The nervous system controls conscious and subconscious (autonomic) activities, and the higher order processes memory, emotion and intelligence. It is composed of the following systems:
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The peripheral nervous system (PNS) that processes the external environment and sensations. The PNS is composed of afferent fibres that originate in peripheral tissues and pass to the spinal cord.
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The regulation of peripheral tissue activity by the autonomic nervous system (ANS). Efferent neurons originate from the spinal cord and pass to peripheral tissues.
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The central nervous system (CNS) (brain and spinal cord) connects the afferent and efferent neurons of the PNS with the brain to regulate and process bodily actions.
In this chapter we summarize the neurotransmitters in the CNS and ANS and how neurotransmission can be modified by drugs.
Central Nervous System
Drug action
Drugs have important therapeutic effects in a variety of disorders of the nervous system. Normal CNS function can also be modified by general anaesthetics and by drugs taken for non-medical use (alcohol, nicotine, caffeine, cannabis, etc.). A full understanding of how drugs affect CNS function is currently hampered by our poor understanding of the ways in which the activity of particular neurons in the brain influence complex processes such as memory, mood and consciousness. Therefore, although the molecular targets and cellular actions of many centrally acting drugs are well established, the exact way in which the events at neuronal level are converted into therapeutically useful actions, as with antidepressants and anxiolytics, is usually much less clear. The action of drugs in Parkinson’s disease ( Chapter 12 ) provides perhaps the best example of how knowledge of the neuronal pathways and neurotransmitters involved, along with knowledge of the pathological deficit, provides a rational basis for drug use.
An important consideration in the design of drugs to have direct effects within the CNS is the requirement that they are able to traverse the blood–brain barrier. This barrier serves a valuable role in protecting the brain from many potentially neurotoxic agents which have gained entry into the systemic circulation, but it also impedes the uptake of most lipophobic drugs into the cerebrospinal fluid. Certain lipophobic drugs, however, can make use of active transport systems to enter the brain, e.g. levodopa in Parkinson’s disease.
Chemical signalling in the CNS
The description of transmitter synthesis, storage and release is largely applicable to both CNS neurotransmission and the PNS. However, chemical transmitters in the CNS operate over quite different time scales.
Neurotransmitters
By convention these are the agents responsible for fast excitatory and inhibitory postsynaptic potentials. Typically they are released by terminal boutons and act on postsynaptic receptors concentrated in postsynaptic densities on a single neuron. Their action is normally rapidly terminated by reuptake or enzymatic degradation. Neurotransmitters commonly act on ionotropic receptors (e.g. N-methyl-D-aspartate (NMDA) acting on NMDAR) though mediators acting on some G-protein-coupled receptors (GPCRs) may produce quite rapid action and thus also be considered neurotransmitters (e.g. noradrenaline acting on α 1 -adrenoceptors can qualify).
Neuromodulators
These are more slowly acting and their effects, both pre- and postsynaptically, may be more diffuse, spreading from the site of release to influence many surrounding neurons. Neuropeptides acting on GPCRs (e.g. somatostatin, substance P) are included in this category. Neuromodulators also include lipid mediators (e.g. prostaglandins, endocannabinoids) and nitric oxide, which are not released in the same way as conventional neurotransmitters. Neuromodulators may be released by the same terminals as neurotransmitters – co-transmission. Neuromodulators are involved in synaptic plasticity and modulate the effects of neurotransmitters on action potential firing rate. Steroids also have a role in synaptic plasticity.
Neurotrophic factors
These act over the longest time scale, regulating neuronal growth and morphology. Many are peptides acting on receptor tyrosine kinases to control gene expression (e.g. brain-derived neurotrophic factor).
A complication in understanding drug action is that, although a drug’s action on its target receptor or enzyme may be manifest within minutes, the clinical effect may be delayed for some days (e.g. antidepressant activity or development of dependence on opioids). These delays are attributed to adaptive changes to drug-induced perturbations and may involve receptor up- or downregulation, modification of transmitter synthesis, etc.
Neurotransmitters in the CNS
Within the CNS, neurotransmitters can be amino acids, for example glutamate is the main fast excitatory transmitter and γ-aminobutyric acid ( GABA) and glycine are the fast inhibitory amino acid transmitters. Aspartate may also serve as an excitatory transmitter acting at glutamate receptors. Other neurotransmitters include noradrenaline, 5-hydroxytryptamine (5-HT, serotonin), histamine, purines, peptides, dopamine, acetylcholine, eicosanoids and endogenous cannabinoids.
Glutamate
Glutamate is synthesized in neural tissues either by transamination of α-ketoglutarate (from the Krebs cycle) or from glutamine by the action of glutaminase. Like most transmitters it is stored in vesicles and released by exocytosis. Its action in the synaptic cleft is terminated mainly by active recapture into either the nerve ending or nearby astrocytes.
Glutamate receptors
There are four types of glutamate receptors: three ionotropic and one metabotropic receptors ( Fig. 11.1 ).
The combination of subunits in ionotropic receptors varies widely so that the properties of the channels in different brain regions can also vary. NMDA receptors mediate a slow excitatory postsynaptic potential and have a greater calcium ion (Ca 2+ ) permeability. NMDA receptors will only open in response to released glutamate if glycine (or d -serine) occupies its binding sites on the NR1 subunits. (Variations in the local concentration of glycine may in some cases have an important regulatory role.) An important property of the NMDA receptor is that it is blocked by magnesium ions (Mg 2+ ) at the resting potential of neurons and the channel will only conduct ions (sodium ion (Na + ), Ca 2+ ) when the block is relieved by depolarization (produced by AMPA or kainate receptors). Entry of Ca 2+ through NMDA receptors is involved in synaptic plasticity (e.g. long-term potentiation (LTP) and also in cell damage (excitotoxicity)) ( Fig. 11.2 ).
Drugs acting on glutamate receptors
Only a few drugs are known to work by affecting glutamate receptors and include ketamine (which produces dissociative anaesthesia and works partly by blocking the NMDA receptor channel) and memantine , advocated for the treatment of Alzheimer’s disease. Several other compounds with potent and selective actions on glutamate receptor subtypes have been identified; they are useful tools in the study of these receptors but do not have a recognized clinical value. One example is phencyclidine (angel-dust), a ‘street’ drug that, like ketamine, may act partially by blocking the NMDA receptor channel.
GABA
GABA is produced from glutamate by glutamic acid decarboxylase. The activity of released GABA is terminated mainly by reuptake into GABAergic neurons and astrocytes.
GABA receptors
There are two main kinds of GABA receptor: GABA A and GABA B ( Fig. 11.3 ). GABA A is a ligand-gated Cl – channel that occurs postsynaptically ( Fig. 11.4 ).
Activation of GABA A receptors tends to clamp the membrane potential close to the chloride ion (Cl – ) equilibrium potential (which is usually near to, or more negative than, the membrane potential) and so decreases electrical excitability. Transmitter action at GABA A receptors typically produces fast inhibitory postsynaptic potentials.
GABA B is a GPCR that acts via G i to:
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inhibit voltage-gated Ca 2+ channels in nerve endings to reduce transmitter release;
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open potassium ion (K + ) channels in nerves to reduce excitability.
Drugs acting on GABA receptors
GABA A receptors are important targets for the therapeutic actions of benzodiazepines and barbiturates . Useful experimental tools for GABA A receptors are muscimol, an agonist, and bicuculline , a competitive antagonist. The convulsant picrotoxin blocks the ion channel directly. Benzodiazepines modulate the binding and activity of GABA by binding to a modulatory site associated with the γ-subunit. Drugs may act as agonists (e.g. diazepam ), antagonists (e.g. flumazenil) and inverse agonists (e.g. β-carbolines) at the benzodiazepine ‘receptor’. Agonists enhance the activity of GABA whereas inverse agonists reduce the activity. Diazepam has anticonvulsant activity whereas flumazenil is proconvulsant. Barbiturates and neurosteroids such as alphaxalone bind to other modulatory sites on the GABA A receptor to enhance GABA action.
Baclofen is an agonist at GABA B receptors and has useful antispastic activity. Phaclofen, an antagonist, is a useful experimental agent.
Glycine
Glycine has two important actions; one direct on the inhibitory glycine receptors, the other as a co-agonist with glutamate on NMDA receptors. It is released particularly from inhibitory interneurons in the brainstem and spinal cord.
Glycine receptors
The glycine receptor is a pentameric ligand-gated Cl – channel made up of glycine-binding α-subunits (α 1 –α 4 ) and β-subunits. The convulsant action of strychnine results from antagonism at the glycine receptor. No clinically useful drugs are thought to act on these receptors.
Noradrenaline (NA) has both pre- and postsynaptic actions in the central nervous system (CNS). The bodies of noradrenergic neurons are found mainly in the pons (especially in the locus ceruleus), the medulla and brainstem (reticular formation) and project diffusely to the cortex, limbic system, hypothalamus, cerebellum and spinal cord. Synthesis, storage, release and reuptake of NA are essentially as described for peripheral sympathetic neurons (see below). The CNS effects of NA are mediated by both α- and β-adrenoceptors acting either pre- or postsynaptically.
α 2 -Adrenoceptors can cause inhibition of calcium ion (Ca2 + ) channels to inhibit transmitter release or activate potassium (K + ) channels to inhibit excitability. β-receptors may increase cell firing rate by inhibiting the hyperpolarizations that follow action potential discharge. Activation of noradrenergic pathways is thought to increase wakefulness and alertness, whereas reduced activity may contribute to depression ( Chapter 12 ). Noradrenergic mechanisms are also involved in the central regulation of blood pressure and in the control of mood. (Some compounds previously thought to act on α 2 -adrenoceptors, e.g. clonidine, are now thought to work at least partly through distinct G-protein-coupled imidazoline receptors.)
Serotonergic neurons are found in the raphe nuclei (in the pons and medulla) and project to many areas of the brain including the cortex, hippocampus, basal ganglia, limbic system and hypothalamus. Activity in 5-hydroxytryptamine (5-HT) pathways is known to modulate mood, emotion, sleep, appetite and vomiting, and to have some role in pain perception. The synthesis of 5-HT is dependent on the plasma concentration of its precursor tryptophan (itself dependent on dietary intake) and on the activity of tryptophan hydroxylase. There are seven classes of 5-HT receptor, all G-protein coupled except for the ionotropic 5-HT 3 receptor. Most types of 5-HT receptors are found in the central nervous system (CNS) where they may act as either excitatory or inhibitory autoreceptors or act on heteroreceptors on the terminals of nerves utilizing other transmitters. Many will have postsynaptic actions. The different G-protein-coupled receptors may link to G q /11, G i/o or to G s .
5-HT released from dense core vesicles in serotonergic neurons is mainly inactivated by reuptake by specific carriers different to those for noradrenaline, but subject to inhibition by some of the same inhibitors (e.g. tricyclic antidepressants), as well as by selective serotonin reuptake inhibitors (SSRIs, Chapter 12 ). 5-HT 1 receptors in the cortex and amygdala are targets for anxiolytic and antidepressant drugs. Actions on 5-HT 2 receptors in the hippocampus and cortex may underlie the hallucinogenic effects of some drugs. 5-HT 3 receptors are found mainly in the brainstem, especially the area postrema, which is concerned with vomiting.
Histamine
Histamine is synthesized from histidine by histidine decarboxylase. Four histamine receptors have been discovered and at least three of the subtypes (H 1 , H 2 and H 3 ) are found in the CNS, although only a few histaminergic pathways have been identified. Nevertheless older H 1 antagonists that are able to cross the blood–brain barrier have useful sedative and anti-emetic actions. These include chlorpheniramine and diphenhydramine.
Purines
Adenosine triphosphate (ATP) is now well established as a neurotransmitter both in the CNS and periphery and has both ionotropic (P 2X ) and G-protein-coupled (P 2Y ) receptors. Adenosine receptors (A 1 , A 2A , A 2B , A 3 ) are G-protein coupled. Caffeine and some other methylxanthines are adenosine receptor antagonists which certainly contribute to some of the side effects of this drug class. Adenosine receptor agonists have potential value as sedatives, anticonvulsants and neuroprotective agents.
Neuropeptides
Many peptides (e.g. somatostatin, enkephalins, substance P, neuropeptide Y) act as neuromodulators, influencing a wide range of CNS activity. In some cases they are released as co-transmitters with monoamines. Peptide receptors are most usually G-protein coupled; no examples of peptides gating ionotropic receptors are documented.
There are three main dopaminergic pathways in the central nervous system (CNS); the nigrostriatal tract , which contains most of the dopamine in the CNS, runs from the substantia nigra – where the cell bodies of the neurons lie – to the corpus striatum. Another dopaminergic pathway, the mesolimbic system , runs from the midbrain to the limbic system and the cortex. A third pathway, the tuberohypophyseal system , runs from the hypothalamus to the anterior pituitary. Dopamine is synthesised by the same pathway that produces noradrenaline (and is in fact a precursor of noradrenaline). Like noradrenaline, it is metabolized by monoamine oxidase and catechol- O -methyltransferase yielding dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).
After release, dopamine can be recaptured by nerve endings using a selective dopamine transporter (T). Dopamine receptors belong to the G-protein-coupled receptor (GPCR) family and comprise five subtypes separated into D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 and D4):
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D 1 -like receptors couple to G s -protein to stimulate adenylate cyclase.
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D 2 -like receptors, acting via G i /G o , inhibit adenylate cyclase, reduce calcium ion (Ca 2+ ) currents and increase outward potassium ion (K + ) currents. The latter effect reduces electrical excitability and one action is to cause autoinhibition of dopamine release.
Functions of dopaminergic pathways : The nigrostriatal pathway is concerned with motor control and damage to these dopaminergic neurons leads to conditions manifesting motor incoordination, notably Parkinson’s disease ( Chapter 12 ). An increase in dopaminergic activity in the mesolimbic/mesocortical system induces stereotypic behaviour. An important role of dopaminergic neurones in schizophrenia is suggested by the valuable antischizophrenic action of D 2 receptor antagonists ( Chapter 12 ). The tuberohypophyseal pathway regulates hormonal release from the pituitary, especially prolactin (reduced) and growth hormone (increased).
Cholinergic nerves are widely distributed in the central nervous system (CNS), the main pathways being from the magnocellular forebrain nucleus to the cortex, from the pons to the thalamus and cortex and the septohippocampal pathway. Cholinergic neurons also have an important role in the control of motion by the striatum ( Chapter 17 ). Synthesis, storage, release and inactivation are the same as in the periphery (see below).
Brain acetylcholine (ACh) has mainly excitatory actions. Both nicotinic and muscarinic receptors are found, both occurring mainly presynaptically. The former are ionotropic, the latter G-protein coupled. Activation of the muscarinic receptors (which are mainly of the M 1 class) inhibits ACh release. Activation of the presynaptic nicotinic receptors (which are fewer) facilitates glutamate and dopamine release. Some postsynaptic nicotinic receptors mediate fast excitatory transmission. Inhibition of postsynaptic potassium ion (K + ) channels by muscarinic receptors can increase neuronal excitability.
Cholinergic pathways are important mainly in arousal, learning and memory and motor control; so that scopolamine for example has amnesic effects when used for premedication and anticholinesterases are advocated for use in Alzheimer’s disease ( Chapter 12 ). Scopolamine is also used to treat motion sickness. The cholinergic activity in the striatum provides a target for drug action in Parkinson’s and Huntington’s diseases (see Chapter 12 ). Cholinergic projections to the cortex influence electroencephalographic (EEG) activity; muscarinic antagonists increase slow wave activity which, paradoxically, causes excitement.
Arachidonic acid and its metabolites, including cannabinoids
Eicosanoids (leukotrienes, prostaglandins and HETES) as well as endogenous cannabinoids are synthesised from arachidonic acid within the brain. Arachidonic acid and the eicosanoids may act as intracellular messengers (for example, modifying ion channel activity) or interact with cell surface receptors. The neuromodulatory roles of eicosanoids are not well established but prostaglandins (PG) appear to be involved in temperature regulation (inhibition of PG production explains the antipyretic action of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)) and perhaps in sleep.
G-protein-linked (G i /G 0 ) cannabinoid (CB 1 ) receptors are found in the hippocampus (related perhaps to the memory-impairing action of cannabis) and in the cerebellum, substantia nigra, mesolimbic system and cortex. Metabolism of arachidonic acid yields the endogenous transmitters 2-arachidonyl glycerol and anandamide. CB 1 receptors act via inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels and activation of mitogen-activated protein kinase. Synthetic cannabinoids (e.g. nabilone) have potential for use as anti-emetics and analgesics.
Autonomic Nervous System
The ANS regulates smooth muscle tone and cardiac function. It also has actions on exocrine and some endocrine secretions, and on intermediate metabolism. Efferent autonomic pathways usually consist of two neurons, a preganglionic fibre synapsing with a postganglionic fibre in the autonomic ganglion. There are also afferent nerves within the ANS but these are not targets of drug action and will not be considered further.
There are two major divisions of the ANS, the parasympathetic and sympathetic ( Fig. 11.5 ). The enteric nervous system of the gut, a third division, is under the influence of the former two. Sympathetic and parasympathetic actions are often in opposite directions. Pharmacologists who do not read dictionaries might find the term ‘sympathetic’ strange. To have sympathy is to have support of an idea or action, and thus the sympathetic nervous system prepares the body for physical activity, whilst the parasympathetic nervous system (‘para’ alteration, or distinct from) often has the opposite effect, relaxing the body and inhibiting physical activity, but in some tissues the action of one branch is unopposed (e.g. contraction of ciliary muscle by parasympathetic action).
The sympathetic nervous system
The cell bodies of sympathetic preganglionic neurons are found in the lumbar and thoracic spinal cord. The preganglionic nerve fibres synapse with postganglionic neurons either just outside the spinal cord, in the paravertebral chains or in the midline (prevertebral) ganglia . The preganglionic fibres branch and synapse with postganglionic neurons in several segments above and below their origin in the spinal cord – an anatomical basis for a diffuse response. Many of the postganglionic fibres from the sympathetic chain join the spinal nerves.
Widespread sympathetic effects also result from the release of catecholamines from the adrenal medulla.
The parasympathetic nervous system
Parasympathetic preganglionic fibres leave the CNS in the cranial nerves (III, VII, IX and X) and in spinal roots from the sacral region of the spinal cord. In contrast to their sympathetic counterparts, parasympathetic ganglia lie close to the target sites and the postganglionic fibres are often entirely within the tissue of the target organ. Most parasympathetic preganglionic fibres connect with only a few postganglionic fibres – an anatomical basis for discrete, localized responses.
The enteric nervous system
The enteric nervous system consists of neurons with cell bodies in the plexuses in the intestinal wall. Autonomic nerves terminate on these cells but the system can operate autonomously in the control of peristalsis and secretion.
Neurotransmitters and Co-Transmitters
The two main neurotransmitters in the ANS are acetylcholine (ACh) and noradrenaline (NA, or norepinephrine), released from postganglionic parasympathetic and sympathetic neurons, respectively ( Fig. 11.6 ). An important exception is the autonomic innervation of sweat glands: although these are anatomically part of the sympathetic system, the postganglionic nerves utilize ACh as the neurotransmitter.
