit the release of histamine.
3. Amino Acid Transmitters
Acetylcholine and the biogenic amines discussed above account for only a small percentage of neurotransmitter activity in the brain. By far the most prevalent transmitters are the amino acid transmitters, with glutamate in particular accounting for about one-third of synaptic activity. The amino acid transmitters are glutamate (and possibly aspartate), γ-aminobutyric acid (GABA) and glycine.
Glutamate is synthesized by transamination of χ-ketoglutarate (Fig. 7) which is produced in the citric acid cycle, which in turn originates from glucose via glycolysis. Aside from its neurotransmitter activity, glutamate, with the highest concentration of any amino acid in brain, is involved in peptide and protein synthesis, in the detoxiﬁcation of ammonia in the brain, and as a precursor of the major inhibitory transmitter in the brain, GABA. With so many roles to play, it is easy to understand why the amino acid is compartmentalized, with one pool involved in intermediary metabolism, and the transmitter pool sequestered in synaptic vesicles. Curiously, glutamate that is released on nerve stimulation is taken up into astrocytes where it is converted to glutamine via glutamine synthetase (Fig. 7). It then diffuses out of these glial cells to neuronal terminals where it is hydrolyzed to glutamate via glutaminase, and stored in vesicles ready for release. Glutamate and aspartate are the major fast excitatory transmitters in the CNS and the spinal cord, with a widespread distribution. Currently, the case for aspartate as a neurotransmitter is not entirely clear, though it may have a distinct role in certain cortical and hippocampal pathways.
There are currently four different subtypes of excitatory amino acid receptors, referred to as AMPA, kainate, NMDA and ACPD, comprising a total of fourteen receptors. The ﬁrst three are ionotropic (ligand gated) receptors and the fourth is metabotropic (G-protein linked). Glutamate as a neurotransmitter has been implicated in excitotoxicity, i.e., as a neurotoxin involved in neurological disorders. Also, glutamate has been shown to play a role in long-term potentiation that may underlie memory and learning.
Two other amino acid transmitters are GABA and glycine, both of which are inhibitory transmitters. The synthesis of GABA from glutamate and its catabolism is depicted in Fig. 8. It has been suggested that 10 to 40 percent of terminals in the cerebral cortex, hippocampus, and substantia nigra use GABA as the major inhibitory transmitter. Other GABAergic areas are the cerebellum, striatum, globus pallidus, and olfactory bulb, as well as the spinal cord.
The two main GABA receptors, each with subtypes are GABAA and GABAB. GABAA is a ligand-gated chloride anion channel whereas GABAB, localized primarily at presynaptic terminals, is a G-protein- linked receptor. Anxiolytic drugs such as diazepam (Valium) bind to the GABAA receptor to modulate its activity. Certain antiepieptic drugs appear to operate by increasing GABAergic activity.
Glycine, a nonessential amino acid, is the second major inhibitory transmitter in the CNS. Serine, arising from glucose, is thought to be the major source of glycine in neurons (Fig. 9). The conversion of serine to glycine is catalyzed by serine hydroxymethyl-transferase with tetrahydrofolate as cofactor. As a neurotransmitter, glycine operates almost exclusively in the spinal cord, with a possible involvement in the lower brain stem and the retina. The glycine receptor is similar to the GABAA receptor in that it promotes hyperpolarization by increasing chloride conductance. The glycine receptor can be identiﬁed by the binding of the convulsant drug strychnine. This observation supports the presumed role of glycine in sensorimotor systems and is further supported by the production of spastic mice who have a genetic defect in the glycine receptor. Recently a new role for glycine has arisen with the ﬁnding that the amino acid regulates the NMDA (glutaminergic) receptor.
4. Release And Reuptake Of Neurotransmitters
Although covered in other articles, two major aspects involving neurotransmiters should be mentioned. These are the mechanisms involved in the release of the transmitters and the reuptake mechanism involving particularly the biogenic amines. With regard to transmitter release, as noted earlier, the agents are sequestered in synaptic vesicles. Brieﬂy, when the neuron is depolarized, calcium enters the terminal and the vesicles at the presynaptic release sites fuse with the plasma membrane and open to release the transmitter. A large number of polypeptides is involved in this complex process that involves both release and re-constitution of the plasma membrane and repletion and recycling of vesicles.
The second process is the role of transporters that are involved in the reuptake of transmitters into the presynaptic terminals. Plasma membrane transporter proteins have been cloned for all the transmitters (but not for choline) and utilized an ATP-dependent process which also requires an Na+ and Cl− as cotransporters. These transporters are different from those that pump the transmitters into vesicles; the vesicle transporters utilize an ATP-dependent proton pump mechanism.
The agents that are covered here are the certiﬁed neurotransmitters. However, it should be kept in mind that in addition to neuropeptides, which at certain sites appear to act as transmitters rather than as neuromodulators, a variety of compounds has also been suggested as having neurotransmitter roles. These would include adenosine, ATP, and a variety of non-peptide hormones. There is very little that is absolute in neuroscience.
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