9 Peter J. Pascoe and Eugene P. Steffey Drugs that act in the central nervous system (CNS) are of fundamental importance to health-care delivery. Some agents are administered to animals to directly improve their well-being. For example, without general anesthesia, modern surgery would not be possible. Some drugs alter behavior and improve animal–human interaction. They may induce sleep or arousal or prevent seizures. Drugs that act in the CNS are sometimes administered in an attempt to understand the cellular and molecular basis for CNS actions (i.e., physiology and pathophysiology) and/or identify the sites and mechanisms of action of other drugs. Finally, CNS actions of some drugs come as unwanted “side effects” when those drugs are used to treat conditions elsewhere in the body. For example, seizures may result from the injection of too much local anesthetic. The first purpose of this chapter is to review principles of organization and function of the CNS. The intent is to lay a foundation from which later discussion on principles and applied aspects of CNS pharmacology can meaningfully follow. Behavior-altering drugs and anesthetics are routinely administered to animals by veterinarians and allied personnel. Appropriate use of these drugs is an important application of our knowledge of CNS pharmacology. Therefore, this chapter will conclude with a review of the principles of contemporary veterinary anesthesiology. The CNS is largely the same anatomically across mammalian species. The brain and spinal cord have evolved to collect information about external and internal changes and to provide integration of this information in such a way as to promote the survival and reproduction of the animal. The information is gathered by sensory neurons that transduce a stimulus (e.g., light, sound, gas in the intestine) to an electrical signal (neuronal depolarization) that is transmitted to the central nervous system. The CNS then interprets this signal, computes a response, and initiates an output to effect an appropriate action (if needed). This response may need very little CNS integration or may need much greater interpretation. For example, an animal that steps on a red hot object stimulates a reflex arc to initiate an immediate withdrawal of the limb without any conscious perception that the object was hot. On the other hand a cat faced with a juicy steak sitting on a kitchen counter must first recognize the steak for what it is, and then compare that with its memory for what such an object might taste like and balance this with the memory of the punishment it received the last time it tried to steal such an object from that location. These latter computations involve complex integration in the CNS, and the neuronal involvement is largely controlled by chemical substances that cause, modify, or inhibit the depolarizations that lead to the final outcome. Although the CNS of most mammals has the same basic organization, it is not surprising that evolutionary pressures have created differences in the relative size of certain components. This is easily demonstrated by examining the olfactory lobes of the brain in a human being and a dog, the latter having a much greater relative size than in people. There are also chemical differences in the CNS of different species that are not as readily explainable but clearly have an impact on our use of drugs to modify CNS activity. It is well known that opioids can cause excitation in horses and sedation in dogs and the distribution of mu and kappa receptors is very different between the two species (Hellyer et al., 2003). In order to understand how drugs may modify activity within the CNS it is necessary to understand the normal processes that are used to alter interactions between cells within the CNS. To modulate incoming signals, mechanisms are necessary that allow acceptance or rejection of a particular impulse. In a few areas within the mammalian CNS there are neurons that are joined by electrical synapses. These synapses are characterized by tight connections between the two cells with ion channels that are aligned between the two cells. This arrangement does not allow the receiving cell to change the signal since depolarization of the first cell will result in depolarization of the second cell. However, this arrangement is useful where it is important that a number of cells fire simultaneously to produce a coordinated response and, since the signal can travel in either direction, it enhances the capability of this system to function in this way. The signal is also transmitted much more quickly between the cells (0.1 ms) so it can generate a very rapid response. Brainstem neurons involved in the coordination of breathing have this type of synapse and so do some neurons involved in the secretion of hormones from the hypothalamus. This electrical coordination allows them to produce a “pulse” of hormone by all firing simultaneously. The vast majority of the neurons in the mammalian CNS, however, communicate by means of chemical signals. The depolarization of the first neuron travels down its axon by virtue of the opening of voltage gated sodium channels (Figure 9.1). At the synapse this wave of depolarization activates voltage-gated calcium channels that allow calcium to flow down the concentration gradient (approximately 10−3M outside the cell to 10−7M inside the cell) into the cytosol of the synapse. The presence of this increased concentration of calcium activates the discharge of vesicles containing a chemical messenger (neurotransmitter) into the synaptic cleft. This neurotransmitter diffuses across the small gap between the neurons and attaches to receptors on the postsynaptic membrane where it might produce one or more of four changes. It might cause a slight depolarization, but not enough to trigger an action potential; it might cause enough depolarization for the generation of an action potential (excitation); it might cause modifications to the internal milieu of the cell such that it could be more or less receptive to further signals (modulation); or it might cause an ionic shift resulting in hyperpolarization of the cell (inhibition). It is then necessary to have some mechanism to terminate that signal so that the postsynaptic neuron can return to its resting state to allow further signals to be received. This can occur by destruction of the neurotransmitter or its uptake into the presynaptic terminal or other surrounding cells. Figure 9.1 Transduction of nociceptive information by free neuronal endings in the dermis. Many receptors are depicted in this figure and it should be recognized that not all nociceptors would have all of these on their surface. (A) Receptors that provide direct transduction of thermal (wavy lines) and mechanical (spiral) stimuli. TRPA1, transient receptor potential A1, which responds to noxious cold; K2P, two-pore potassium channel; ASIC, acid-sensing ion channel, which responds to mechanical stimuli as well as protons; Piezo, responds to mechanical stimuli; TRPV4 and TRPV1, respond to hot thermal stimuli; T-Type calcium channel responds to mechanical stimuli. (B) Inflammatory mediators that may increase the likelihood of a nociceptor depolarizing. B1 and B2, bradykinin receptors; ET, endothelin receptor; GPCR, G protein-coupled receptor; 5HT, 5-hydroxytryptamine; P2X, purinergic receptor-2X; RTK, receptor tyrosine kinase; NGF, nerve growth factor; IL1β, interleukin-1β; ATP, adenosine triphosphate. (C) Inhibitory mediators that may decrease the likelihood of a nociceptor depolarizing. GABA, γ-amino butyric acid; Ach, acetylcholine; M2, muscarinic receptor-2; SST and SSTR, somatastatin and its receptor; CB, cannabinoid receptor; 2-AG, 2-arachidonylglycerol, a cannabinoid agonist; MGluR, metabotropic glutamate receptors; α2, α-2 adrenergic receptor; A1, adenosine receptor. In order for an animal to experience its environment it must be able to convert multiple different forms of incoming energy into neuronal depolarization. This has led to the evolution of a large number of specialized receptors and chemicals that can transduce the incoming signal into something understandable by the animal. Photoreceptors in the eye use rhodopsin and a variety of opsins that are activated by light and amplified by connecting with a G protein-coupled receptor (GRPC). The mechanisms by which the specialized mechanoreceptors in the skin, the Meissner and Paccinian corpuscles, transduce stimuli are still not completely understood. The nerve terminals in these receptors have a variety of potassium and sodium channels that may be involved but the details have yet to be discerned. Nociceptors are known to use multiple receptors to transduce the noxious stimuli into electrical impulses. They respond to direct stimuli such as heat as well as chemical stimuli released from damaged tissue. The transient receptor potential vallinoid (TRPV) family of receptors (TRPV-1, TRPV-2, TRPV-3, TRPV-4) are involved in the transduction of thermal stimuli and respond to specific ranges of temperature (e.g., TRPV-3 responds to temperatures between 31 and 39°C vs. TRPV-1 to temperatures >42°C). The TRPV-1 receptor is also important in peripheral sensitization and in chronic pain states as it is upregulated in these conditions. Capsaicin is a TRPV-1 agonist and, because it continues to activate the channel, may lead to excessive calcium influx into the cell and cell death. In humans, a capsaicin patch has been developed that is applied to localized areas of neuropathic pain (e.g., postherpetic neuralgia) and can significantly reduce pain in some patients for several months after application(Wagner et al., 2013). Another TRPV-1 agonist, resiniferatoxin, has been used to treat osteosarcoma pain in dogs (Brown et al., 2005). There is a great deal of interest in TRPV-1 agonists and antagonists for the treatment of pain but this receptor is also involved in thermoregulation so systemic application of some of these drugs can lead to hyper- or hypothermia. As indicated in Figure 9.1, there are many other receptors on nociceptors and some of these will also tend to hyperpolarize the nociceptor making it less likely to fire. Examples of this include presence of opioid and α2-adrenergic receptors on some of these neurons, which supports the action of these classes of drugs as peripherally acting analgesics. The peripheral nociceptors are also affected by mediators released as a result of tissue damage. These mediators may not directly cause depolarization but may sensitize the nociceptor to other stimuli leading to the phenomenon of peripheral hyperalgesia. These inflammatory mediators include prostaglandins, bradykinin, histamine, serotonin, cytokines (e.g., IL1β, TNFα), nerve growth factor, purines, endothelin, and protons. Many of these mediators have been pharmacological targets in the management of acute and chronic pain. The cellular mechanisms that occur to allow these events to happen are complex and involve many steps. The neurotransmitters involved can be classed into three basic groups: the amino acids, the amines, and the peptides. Amino acids can be absorbed from the extracellular fluid but usually involve active transport molecules to achieve this and some are immediately ready to use in this form. The amines and γ-amino-butyric acid (GABA) need to be synthesized from smaller building blocks that require the presence of enzymes. These enzymes are generally made in the cell body and diffuse slowly down the length of the axon to the axon terminal (Figure 9.2). This slow axonal transport occurs at 0.5–5 mm/day. Once an amino acid or amine is present in the nerve terminal it is packaged into synaptic vesicles (40–60 nm in diameter) using an active transporter system. For these small molecules the synaptic vesicles are seen as small clear-core vesicles on electron microscopy. The peptides, on the other hand, are manufactured in the cell body and packaged into larger vesicles at this site. They are actively transported to the axon terminal using microtubules and ATP-requiring proteins such as kinesin to achieve this (Figure 9.2). These large dense-core vesicles (appearance on electron microscopy) move at about 400 mm/day down the axon, so this occurs much faster than the diffusion of the enzymes needed for GABA and amine production. The synaptic vesicles tend to cluster around dense areas of the synaptic membrane (called active zones) that contain the necessary proteins to achieve transmitter release. The active zones have calcium channels that provide the stimulus for activation of the cascade required for docking and exocytosis of the synaptic vesicle. One family of these proteins, referred to as the SNARE proteins (soluble N-ethylmaleimide attachment protein receptors) form complexes between the synaptic vesicle and the cell membrane (docking) and help promote the next step in the process (fusion of the membranes) so that the contents of the vesicle can be ejected into the synaptic cleft (exocytosis). These proteins are cleaved by botulinum and tetanus toxin, thus preventing neurotransmitter release (Breidenbach and Brunger, 2005). In the case of botulinum toxin, this effect remains peripheral at the neuromuscular junction whereas tetanus toxin is transported to the CNS where its effects occur mainly in inhibitory neurons, thus explaining the different manifestations of the two diseases (paralysis with botulinum and muscular rigidity with tetanus). The synaptic vesicles may then be reformed (endocytosis) with the aid of proteins called clathrins and recycled to be filled again with more neurotransmitter. The whole process from formation, exocytosis to endocytosis, and refilling of these synaptic vesicles can be carried out in about 1 minute, thus enabling frequent signaling from the terminal. Many synaptic terminals contain both small clear-core (amino acids and amines) and large dense-core vesicles (peptides). The peptide-containing vesicles are not usually released as readily as the clear-core vesicles and require a greater concentration of intracellular calcium for their release (usually the result of rapid repetitive depolarization of the neuron), thus providing the potential for a different signal to be associated with a more intense stimulus. Many presynaptic terminals have receptors on them that respond to the neurotransmitter being released (autoreceptors). This is usually presented as a feedback loop, which results in the inhibition of further release of the neurotransmitter. Figure 9.2 Neuron that is involved in chemical transmission. Enzymes and peptides are made in the cell body and transported to the axon terminal. The transport of enzymes is slow, whereas peptide synaptic vesicles are transported actively down the microtubules. Neurotransmitters are packaged into synaptic vesicles and these accumulate near the synaptic cleft. When the cell depolarizes the synaptic vesicles merge with the outer cell membrane and release neurotransmitter into the synaptic cleft. This chemical acts on the receptors on the postsynaptic membrane to alter postsynaptic cell function. Some neurotransmitters are destroyed in the cleft, some are reabsorbed into the axon terminal, and some may be absorbed by neighboring glial cells and destroyed or recycled into the axon terminal. The receptors on the postsynaptic membrane can be divided into two types: the ionotropic or ligand-gated receptors and the metabotropic receptors. Ionotropic receptors allow the immediate passage of an ion across the cell membrane. For the most part, these are proteins that allow passage of sodium, calcium, potassium, or chloride. The metabotropic receptors activate a process inside the cell that may alter ionic conduction through another channel or they may alter the production of other substances within the cell that could change how the cell reacts to further stimulation. This process is very powerful because it can amplify the initial signal received. One receptor might activate a cellular enzyme that then catalyzes the production of many molecules, and each of these may further amplify the effect by activating further reactions. Normally, the signal from an ionotropic receptor is seen almost immediately, whereas the effect from a metabotropic receptor may take longer and may last longer after the stimulus. In the CNS an individual neuron may receive input from hundreds of other neurons. Each synapse with its neurotransmitter can either excite (increase the resting membrane potential toward 0) or inhibit (decrease the resting membrane potential to a more negative value). The final effect on that individual neuron will be a result of the type of input it receives and the relative timing of that input. If there is simultaneous input from several excitatory neurons at the same time, it is likely that the neuron will depolarize and send a signal on to the next cell in the pathway. This is referred to as spatial summation. On the other hand, if a single input kept on firing it might achieve enough depolarization to trigger an action potential. This is referred to as temporal summation. If this neuron had received several signals from inhibitory neurons during this period the magnitude of the excitatory signal would have to be greater in order for the neuron to achieve a threshold for the action potential. Note, however, that inhibition under these conditions is not normally absolute and that if a strong enough stimulus is applied it will overcome the inhibition. The attachment of a neurotransmitter to a receptor could be followed by a number of events. The receptor could have an effect and then the neurotransmitter and the receptor could be absorbed into the cell, thus terminating this effect (receptor internalization). The neurotransmitter could be destroyed by a chemical reaction catalyzed by an enzyme located nearby in the synaptic cleft. Some of the fragments of the molecule could then be absorbed again into the presynaptic terminal and reassembled into the original neurotransmitter while some fragments diffuse into the surrounding extracellular fluid. Lastly, the molecule could diffuse off the receptor as the concentration gradient reverses and it could be taken up into the presynaptic terminal or into surrounding glial cells for further transport back into the presynaptic terminal. These actions usually require the presence of transporter proteins for maximal efficiency. There are a number of criteria for establishing a chemical as a neurotransmitter and a great deal of effort has been taken to ensure that these criteria are met by potential candidates. Just finding a chemical in the CNS does not mean that it is a neurotransmitter. In the past, this kind of proof was difficult to obtain because an individual synapse is so small and being able to record from it is so technically challenging. Even with molecular biological techniques it is not simple but there have been a number of instances where a receptor has been discovered before the neurotransmitter that binds to it. Glutamate is generally considered to be an excitatory neurotransmitter and is used in about half of the synapses in the brain. It is a nonessential amino acid that does not cross the blood–brain barrier so it has to be synthesized by the neuron (Table 9.1 ). Once it has been released into the synaptic cleft it is removed via a high-affinity uptake process on the presynaptic terminal and local glial cells involving excitatory amino acid transporters (EAATs). So far, five of these EAATs have been identified and their locations in the brain and relative activities vary (Bridges and Esslinger, 2005). The glutamate taken up in glial cells is converted to glutamine, which can then be absorbed by the presynaptic terminal and converted back to glutamate. Both EAATs and vesicular glutamate transporters (VGLUTs) have become targets for pharmacological manipulation. Glutamate acts on three families of ionotropic receptors and three classes of metabotropic receptors. The ionotropic receptors are named after the agonists that were first shown to activate them: N-methyl D-aspartate (NMDA receptor); α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA receptor); and kainate (kainate receptor). As with most of these receptors, they are composed of four or five subunits of membrane-spanning proteins and this gives rise to the possibility of many forms for each receptor (Table 9.1 ). These variations provide a basis for pharmacological targeting of individual receptors. The metabotropic receptors are divided into three classes, with class I (mGluR1 and 5) acting via Gq/11 proteins to increase phospholipase C (excitatory) and classes II (mGluR2–3) and III (mGluR4, mGluR6–8) acting via Gi/Go proteins to inhibit adenylyl cyclase activity (inhibitory). So, although the major effects of glutamate are excitatory, there are parts of the brain where it can act as an inhibitory neurotransmitter. The NMDA receptors are important in the practice of anesthesia and analgesia because drugs that are antagonists at this receptor (cyclohexanones such as ketamine and tiletamine) are commonly used. At least six binding sites have been identified on the NMDA receptor for pharmacological activity. The site that binds glutamate (1) opens the channel to the entry of sodium and calcium into the cell. This site appears to need glycine to be bound to the receptor (2) for the glutamate to be fully effective. A third site within the channel binds phencyclidine and other cyclohexanones (3). There is also a voltage-gated magnesium binding site (4) within the channel; the ejection of magnesium from this site with depolarization opens the channel for further activity. There are also an inhibitory divalent site that binds zinc (5) near the mouth of the channel and a polyamine regulatory site (6) that potentiates the currents generated from the receptor when it is activated. The NMDA receptor is thought to affect long-term potentiation, memory, and plasticity of the nervous system. Long-term potentiation is likely involved with the modulation of nociceptive input. Activation of the receptor is also involved in the process of excitotoxicity leading to neuronal death. Table 9.1 Small molecule neurotransmitters with their origins, transport proteins, method of catabolism, and receptors This is an inhibitory neurotransmitter, which is found in high concentrations in the medulla and spinal cord. Because glycine is found in all tissues in the body it has been difficult to isolate its activity in the CNS. The glycine receptor is a pentameric structure, and four α-subunits and one β-subunit have been identified. It is a ligand-gated chloride channel allowing the ingress of chloride ions, making the inside of the cell more negatively charged (hyperpolarization). The glycine and strychnine binding sites are located on the α1 subunit. Once released into the synaptic cleft, glycine is taken back up into the presynaptic terminal or into surrounding glial cells by an active transporter for glycine (GLYT1-2), with GLYT-2 being the version mainly expressed on neurons. As indicated above, glycine interacts with glutamate at the NMDA receptor and GLYT is found in those neurons despite a lack of glycine receptors. This is the major inhibitory neurotransmitter within the CNS and is present in as many as one-third of all synapses in the CNS. By comparison with its concentrations in the CNS it is found only in trace amounts elsewhere in the body. GABA is made from L-glutamic acid and this reaction is catalyzed by glutamic acid decarboxylase (GAD); this irreversible reaction needs a cofactor – pyridoxal phosphate (PLP a form of vitamin B6). There are two forms of GAD (GAD65 and GAD67) and GAD65 has a higher affinity for PLP, making its activity more easily regulated. GABA is broken down to succinic semialdehyde by GABA-transaminase (GABA-T), which also requires PLP and this can then enter the Krebs cycle via further breakdown to succinic acid. Since both GAD and GABA-T are dependent on PLP, a diet deficient in vitamin B6 can lead to a decreased level of GABA in the brain with resulting seizures. GABA may be broken down into a number of other metabolites including γ-hydroxybutyric acid (GHB). There is some evidence that the breakdown to GHB is a reversible response and that GHB might be used in the brain to make GABA. GHB has been used in anesthesia and is now an abused street drug; part of its action might be to promote the production of GABA, although a specific GHB receptor is proposed, and GHB is a micromolar (exogenous administration) agonist at the GABAB receptor and a nanomolar agonist at α4βδ GABAA receptors. Once GABA is released into the synaptic cleft its action is terminated mainly by reuptake into the presynaptic terminal using GABA transporters. Some GABA is taken up into surrounding glial cells using the same mechanism but there does not appear to be a mechanism for transfer of this GABA back to the neuron, so the latter must synthesize more GABA to make up for the amount lost. The GABA receptors are divided into an ionotropic group (GABAA, GABAC) and a metabotropic group (GABAB). The GABAA receptor (Figure 9.3) is a ligand-gated chloride channel and when activated will tend to hyperpolarize the cell. It contains four subunits, and at least 21 proteins (α1−7, β1−4, γ1−4, Δ, ϵ, θ, ρ1−3) have been identified that can be used to make up this receptor, giving it a great deal of structural diversity. It has been shown that some of these variations have different relative sensitivities to GABA providing the potential for different levels of response to release of the same neurotransmitter. The inhalant anesthetics may activate the GABAA receptor but this is unlikely to be the only site of action. Propofol and etomidate enhance the action of GABA at the receptor at low concentrations and directly activate the GABAA receptor at higher concentrations, while barbiturates are much less selective for this receptor. The benzodiazepines have a separate binding site on the receptor that enhances the opening of the channel when natural GABA attaches to its binding site (Figure 9.3). Alfaxalone may affect the GABA receptor by binding to the transmembrane portion of the receptor (Akk et al., 2009). The GABAB receptor is coupled to Gi proteins that are indirectly linked to potassium channels (increased conductance) and calcium channels (decreased conductance). The latter effect is important for GABAB receptors located on the presynaptic membrane since this will decrease the amount of calcium released into the cell following an action potential and therefore decrease the release of GABA from the terminal (autoinhibitory response). It is thought that baclofen reduces GABA release via this mechanism. Figure 9.3 GABAA receptor showing the pentameric structure and protein subtypes that make up the receptor. Neurotransmitters and drugs attach to different subunits on the receptor. Acetylcholine (ACh) is synthesized from choline and acetyl coenzyme A (acetyl CoA) in a reaction catalyzed by choline acetyltransferase (ChAT). Choline is mainly derived from the blood and from the phospholipid, phosphatidylcholine, and is transported into cells by a high-affinity transporter. Acetyl CoA is derived from glucose or citrate in the mammalian CNS. The synthesized ACh is packed into vesicles via a vesicular acetylcholine transporter. Once released into the synaptic cleft, the ACh attaches to a receptor. In the CNS most of these are nicotinic receptors (nAChRs), another group of pentameric proteins with multiple possible subunits (α2−9, β1−4, γ, Δ). These are nonspecific ion channels that are excitatory. Some areas of the CNS, especially the forebrain and striatum, also contain muscarinic receptors that are metabotropic G protein-coupled receptors (M1–5). Activation of these receptors has an inhibitory effect on dopamine-mediated motor responses. The synaptic cleft also contains acetylcholinesterase (AChE), which is a highly efficient enzyme (5,000 molecules of ACh hydrolyzed/ second/ molecule AChE) that promotes the breakdown of ACh to choline and acetic acid. The choline is taken back up into the nerve terminal for remanufacture to ACh. Atropine acts on central muscarinic receptors but is not specific to any one subtype. Organophosphates block the action of AChE, thus allowing accumulation of ACh in both the PNS and CNS. This leads to typical signs of parasympathetic activation—salivation, lacrimation, urination, diarrhea, and bradycardia – but may also be accompanied by convulsions and eventually coma and death. Dopamine is synthesized from tyrosine, with tyrosine hydroxylase (TH) catalyzing the conversion of tyrosine to L-DOPA and DOPA decarboxylase catalyzing the conversion to dopamine. The production of an activated phosphorylated TH is dependent on calcium ion concentration, cyclic AMP, and a tetrahydrobiopterin (BH4). The latter binds to a site on TH that can also bind dopamine, so increasing concentrations of dopamine will inhibit the production of more dopamine. Dopamine is packed into synaptic vesicles by a vesicular monoamine transporter (VMAT) and can then be released into the synapse from these vesicles. Termination of the action of dopamine is mainly by reuptake into presynaptic terminals by a dopamine transporter (DAT). The resorbed dopamine is converted to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase in the nerve terminal. Dopamine taken up by surrounding glial cells is converted to homovanillic acid by catecholamine-O-methyltransferase (COMT). There are species differences in the relative importance of these reactions. Dopamine receptors can be divided into two forms, D1 and D2-like. Dopamine1 and D5 are classed together and D2–4 are the D2-like receptors. These are all metabotropic G protein-coupled receptors. The D1 receptors are linked to a Gs protein that increases the cellular concentration of cAmp while the D2 receptors are linked to a Gi protein having the opposite effect. D1 receptors are generally found on postsynaptic membranes and while D2 receptors are present on some postsynaptic sites they are more commonly found as autoreceptors on the presynaptic membrane. At this site they seem to be able to affect both synthesis and release of dopamine from the nerve terminal. Dopamine is found in a number of regions of the brain but its presence in the corpus striatum is thought to play a major role in motor coordination and locomotion. Dopamine is also involved with reward, reinforcement, and motivation, and it is this aspect that contributes to its role in drugs of addiction. For example, cocaine inhibits DAT, thus prolonging the presence of dopamine in the synaptic cleft and prolonging its action on the postsynaptic membrane. Phenothiazines are thought to be dopamine antagonists and hence they reduce motivation and action while monoamine oxidase inhibitors will increase dopamine release and are used in the treatment of depression. Drugs that block D2 receptors will decrease the release of dopamine and at high enough doses will produce catalepsy. These are much less important neurotransmitters within the CNS compared with dopamine (about one-quarter to one-third of the number of neurons containing dopamine) but are also involved in wakefulness, attention, and feeding behavior. These neurotransmitters play a dominant role in autonomic nervous system function, and were fully described in Chapter 7. Norepinephrine is produced from dopamine with the aid of dopamine-β hydroxylase and epinephrine is further synthesized with the aid of phenylethanolamine-N-methyltransferase. The latter is found in a discrete number of neurons that are different from those secreting norepinephrine. Both neurotransmitters are packed into vesicles using VMAT and are metabolized by monoamine oxidase and COMT when taken back up into the cell. Norepinephrine is removed from the synaptic cleft by norepinephrine transporter (NET) and this will also transport epinephrine – no specific epinephrine transporter has been identified. The α- and β-adrenergic receptors for these neurotransmitters are G protein-coupled metabotropic receptors and are further divided into α1A−D, α2A−C, and β1−3. The α1A−D are associated with a Gq protein that results in a slow depolarization due to the inhibition of K+ channels while the α2A−C receptors are associated with a Gi protein that results in hyperpolarization. The α2 receptors are found on both presynaptic and postsynaptic terminals. They act as autoreceptors on the presynaptic terminal to decrease the release of norepinephrine. Since wakefulness is dependent on tonic activity on these neurons it follows that the inhibition of this activity would tend to lead to sedation and lack of movement. This is the principle behind the use of α2 agonists, which decrease the release of norepinephrine and may hyperpolarize the postsynaptic cells as well. α2 antagonists have the opposite effect and can cause central excitation when administered alone. Histamine is produced from the amino acid histidine, catalyzed by the enzyme histidine decarboxylase. It is transported into vesicles using VMAT and released into the synaptic cleft where it can act on one of three histamine receptors (H1−3). Chapter 19 should be consulted on histamine’s role outside of the CNS. No plasma membrane transporter has been identified for histamine but it is metabolized by histamine methyltransferase and monoamine oxidase. The histamine receptors are G protein-coupled metabotropic receptors. H1 is coupled with a Gq protein affecting inositol phospholipase, H2 is coupled with a Gs protein that increases the cAmp concentrations, while the H3 receptor is coupled with a Gi protein with opposing effects. It is thought that the H3 receptor is the autoreceptor on the presynaptic terminal involved in decreasing the release of histamine and possibly other neurotransmitters present in the same cells. Histamine is also thought to be involved in aspects of wakefulness and is strongly associated with the vestibular apparatus, explaining the use of antihistamines in the control of motion sickness and that drowsiness is a common effect with antihistamines that cross the blood–brain barrier. 5-Hydroxytrypta-mine (5-HT) is synthesized from tryptophan via 5-hydroxytryptophan catalyzed by the enzymes tryptophan-5-hydroxylase and then aromatic L-amino acid decarboxylase. Tryptophan is transported into the brain via an active process that also transports other large neutral amino acids. This means that the production of 5-HT is dependent not only on the concentration of tryptophan in the diet but also on the relative amounts of tryptophan. Dietary restriction of tryptophan depletes 5-HT production while increased dietary tryptophan increases 5-HT production up to a point where the tryptophan-5-hydroxylase enzyme system becomes saturated. As with many biological systems a treatment that alters one component may be compensated for by changes in another component. For example, increased dietary tryptophan could be compensated for by a decrease in tryptophan-5-hydroxylase. Once synthesized 5-HT is packed into vesicles using VMAT and once released, it is transported back into the cell by a specific 5-HT transporter (SERT). This protein is the target for a number of therapeutic agents called the selective serotonin reuptake inhibitors (SSRIs), of which fluoxetine (Prozac) is one. Once taken up, 5-HT is mainly broken down using monoamine oxidase. At least 12 5-HT receptors have been identified (5-HT1A−E, 5-HT2A−C, 5-HT3−7), with the majority being G protein-coupled metabotropic receptors. The exception to this is 5-HT3, which is a ligand-gated ionotropic receptor that allows influx of cations to cause excitation of the postsynaptic membrane. The 5-HT1 receptors are coupled with Gi proteins and 5-HT2 with Gq proteins, and the others are thought to be associated with Gs proteins (with the exception of 5-HT5, which is probably associated with a Gi protein). 5-HT is also involved in the regulation of sleep and attention and it plays a role in nociception and the control of emesis. Some potent antiemetics such as ondansetron and granisetron are 5-HT3 antagonists. The 5-HT3 receptor may be involved in the mechanism of action of inhaled anesthetics (Solt et al., 2005; Stevens et al., 2005). Serotonin syndrome is a condition described in people that presents with multiple signs, including alterations in conscious state (agitation, anxiety, seizures to lethargy, and even coma), autonomic dysfunction (central and peripheral actions of 5-HT hyperthermia, sweating, tachycardia, hypertension, dyspnea, dilated pupils), and neuromuscular changes (myoclonia, hyperreflexia, and ataxia). This syndrome is being reported more commonly because of the many drugs being prescribed that affect the 5-HT system. Amitriptyline, tramadol, meperidine, and St John’s wort all reduce 5-HT uptake, while selegiline and St John’s wort reduce 5-HT catabolism. Combinations of these drugs or excessive doses of a single agent can lead to this syndrome (Jones and Story, 2005). In dogs a similar syndrome has been described following ingestion of 5-hydroxytryptophan (Gwaltney-Brant et al., 2000).
Introduction to Drugs Acting on the Central Nervous System and Principles of Anesthesiology
Introduction to CNS Drugs
Neuroanatomy and Neurophysiology
Transduction
Presynaptic Processes
Postsynaptic Processes
The Neurotransmitters and their Receptors
The Amino Acids
Glutamate:
Neurotransmitter
Synthesizedfrom
Transport ofraw materialintopresynapticterminal
Rate-limiting stepin synthesis
Vesicletransport
Reuptake
Catabolism
Ionotropicreceptors
Metabotropicreceptors andassociated g protein
Glutamate
Glutamine or α-oxoglutarate
Excitatory amino acid transporter (EAAT)
Vesicular glutamate transporter (VGLUT)
EAAT1–5
Glutamine synthetase
NMDA (NR1, NR2A–D)
Class I (mGluR1&5) Gq/11
AMPA (Glu R1–4)
Class II (mGluR2–3) Gi/Go
Kainate (Glu R5–7, KA1–2)
Class III (mGluR4, mGluR6–8) Gi/Go
Glycine
Serine?
Serine trans-hydroxymethylase & D-glycerate dehydrogenase
Glycine transporter (GLYT1–2)
Glycine (α1–4, β subunits)
None
GABA
L-glutamic acid
EAAT
Glutamic acid decarboxylase (GAD65 and67)
Vesicular GABA transporter (VGAT)
GABA transporters (GATs)
GABA transaminase
GABAA andC
GABAB Gi
Acetylcholine
Choline and acetyl CoA
High affinity transporter
Choline transport
Vesicular acetylcholine transporter
High affinity transporter of choline
Acetylcholinesterase (AChE)
Nicotinic AChRs (α2–9, β1–4, γ, Δ subunits)
Muscarinic (M1–5) Gq/11 − M1, M3, M5 Gi − M2, M4
Dopamine
Tyrosine
Diffusion
Tyrosine hydroxylase (TH)
Vesicular monoamine transporter (VMAT)
Dopamine transporter (DAT)
Monoamine oxidase (MAO) and catecholamine-o-methyltransferase (COMT)
None
D1 and D5 Gs D2, D3, D4 Gi
Norepinephrine and epinephrine
Tyrosine
Diffusion
Tyrosine hydroxylase (TH)
Vesicular monoamine transporter (VMAT)
Monoamine oxidase (MAO) and catecholamine-o-methyltransferase (COMT)
None
α1A–D Gq α2A–C Gi β1–3 Gs
Histamine
Histidine
Diffusion
Histidine decarboxylase
Vesicular monoamine transporter (VMAT)
?
Monoamine oxidase (MAO) and catecholamine-o-methyltransferase (COMT)
H1 Gq H2 Gs H3 Gi
5-HT, Serotonin
Tryptophan
Active transport across the blood–brain barrier
Tryptophan-5-hydroxylase
Vesicular monoamine transporter (VMAT)
Specific 5-HT transporter (SERT)
Monoamine oxidase (MAO)
5-HT3
5-HT1A–E,5 Gi 5HT2 Gq 5HT4,6,7 Gs
Glycine:
GABA:
The Amines
Acetycholine:
Dopamine:
Norepinephrine and epinephrine:
Histamine:
5-Hydroxytryptamine or serotonin:
Peptides
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