Neurotransmitters are typically stored in which of the following parts of a neuron?

Role of Neurotransmitters

As noted previously, the richly innervated nerve plexuses and neuroendocrine associations of the CNS and ENS provide the hardwiring for the brain-gut axis. Mediation of these activities involves neurotransmitters and neuropeptides commonly found in the CNS and intestine. Depending on their locations, these substances have integrated activities on both GI function and human behavior. This observation is not surprising because the hardwiring between brain and gut is established from an anlage that begins as one unit (neural tube) and then differentiates with the growing organism into the “big brain” and the “little brain” in the gut. As shown inFigure 22.3, the development of the nervous system in the embryo begins with the neural crest. Over timethe neural crest grows and differentiates into the forebrain, midbrain, and spinal cord. From the future spinal cord, spinal ganglia migrate into the early gut to become the future ENS. Therefore, the ENS, spinal cord, and CNS are “hardwired.” No other organ system is as closely connected to the brain as the GI system. This helps explain the close relationship clinically between psychosocial features and gut functioning: the brain-gut axis.

For example, the stress hormone corticotropin-releasing factor (CRF) has central stress modulatory effects yet different intestinal physiologic effects. CRF produces gastric stasis and an increase in the colonic transit rate in response to psychologically aversive stimuli106 and can increase visceral hypersensitivity107 and alter immune functioning78; therefore, CRF may play a role in stress-induced exacerbations of IBS (seeChapter 122),108 cyclic vomiting syndrome (seeChapter 15),109 and other stress-mediated disorders.

Peptides may be secreted at nerve endings as neurotransmitters or directly from cell walls and thus have local or paracrine effects. Several key neurotransmitters act within the brain-gut axis.77,110 Acetylcholine is the main mediator of the parasympathetic system and drives motility in the enteric system; disturbances of this activity can lead to constipation and gastroparesis. Biological amines such as serotonin, norepinephrine, and dopamine act in the periphery to mediate the effects of the sympathetic nervous system to regulate the balance between constipation and diarrhea and centrally to modulate mood, emotional behavior, and pain. Calcitonin gene-related peptide (CGRP), bradykinins, and tachykinins (e.g., substance P) are involved in visceral hyperalgesia and pain syndromes. The opioid system can raise the threshold for pain and impair peristalsis and secretion; centrally it may paradoxically produce hyperalgesia.111

These associations have relevance in terms of treatment. Chronic GI pain is modulated by the gate control system of the brain-gut axis (see alsoChapter 12). Therefore, because certain areas of the brain have the capability to up- or down-regulate incoming visceral signals, neurotransmitters common to both brain and gut (e.g., noradrenergic and serotonergic neurotransmitters) can be used to attempt to reduce the painful experience. A Rome Foundation Working Team Report112 has recommended the use of central neuromodulators (previously identified as antidepressants, antipsychotics, and other psychotropics, as used in psychiatry) for treatment of chronic GI pain or other GI functions via this brain-gut axis pain control mechanism and their possible central effects on neurogenesis (see later).112

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 D2 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.

Peripheral Neurotransmitters and Endothelium-Derived Factors Opposing Penile Erection

Maintenance of intracorporal smooth muscle in a semi-contracted (flaccid) state likely results from three factors: intrinsic myogenic activity (Andersson and Wagner, 1995);adrenergic neurotransmission; and endothelium-derived contracting factors such as angiotensin II, PGF2α, and endothelin-1. Detumescence after erection results from resumption of these factors as well as cessation of NO release, the breakdown of cyclic guanosine monophosphate (cGMP) by phosphodiesterases (PDEs), and/or sympathetic discharge during ejaculation.

Norepinephrine is generally accepted as the principal neurotransmitter mediating penile flaccidity (Andersson, 2011). Both α1-adrenergic and α2-adrenergic fibers and receptors have been demonstrated in the corpora cavernosa and surrounding the cavernous arteries (Prieto, 2008). Research findings support a functional predominance of postjunctional α1-adrenergic receptors for contraction and of prejunctional α2-adrenergic receptors for downregulating release of norepinephrine and the vasodilator nitric oxide (NO) (Prieto, 2008). Stimulation of adrenergic receptors by norepinephrine produces contraction in penile vessels and the corpora cavernosa; this process is mediated by Ca2+ entry into smooth muscle cells via membrane calcium channels. Cellular calcium sensitization mechanisms also contribute and are mediated by protein kinase C (PKC), tyrosine kinases, and Rho-kinase (Andersson, 2011).

Endothelin-1 is a potent vasoconstrictor and mediator of penile detumescence (Holmquist et al., 1990;Saenz de Tejada et al., 1991). Two receptors for endothelin, endothelin-A and endothelin-B1, mediate the biologic effects of endothelin in vascular endothelial tissue: endothelin-A receptors mediate contraction, whereas endothelin-B1 receptors induce relaxation. By action on endothelin-A receptors, endothelin induces slow-developing, long-lasting contractions in the corpora cavernosa and cavernosal arteries. Endothelin also potentiates the constrictor effects of catecholamines on trabecular smooth muscle (Christ et al., 1995). Blockade of the endothelin-A receptor ameliorates impaired penile hemodynamics in animal models of obesity (Sanchez et al., 2014).

Several constrictor prostanoids, including prostaglandin I2 (PGI2), prostaglandin F2α (PGF2α), and thromboxane A2 (TXA2), are synthesized by the human cavernous tissue. Prostanoids induce spontaneous contraction in isolated trabecular muscle (Christ et al., 1990) and inhibit the relaxant effects of NO (Azadzoi et al., 1992;Minhas et al., 2001). The contractile effects of prostanoids in corporal tissue appear to be mediated by thromboxane A2 (TP) receptors (Angulo et al., 2002).

V.A.1. Acetylcholine (ACh)

ACh is formed in a single enzymatic step. The enzyme, choline acetyltransferase, catalyzes the esterification of choline by acetyl-CoA.

The transferase is specific to cholinergic neurons and is not expressed in any other cell type. (The term cholinergic is used to denote a cell that releases ACh as a neurotransmitter. Similarly, glutaminergic, dopaminergic, and serotonergic indicate that a neuron releases glutamate, dopamine, or serotonin, respectively. If a cell responds to ACh, that cell is called cholinoceptive, a term used infrequently for the other neurotransmitters; e.g., “dopaminoceptive” is unusual.) The formation of ACh is limited by the supply of choline. Choline is not made in nervous tissue, but must be obtained through the cerebrospinal fluid from dietary sources or recaptured from the synaptic cleft from the ACh released and hydrolyzed by the enzyme acetylcholinesterase (see later discussion).

There are two general classes of acetylcholine receptors (AChR): nicotinic, responding to the alkaloid nicotine, and muscarinic, responding to the mushroom poison, muscarine. ACh is excitatory at the neuromuscular junction, where it binds to postsynaptic nicotinic AChRs. As we saw with Loewi's experiment, it is an inhibitory (parasympathetic) transmitter to the heart through muscarinic AChRs. In the periphery, ACh is also the transmitter for all preganglionic neurons of the autonomic nervous system. In the brain, there are many cholinergic systems, for example, cholinergic neurons in the nucleus basalis have widespread projections to the cerebral cortex.

Nicotinic AChRs are ionotropic, meaning that, when they bind ACh, they open up to pass ions from the extracellular space into the postsynaptic neuron. Muscarinic AChRs are metabotropic. These receptors activate various second messenger pathways to produce biochemical changes within the postsynaptic neuron. Thus, as with other neurotransmitters, ACh can excite or inhibit depending on the postsynaptic receptor.

Neuropeptides, Neurotransmitters, and Neurohormones

One of the features of the neuroendocrine system is that it uses neuropeptides as both neurotransmitters and neurohormones. The termneurotransmitter is applied traditionally to a substance that is released by one neuron and acts on an adjacent neuron in a stimulatory or inhibitory fashion. The effect is usually rapid, brief, and confined to a small area of the neuronal surface. In contrast, ahormone is a substance that is released into the bloodstream and usually travels to a distant site to act over seconds, minutes, or hours to produce its effect over a large area of the cell or over many cells.Neuropeptides can act in either fashion. For example, the neuropeptide vasopressin, produced by the neurons of the supraoptic and paraventricular nuclei, is released into the bloodstream and has a hormonal action on the collecting ducts in the kidney. Vasopressin is also released within the central nervous system (CNS), where it acts as a neurotransmitter. Similarly, the neuropeptide substance P acts as a neurotransmitter in primary sensory neurons that convey pain signals and as a neurohormone in the hypothalamus.

The influence of neurohormones and neuropeptides on the brain can be divided into two broad categories: organizational and activational.Organizational effects occur during neuronal differentiation, growth, and development and bring about permanent structural changes in the organization of the brain and therefore brain function. An example of this is the structural and organizational changes brought about in the brain by prenatal exposure to testosterone.Activational effects are those that change preestablished patterns of neuronal activity, such as an increased rate of neuronal firing caused by exposure of a neuron to substance P or vasopressin.

Numerous neuropeptides are found in the brain, where they have a wide variety of effects on neuronal function (Table 50.1). Current understanding of all the actions of neuropeptides in the nervous system is far from complete.

Neurotransmitters

Neurotransmitters and neuromodulators are the molecules responsible for the transmission of information on chemical synapses. For a molecule to be considered as a neurotransmitter (i) must be stored in vesicles together with the enzymes responsible for its synthesis; (ii) must be released in response to an increase in intracellular Ca2+; and (iii) the exogenous administration of the neurotransmitter should elicit the same response as it were endogenously produced.

Neurotransmitters can be classified into two groups: (i) classic, such as amino acid derivatives and (ii) neuropeptides. The main neurotransmitters associated with learning and memory, together with its receptors and signaling systems, are given in Table 8.1.

Table 8.1. Main Neurotransmitters Associated with Learning and Memory, its Receptors and Canonical Signaling Pathways

Abstract

Neurotransmitters are chemical messengers by which neurons communicate with each other. High affinity uptake of neurotransmitters is mediated by transporter proteins and is the most common mechanism for the termination of neurotransmitter signaling. Transporters clear neurotransmitters not only to control the timing of neurochemical communication, but also to recapture transmitter molecules for later reuse. In addition to their obvious and critical role in neurotransmitter homeostasis, transporters are also important targets for therapeutic drugs as well as drugs of abuse and known neurotoxins. Here, we summarize the mechanism of transporter function, how transporter protein structure defines the functional properties of transporters, the cellular signals, and determinants that regulate transporters, and how disease states are related to neurotransmitter transporter dysfunction.

Removal or Destruction of the Neurotransmitter Shuts Off the Neurotransmitter Signal

Neurotransmitters bind to their receptor by mass action. This principle states that the rate of binding is proportional to the concentration of free ligand (neurotransmitter) and free receptor, and the rate of unbinding or desorption is proportional to the concentration of bound ligand. This is stated succinctly in the equations

[4.2.1]L+P→konL⋅PL⋅P→koffL +P

Thus, the occupancy of the receptor P with the neurotransmitter L will decrease only when the free ligand concentration falls. Lowering the concentration of free neurotransmitter in the synaptic gap, therefore, will shut off the continued effect on the post-synaptic cell. As shown in Figure 4.2.7, there are three general ways to achieve this end: (1) destruction of the neurotransmitter by degradative enzymes; (2) diffusion of the neurotransmitter away from the post-synaptic receptors; and (3) reuptake of the neurotransmitter either by the pre-synaptic terminal or by other cells.

Neurotransmitters Shuttle Information from Neuron to Neuron

Neurotransmitters are the messengers of the nervous system. They are relatively small molecules that carry information across synapses from a nerve cell to its neighboring cells and are a critical part of the internal machinery controlling animal behavior. Generally speaking, the neurotransmitter is held in membrane-bound vesicles near the synapse. The nerve cell with these vesicles is the presynaptic cell. When stimulated, the vesicles merge with the cell membrane of the presynaptic cell, and the neurotransmitter is released into the synapse, or “synaptic space.” The neurotransmitter molecules cross the synaptic space and match with receptor molecules in the membrane of the postsynaptic cell, causing depolarization in that membrane and continuing the transmission of the impulse. These receptors are critically important; for each neurotransmitter there are several receptor molecule types, guaranteeing a transmitter-specific message. Each neurotransmitter has many different functions in the nervous system, and the receptor type involved in regulating a behavior often tells us more about the behavior than the identity of the neurotransmitter might tell us. The most common neurotransmitter is acetylcholine, which often is the messenger between axons and muscles as well. Other common neurotransmitters are octopamine, serotonin, and dopamine; they usually function in the central nervous system. All of these neurotransmitters are found in both vertebrates and invertebrates.

Key Term

Neurotransmitters are small molecules that carry messages among axons and between the nervous system and other tissues and organs.

Key Term

Acetylcholine is a neurotransmitter that acts, in many animals, at synapses between nerves and muscles.

For this system to work, the neurotransmitter must be removed from the synapse after the signal is no longer needed. This happens by either cleaving the neurotransmitter to inactivate it or by re-uptake of the neurotransmitter into the presynaptic cell. For instance, a specialized enzyme called acetylcholine esterase breaks down acetylcholine in the synapse. The components can then be recycled. In contrast, serotonin is taken up directly by the presynaptic cell (see Figure 2.3).

Note

Insecticides like malathion, which is commonly used in mosquito control, are acetylcholine esterase inhibitors. This means the insecticide prevents the enzyme that breaks down acetylcholine in the synapses from acting. The resulting accumulation of acetylcholine results in uncoordinated firing of nerves and leads to death of the insect.

Abstract

Neurotransmitters are the chemical messengers that allow electrical signals from neurons to be transmitted to the postsynaptic neuron or effector target. A substance is generally considered a neurotransmitter if it is synthesized in the neuron, is found in the presynaptic terminus and released to have an effect in the postsynaptic cell, is mimicked by exogenous application to the postsynaptic cell, and has a specific mechanism for termination of its action. Various types of molecules, ranging from simple gases, such as nitric oxide (NO), to complex peptides, such as pituitary adenylate cyclase-activating peptide, satisfy these criteria. Most small-molecule neurotransmitters, such as acetylcholine and dopamine, are synthesized in the cytoplasm of the nerve terminal and transported into vesicles; a variety of substrates and biosynthetic enzymes are involved in the synthesis of small-molecule neurotransmitters. Only 12 small-molecule neurotransmitters have been identified, but over 100 neuroactive peptides have been identified. Unlike small-molecule neurotransmitters, neuropeptides are encoded by specific genes and are synthesized from protein precursors formed in the cell body. The emerging understanding of atypical neurotransmitters such as the gases NO and CO, lipid mediators, and the phenomena of gliotransmitter action and exosomal transmission is constantly revising the understanding of what constitutes a “neurotransmitter.”