Neurons communicate with each other through the use of chemical messengers called

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.

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.

Some Central Concepts on Cell-to-Cell Communication

Adaptability and survival of all organisms depends on the coordinated communication between cells and the external environment. Synaptic communication is defined as the interchange of chemical substances between neurons and, as in any other way of communication, requires three basic components: the signal transmitter, the signal transducer, and the signal receiver. This notion was initially proposed at the end of nineteenth century, when Santiago Ramon y Cajal conceived that neurons possessed three main regions: (i) the signal receiving region formed by the dendrites and soma, (ii) the transducer region, composed of the axon, and (iii) the signal emitting region formed by terminal axonal or synaptic button (DeFelipe, 2010). To date, in signal transduction research in nervous system it is accepted that the signal emitting region is the presynaptic axon, the signal receiver region is any point of the postsynaptic neuron where neurotransmitter is released, and the transducer mechanism is composed by the receptors, ion channels, enzymes, transcription factors, and any biochemical element modified in the postsynaptic neuron, which lead to a correct decodification of the message and long-term changes on receptive neurons.

Some of the main steps in the process of chemical synaptic communication are depicted on Figure 8.2. Presynaptic terminal produces specific messengers that are released to the synaptic space and are recognized by particular receptors on the postsynaptic cell. This event leads to the activation of particular signaling pathways that involve the production of second messengers, activation of initial and intermediate kinases, nuclear translocation of transcription factors, and also to epigenetic modifications and changes on the translational machinery, which, in turn, will convert cell stimulation to long-term changes on gene expression profiles potentially related to learning and memory.

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.”

Neurotransmitters

Neurotransmitters are chemical compounds released by neurons after depolarization that act on other neurons to produce a response (Fig. 3). The response produced by a neurotransmitter is mediated by a neurotransmitter receptor capable of recognizing it. Neurotransmitters are the principal means by which neurons transfer information to each other. Characteristics of a neurotransmitter include its synthesis in the neuron, concentration in membrane-enclosed vesicles at presynaptic terminals, release by neuron terminal depolarization, induced activity at the postsynaptic terminal as a consequence of receptor binding, and removal from the synapse to terminate this effect. The defining characteristics of neurotransmitters have become less stringent due to evidence of some neurotransmitter release at nonsynaptic sites and because of the properties of unusual neurotransmitter-like molecules such as nitric oxide.

There are many different neurotransmitter molecules (Fig. 4). They can be categorized as small molecules and much larger neuropeptides. The smallest neurotransmitter may be nitric oxide, with a molecular weight of 30, whereas the neurotransmitter peptide endorphin is composed of 30 amino acids and has a molecular weight of more than 3000—a 100-fold difference in size. Most neurotransmitters are localized to discrete parts of the nervous system, but three (adenosine, glutamate, and glycine) are present in every cell of an organism. Some neurotransmitters, including acetylcholine, norepinephrine, serotonin, and dopamine, can produce excitatory or inhibitory effects depending on the receptors on which they act. The diversity of structural and functional properties makes it difficult to categorize neurotransmitters.

The functional properties of a neurotransmitter differ in several important ways beyond the response produced at the postsynaptic site. Differences include their site of production within the neuron, the kinetics or time course of their response, and the method of removal from the synapse after release.

Small molecule transmitters, such as acetylcholine, epinephrine, norepinephrine, serotonin, and dopamine, are produced at the presynaptic terminal by local enzymes. All these except acetylcholine are produced from amino acid precursors, such as tyrosine (epinephrine, norepinephrine, and dopamine) or tryptophan (serotonin). Acetylcholine is produced by the acetylation of choline, a common nutrient. Peptide neurotransmitters such as enkephalin, dynorphin, cholecystokinin, and substance P are produced by the cleavage of much larger protein precursors primarily in the cell body of the neuron near its nucleus. The active neuropeptide products are packaged in secretory granules and then transported to their sites of release. One consequence of this difference between small and large neurotransmitters is that under conditions of high activity the neuropeptide supply at the presynaptic terminal can be exhausted.

The response kinetics for neurotransmitters differs depending on the type of receptor on which they act. Neurotransmitters acting on ion channel receptors such as glutamate (excitatory) and GABA (inhibitory) produce very fast responses (milliseconds). Glutamate and GABA also act on another class of receptors referred to as metabotropic or G protein-coupled receptors. These responses are much slower and can last for seconds to hours. The response mediated by an ion channel receptor results from the flow of ions (sodium, potassium, chloride, or calcium) that occurs when the transmitter opens the channel. Responses mediated by G protein-coupled receptors occur more slowly because they result from the activation of an extended series of enzymes.

There are two principal mechanisms by which neurotransmitters are removed from the synaptic space. The majority of neurotransmitters, including all neuropeptides and many small neurotransmitters, either diffuse away from their site of release or are destroyed by enzymes present on cell membrane surfaces. Acetylcholine is a classic example because it is very rapidly destroyed by acetylcholine esterase, which hydrolyzes the ester bond between the acetic acid and choline components of the neurotransmitter. Neuropeptides are degraded into their constituent amino acids by protease enzymes. Some small molecule neurotransmitters (e.g., norepinephrine, dopamine, and serotonin) are recaptured by the presynaptic terminal through a process called reuptake. Reuptake provides a means of recycling the transmitter so that high levels of neurotransmission can be maintained.

Neurotransmitters

Neurotransmitters are responsible for sending the messages from one neuron to the next. While they exist throughout the body, they are most prevalent in the brain. Understanding brain function and responses to various psychopharmacological agents depends on a basic understanding of these internal chemicals. Classifying neurotransmitters is complicated because there are over 100 different ones. Fortunately, the seven “small molecule” neurotransmitters (acetylcholine, dopamine, gamma-aminobutyric acid (GABA), glutamate, histamine, norepinephrine, and serotonin) do the majority of the work. Another complicating factor is that neurotransmitters may have a number of subtypes, serotonin having 15, as an example.157 Endorphins and oxytocin are neuropeptides that are sometimes considered to be neurotransmitters, and β-endorphin is associated with the feeling of pleasure in humans. Exercise causes β-endorphin and serotonin levels to significantly increase in horses.158 This is likely to happen in human runners too. It is also thought some neurotransmitters may play a role in stereotypies.159 Neurotransmitters do have general functions that hold true even across species, as will be described later in the book.

The equine brain has not been well studied relative to which neurotransmitters are associated with which nuclei or specific functions. Each nucleus may have multiple neurotransmitters, and there can be considerable differences in their proportions between species. This explains why a drug that works in one species may not be as effective for a similar problem in another. It is important to understand that the choice of a psychopharmacological drug is based on empirical data, so depending on the patient’s response, it might be necessary to modify doses or drugs used.

Neurotransmitters

Neurotransmitters are chemicals in the central nervous system that relay signals between neurons by crossing the small gap (synapse) between neurons. The neurotransmitters are stored in vesicles close to the synaptic membrane, and when they are released into the synapse they bind to receptors in the synaptic membrane of the opposite neuron. The effect of this depends upon the properties of the receptor. In most cases receptor binding causes depolarisation of the receptor site. In general this results in the cell firing an action potential, and therefore has an excitatory effect. Some neurotransmitters cause hyperpolarisation of the receptor site, and this results in inhibition of the target neuron.

For a chemical to be regarded as a neurotransmitter it must fulfil a number of criteria (Fig. 1). There must be evidence that it is synthesised in the presynaptic neuron. The precursors and enzymes associated with synthesis must be found in the presynaptic neuron. It must be released when the presynaptic receptor is stimulated, and bind to the postsynaptic receptor, causing a biological effect. There must also be evidence of a mechanism for deactivating the chemical in the synapse, or for its reuptake.

The first neurotransmitter to be described was acetylcholine, in 1914. Since then a wide variety of neurotransmitters have been identified. The most common neurotransmitter in the CNS is glutamate, present in more than 80% of synapses in the brain. Gamma-aminobutyric acid (GABA) is present in the majority of other synapses. Other neurotransmitters are present in fewer synapses, but are of greater significance in the aetiology and treatment of mental illness – in particular dopamine, serotonin, noradrenaline and acetylcholine.