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- 3. Organisation of the nervous system To understand psychiatric disorders, it is important to understand the normal structure and function of the nervous system The central nervous system (CNS; brain, spinal cord) and peripheral nervous system (PNS) are composed of two main types of neural cells:1,2 • Neurones – basic nerve cells, which transmit messages throughout the nervous system, resulting in functions as diverse as tasting, thinking, and moving • Glial cells – provide structural and functional support to neurones • Microglia provide a phagocytic role: destroy invading microorganisms, removing cell debris, and promoting tissue repair • Macroglia include oligodendrocytes, Schwanm cells, astrocytes, and ependymal cells, which have a variety of supportive functions within the nervous system 3 1. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 2. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003
- 4. Neurones 4 1. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003; 2. Kandel et al. Principles of Neural Science. 4th edition. 2000; 3. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 4. Oxford Concise Medical Dictionary. 2nd edition. 1998 Cell body The cell body contains the cellular machinery that keeps the neurone alive, e.g., the nucleus1 Myelin sheath The myelin sheath is a whitish, fatty layer that wraps around the axons of most neurones and serves to increase the transmission speed of an action potential along the axon1 Axons with a myelin sheath are known as ‘myelinated axons’2 Axon terminals Axon terminals are the regions at the end of an axon that release neurotransmitters1 Dendrites Dendrites receive information from other neurones1 Each neurone typically has more than one dendrite3 Nucleus The nucleus is critical for the neurone’s vitality; it contains the genetic material (genes) needed for cell division/ development, and protein synthesis1,4 Axon Most neurones have a single axon3 An axon transmits the signal generated by the neurone (the action potential) through the nervous system1 Information flow
- 5. A Anatomical regions of the brain 5 PNS=peripheral nervous system 1. Kandel et al. Principles of Neural Science. 4th edition. 2000; 2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009 Diencephalon The diencephalon is surrounded by the cerebral hemispheres and includes:1 Thalamus The thalamus is a relay station for all sensory information (except smell) from the PNS to the cerebral cortex Hypothalamus The hypothalamus is a major regulator of internal body functions, such as eating, drinking, maternal behaviour, and sleep cycles; it also plays a role in motivation through initiating and maintaining behaviours a person finds rewarding Cerebrum The cerebrum is known as the ‘seat of intelligence’.2 It is divided into two hemispheres and is made up of three basic regions (see next slide) Cerebellum The cerebellum is a highly folded structure located at the posterior of the brain. It is important in maintaining posture and for coordinating head and eye movements, and is also involved in fine tuning of muscle movements and in learning motor skills1 Spinal cord Midbrain Brainstem Located between the spinal cord and the cerebrum, the brainstem is involved in involuntary functions, such as control of blood pressure and breathing, as well as arousal1 Pons Medulla oblongata
- 6. Cerebrum 6 CNS=central nervous system 1. Price & Wilson. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. 2003; 2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 3. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003 Sulci Cerebral cortex The cerebral cortex is the main functional unit of the cerebrum, a layer of grey matter (neuronal cell bodies and dendrites) 2–4 mm thick on the outer surface of the brain that is essential for conscious behaviour2 The surface of the cerebral cortex is characterised by raised ridges of tissue called gyri, separated by shallow grooves called sulci1 Gyri Grey matter Grey matter is made up of neuronal cell bodies, dendrites, and axon terminals3 White matter White matter consists of glial cells and bundles of myelinated axons that relay messages between the cerebral cortex and other parts of the CNS3 The cerebrum is divided into two hemispheres that receive sensory information from, and control the movement of, the opposite side of the body1 The cerebrum is made up of three main regions:1,2 • The cerebral cortex • The underlying white matter • Several subcortical structures, including the basal ganglia Basal ganglia Deep below the cerebral cortex are interconnected nuclei, collectively known as the ‘basal ganglia’2
- 7. Lobes of the brain Deep grooves, called fissures, separate the lobes of the brain:1 • Each cerebral hemisphere has four lobes that can be identified on the surface of the brain2,3 • A fifth lobe, the insula, lies deep within the brain2 7 1. Price & Wilson. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. 2003; 2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 3. Martin. Neuroanatomy Text and Atlas. 3rd edition. 2003
- 9. Electrical neurotransmission1 Following sufficient excitatory stimulation of the neurone, an action potential is generated at the origin of the axon Neurotransmission 9 1. Adapted from: Kandel et al. Principles of Neural Science. 4th edition. 2000 Chemical neurotransmission1 When the action potential reaches the axon terminal it stimulates the release of chemical neurotransmitters
- 10. The synapse 10 1. Kandel et al. Principles of Neural Science. 4th edition. 2000 • Neurones do not physically touch one another; two neurones are separated by a gap, known as a synaptic cleft1 • Binding of chemical signals to the postsynaptic neuron can:1 • Excite – increasing the generation of action potentials • Inhibit – decreasing the generation of action potentials • Induce other biochemical processes
- 11. An action potential reaches the axon terminal of the presynaptic neurone1 Vesicles fuse with the cell membrane of the presynaptic neurone, causing an influx of calcium ions, which causes the neurone release stored neurotransmitters into the synaptic cleft1 The neurotransmitters cross the synaptic cleft and bind to specific receptors on the postsynaptic neurone1 Depending upon the receptor type, when a neurotransmitter binds to the receptor on the postsynaptic neurone it can either act by:2 • Rapidly opening or closing an ion channel in the cell membrane, thereby generating or inhibiting an action potential • Synthesising a second messenger (e.g., cyclic AMP) • Releasing calcium ions (Ca2+) that may interact in a wide variety of biochemical processes Process of chemical neurotransmission 11 AMP=adenosine monophosphate 1. Purves et al. Neuroscience. 4th edition. 2008; 2. Tortora & Derrickson. Principles of Anatomy and Physiology. 12th edition. 2009; 3. Kandel et al. Principles of Neural Science. 4th edition. 2000; 4. Sadock et al. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol 1–2. 2009 1 2 3 4 5 The neurotransmitters are cleared from the synaptic cleft by:3,4 • Reuptake into the presynaptic neurone • Removal by astrocytes • Diffusion away from the synapse • Breakdown by enzymes 1 2 3 4 5
- 13. Neurotransmitters and receptors 13 NMDA=N-methyl-D-aspartate; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA=gamma-aminobutyric acid 1. Kandel et al. Principles of Neural Science. 4th edition. 2000; 2. Purves et al. Neuroscience. 4th edition. 2008; 3. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. 2013; 4. Wierońska et al. Pharmacol Ther 2016;157:10–27; 5. Grieg et al. Recent Pat CNS Drug Discov 2013;8(2):123–141; 6. Sadek & Stark. Neuropharmacology 2016;106:56–73 Neurotransmitter Receptor subtypes Glutamate Ionotropic receptors: non-NMDA (AMPA, kainate, NMDA receptors; metabotropic receptors (mGluR1-8 subtypes)4 GABA GABAA-C subtypes Serotonin 5-HT receptors (5-HT1A-F, 5-HT2A-C, 5-HT3-7 subtypes) Noradrenaline α-adrenergic receptors (α1A-C, α2A-C subtypes); β-adrenergic receptors (β1-3 subtypes) Dopamine Dopaminergic receptors (D1-5 subtypes) Acetylcholine Cholinergic receptors: muscarinic receptors (M1-5 subtypes);5 nicotinic receptors Histamine Histaminic receptors (H1-4 subtypes)6 Neurotransmitter receptor subtypes1-3
- 14. • Glutamate is the principal excitatory neurotransmitter in the CNS1 • Glutamate is an amino acid that is produced from glutamine1 • Glutamate is removed from the synapse by transporters on specialised neurones, metabolised to glutamine, then resupplied to the relevant neurone terminals1 Glutamate 14 CNS=central nervous system 1. Purves et al. Neuroscience. 4th edition. 2008; 2. Stahl. Stahl’s Essential Psychopharmacology. 2013 Cortico–brainstem glutamate projection2 Regulates neurotransmitter release from the brainstem Cortico–striatal glutamate pathway2 Thalamo–cortical glutamate pathways2 This pathway innervates pyramidal neurones in the cortex Cortico–thalamic glutamate pathways2 Hippocampal–striatal glutamate pathway2 HO O O O NH2 Cortico–cortical glutamate pathways2 These can be direct, or indirect via GABA neurones
- 15. GABA – gamma-aminobutyric acid 15 • GABA is found throughout the brain, rather than being localised to specific areas or pathways1 • There are three types of GABA receptor, which although varied can typically be separated as follows:1 • GABAA – ionotropic chloride channel • GABAB – metabotropic G-protein coupled receptor • GABAC – ionotropic chloride channel • Glycine, the other major inhibitory neurotransmitter, has a more localised distribution, and is mostly found in the spinal cord1 . Note glycine is also a necessary co-factor on NMDA receptors GABA=gamma-aminobutyric acid 1. Purves et al. Neuroscience. 4th edition. 2008 H2N O OH • Most inhibitory neurones in the brain use GABA or glycine – as many as a third of the inhibitory synapses in the brain use GABA1 • The predominant precursor for GABA is glutamate1 • GABA is removed from the synapse by specific transporters, and the retrieved GABA is metabolised1
- 16. Serotonin • Serotonin (also known as 5-HT) is a neurotransmitter that is found throughout the body.1 High concentrations are found in the CNS, platelets, and certain cells in the gastrointestinal tract1 • There are many receptor subtypes for serotonin; the roles of these receptor subtypes are not fully elucidated • Serotonergic neurones project widely throughout the brain from their origin in the raphe nuclei of the brainstem2,3 16 CNS=central nervous system 1. Brunton et al. Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th edition. 2006; 2. Purves et al. Neuroscience. 4th edition. 2008; 3. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. 2013 NH2 HO N H Spinal cord Serotonergic projections to the spinal cord may regulate pain3 Cerebral cortex Within the forebrain, serotonin is thought to regulate sleep and wakefulness2 Raphe nuclei
- 17. Noradrenaline 17 1. Stahl. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd edition. 2000; 2. Purves et al. Neuroscience. 4th edition. 2008; 3. Dunn & Swiergiel. Eur J Pharmacol 2008;583:186–193 Cerebellum The noradrenergic projections to the cerebellum is thought to mediate motor movements, especially tremor1 Spinal cord The noradrenergic projection to the brainstem controls blood pressure1 Prefrontal cortex Some noradrenergic projections to the frontal cortex are thought to help regulate mood; others are thought to mediate attention1 The noradrenergic projection to the limbic cortex is thought to mediate emotions, energy, fatigue, and psychomotor agitation/retardation1 Locus coeruleus Noradrenergic projections from the locus coeruleus project to the back of the brain, and are important in arousal and attention1-3 • Noradrenaline (also called norepinephrine) is a neurotransmitter of neurones in the locus coeruleus1,2 • The principal function of the locus coeruleus is to prioritise competing incoming stimuli, whether external (e.g., a threat from the environment) or internal (e.g., pain), and to focus attention1 HO NH2 HO OH
- 18. Dopamine 1. Purves et al. Neuroscience. 4th edition. 2008; 2. Kandel et al. Principles of Neural Science. 4th edition. 2000; 3. Stahl. Essential Psychopharmacology. 2013 HO NH2 HO Dopamine is involved in movement control, motivation, reward, and reinforcement; many addictive substances work by affecting dopaminergic neurones1-3 • Dopamine is produced from the precursor molecule DOPA (dihydroxyphenylalanine) by DOPA decarboxylase1 • Dopamine is removed from the synapse by specialised dopamine transporters, and is catabolised by monoamine oxidase (MAO) and catechol-O- methyltransferase (COMT)1 Mesocortical pathway Here, dopamine influences perception, cognition, and social behaviour2,3 Nigrostriatal pathway Dopamine has influence over control of fine movements and initiation of movement2,3 Tuberoinfundibular pathway Dopamine normally inhibits the release of prolactin3 Mesolimbic pathway Dopamine is thought to be involved in emotion and memory, pleasurable sensations and reward, the euphoric effects of addictive substances, as well as psychotic symptoms, such as delusions and hallucinations2,3
Editor's Notes
- To understand psychiatric disorders, it is important to have a working understanding of the normal structure and function of the nervous system. The central nervous system (CNS; brain, spinal cord) and peripheral nervous system (PNS) are made up of neurones and glial cells (sometimes called neuroglia) as explained on the slide.[Tortora & Derrickson, 2009; Martin, 2003] References: Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- The neurone constitutes the functional unit of the nervous system; there are over 100 billion neurones in the brain.[Purves et al., 2008; Martin, 2003; Kandel et al., 2000] Each neurone has the ability to interact with and influence many other cells, which creates a system of intricate complexity.[Purves et al., 2008] There are several different classes of neurones – a simplified neurone is shown on the slide, along with explanations of its various component parts.[Martin, 2003] Although there are different types of nerve cells, the complexities of human behaviour stem not from the specialism of different types of neurones, but rather from the association of a great many neurones into coherent, and precise, anatomical circuits.[Kandel et al., 2000] In this way, nerve cells with similar properties can effect a variety of different functions, depending on how they are interconnected.[Kandel et al., 2000] Neurotransmitters – chemicals in the nervous system that transmit nerve impulses between neurones. Action potential – in neurophysiology, an electrical charge that moves through an axon. References: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000. Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Other references used on slide: Oxford Concise Medical Dictionary. 2nd edition. © Oxford University Press, 1998. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- The brain is divided into four anatomical regions: the diencephalon, brainstem, cerebrum, and cerebellum, as described on the slide.[Kandel et al., 2000; Tortora & Derrickson, 2009] References: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- The cerebral cortex is the main functional unit of the cerebrum.[Tortora & Derrickson, 2009] The three main functional areas of the cerebral cortex are:[Tortora & Derrickson, 2009; Prise & Wilson, 2003] motor areas that control voluntary movement (primary, secondary, and association motor areas) sensory areas that allow for visual, auditory, gustatory, olfactory, and sensory perception (primary, secondary, and association sensory areas) areas associated with higher mental functions. The surface of the brain is highly convoluted, with folds and grooves.[Martin, 2003] These convolutions are an evolutionary adaptation that allows a greater surface area to fit within the confined, and limited, space of the skull.[Martin, 2003] The elevated convolutions are called ‘gyri’, and the grooves are called ‘sulci’, as shown on the slide.[Martin, 2003] Gustatory – relating to the sense of taste. Olfactory – relating to the sense of smell. Nuclei – in neuroanatomy, localised masses of grey matter in the CNS. References: Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003. Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- The brain can be thought of as comprising five ‘lobes’ – the four lobes of the cerebral cortex and a fifth lobe, the insula, deep within the brain, as shown on the slide.[Martin, 2003; Tortora & Derrickson, 2009; Price & Wilson, 2003] The lobes of the cerebral cortex are named after the cranial bones that overlie them (frontal, parietal, occipital, and temporal).[Martin, 2003] The lobes have distinct functions. The frontal lobe has a diverse range of behavioural functions, including movement, speech, cognition, and emotion.[Martin, 2003] The parietal lobe mediates perceptions of touch, pain, and proprioception.[Martin, 2003] The occipital lobe can be thought of as the visual processing centre, containing the primary visual cortex.[Martin, 2003] Finally, the temporal lobe controls a range of sensory functions, and is important in memory and emotion.[Martin, 2003] References: Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003. Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- Information moves through the nervous system via two integrated forms of communication – electrical neurotransmission and chemical neurotransmission, as shown on the slide.[Kandel et al., 2000] An action potential is generated at the origin of the axon following sufficient excitatory stimulation of the neurone. The action potential is created by movement of electrically charged particles (ions) in and out of the neurone through pores (ion channels) in the cell membrane in a particular pattern, travelling along the length of the axon.[Kandel et al., 2000] When the action potential reaches the axon terminal it stimulates the release of chemical neurotransmitters.[Kandel et al., 2000] After the action potential has induced the release of chemical neurotransmitters, the neurotransmitters pass information to the next neurone.[Kandel et al., 2000] Reference: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.
- Neurones do not physically touch one another; two neurones are separated by a gap, known as a synaptic cleft.[Kandel et al., 2000] Because neurones do not touch, and an action potential cannot ‘jump’ across a synaptic cleft, the signal must be converted to a chemical signal to enable communication between neurones to occur.[Kandel et al., 2000] The presynaptic neurone uses chemical signals (neurotransmitters) to increase (excite) or decrease (inhibit) the generation of action potentials in the postsynaptic neurone. It is also possible to effect other biochemical processes, such as cell signalling pathways, in the postsynaptic neurone. This complex interconnectivity gives rise to the rich functional communication network that is the central nervous system.[Kandel et al., 2000] Presynaptic neurone – a neurone from which an electrical impulse is transmitted across a synaptic cleft to a postsynaptic neurone by the release of a chemical neurotransmitter. Postsynaptic neurone – a neurone to which an electrical impulse is transmitted across a synaptic cleft by the release of a chemical neurotransmitter from the axon terminal of a presynaptic neurone. Reference: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.
- The idea that neurotransmission occurs at synapses and is mediated by chemicals was, at first, a contentious issue.[Purves et al., 2008] It was in the first half of the 1900s that experiments proved chemical neurotransmission occurred.[Purves et al., 2008] The process is outlined in brief on the slide.[Purves et al., 2008; Kandel et al., 2000; Tortora & Derrickson, 2009; Sadock et al., 2009] Briefly, an action potential arrives at the terminal end of the presynaptic neurone, which means that the membrane potential at the terminal is altered.[Purves et al., 2008] This altered potential causes voltage-gated ion channels to open, leading to a rapid influx of calcium (detail not shown on slide).[Purves et al., 2008] The increased calcium within the neurone terminal (which is just a transient effect) causes vesicles to fuse with the membrane, and release their contents into the synaptic cleft.[Purves et al., 2008] Among the released contents are neurotransmitters, which bind to specific receptors on the postsynaptic neurone.[Purves et al., 2008] The effect of this binding varies, but usually leads to altered conductance of the postsynaptic neurone, and the propagation of the action potential.[Purves et al., 2008] Vesicle – a membrane-enclosed sac that stores or transports substances. Receptor – a protein molecule on a cell membrane that binds to a specific chemical, such as a neurotransmitter or drug, and produces a specific physiological effect. Reuptake – a mechanism by which a neurotransmitter is taken back into the axon terminal that released it; the most common mechanism for removal and inactivation of neurotransmitters. Astrocyte – a class of glial cells; functions include maintenance of extracellular ionic environment, and structural and metabolic support of neurones. Diffusion – in regard to neurotransmission, a mechanism by which neurotransmitters drift out of the synaptic cleft. References: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.
- There are many different neurotransmitters in the CNS, each binding to a specific receptor type which has a distinct distribution and role within the CNS.[Purves et al., 2008; Kandel et al., 2000; Stahl, 2013] Some common neurotransmitters are listed in the table on this slide. Defects in many neurotransmitter pathways have been implicated in psychiatric disorders. The variety of neurotransmitters that operate within the CNS adds to the functional complexity of the brain.[Purves et al., 2008] Different neurotransmitters can produce different responses on the same neurone; e.g., a neurone might be excited by serotonin but inhibited by the binding of GABA.[Purves et al., 2008] Exactly what constitutes a neurotransmitter has been the subject of some disagreement but, generally, a neurotransmitter must:[Purves et al., 2008] be present within the presynaptic neurone be released in response to presynaptic depolarisation, and the release must be calcium-dependent have specific receptors on the postsynaptic neurone. References: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th eition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013. Other references used on slide: Grieg NH, Reale M, Tata AM. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors. Recent Pat CNS Drug Discov 2013; 8 (2): 123–141. Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 2016; 106: 56–73. Wierońska JM, Zorn SH, Doller D, Pilc A. Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment. Pharmacol Ther 2016; 157: 10–27.
- Control of the CNS can be thought of in terms of a balance between ‘go’ (excitatory) and ‘stop’ (inhibitory) signals.[Purves et al., 2008; Stahl, 2013] If the sum of the ‘go’ signals that a neurone receives outweighs the sum of the ‘stop’ signals, then that neurone will exist in an active state, and will continue to signal to the downstream neurone.[Purves et al., 2008; Stahl, 2013] The main excitatory neurotransmitter in the CNS is glutamate; the main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA).[Purves et al., 2008] Glutamate is arguably the most important neurochemical for normal brain function.[Purves et al., 2008] Nearly all excitatory neurones in the CNS are glutamatergic – more than half of the neurones in the brain.[Purves et al., 2008] It is noteworthy, though, that high concentrations of glutamate are neurotoxic.[Purves et al., 2008] There are three types of receptor to which glutamate can bind (named after the agonists that activate them), each of which has slightly different properties:[Purves et al., 2008] NMDA (N-methyl-d-aspartate) AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) kainate (kainic acid). References: Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.
- GABA is the main inhibitory neurotransmitter found in the brain.[Purves et al., 2008] GABA is synthesised predominantly from glutamate, by the enzyme glutamic acid decarboxylase that is found almost exclusively in GABAergic neurones.[Purves et al., 2008] The ionotropic GABA receptors are usually inhibitory, because when activated they allow the flow of negative chlorine ions across the membrane – reducing the potential for neuronal signalling.[Purves et al., 2008] Chemicals that function as GABA agonists have been used to treat various conditions, and include anticonvulsants, anxiolytics, benzodiazepines, and hypnotics.[Stahl, 2013] References: Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.
- Serotonin (also known as 5-HT) is a neurotransmitter that is found throughout the body.[Brunton et al., 2006; Stahl, 2013; Purves et al., 2008] The wide dispersal of serotonergic neurones throughout the brain enables serotonin to be involved in modulating diverse body functions. Body functions modulated by serotonin include:[Brunton et al., 2006] mood sleep cognition sensory perception pain perception movement regulation of internal temperature appetite sexual behaviour hormone secretion. References: Brunton LL, Lazo JS, Parker KL (eds). Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill, 2006. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.
- Noradrenaline acts on two classes of adrenergic receptor, α and β.[Purves et al., 2008] Noradrenergic neurones project widely throughout the brain, and there are many brain areas where serotonin, noradrenaline and dopamine projections overlap, allowing interactions.[Stahl, 2013] Noradrenaline and the locus coeruleus are thought to have important input into the control the CNS exerts over mood, cognition, stress, arousal, pain, and other functions.[Stahl, 2013; Dunn & Swiergiel, 2008] Malfunction of the locus coeruleus is thought to underlie disorders such as depression, anxiety, and disorders of attention and information processing.[Stahl, 2013] Low or abnormal noradrenaline activity is, theoretically, characterised by impaired attention; concentration, working memory and information processing difficulties; as well as psychomotor retardation, fatigue, and apathy.[Stahl, 2000] In addition, abnormalities in the noradrenergic projection to the hypothalamus, which mediates stress response, are indicated in depressive and anxiety disorders.[Dunn & Swiergiel, 2008] References: Dunn AJ, Swiergiel AH. The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 2008; 583 (2–3): 186–193. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd edition. © Cambridge University Press, 2000. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.
- Dopamine is believed to be involved in motivation, reward, and reinforcement.[Purves et al., 2008] Dopamine also plays an essential role in the control and coordination of movement.[Purves et al., 2008] Dopamine receptors all influence the activity of the second messenger, cyclic AMP, which is involved in many biochemical processes within a neurone.[Kandel et al., 2000] Dopamine receptor subtypes D1 and D5 increase the levels of cyclic AMP, whereas D2, D3, and D4 subtypes decrease the levels of cyclic AMP.[Kandel et al., 2000] Thus, depending on which receptor subtype the neurotransmitter binds with on the postsynaptic neurone, dopamine can increase or decrease cellular activity.[Kandel et al., 2000] Dopamine, and its actions within the CNS, is critical to the underlying disease state of many conditions, including Parkinson’s disease, which is characterised by a dearth of dopamine, and schizophrenia, which appears to be caused by an overactivity of dopamine within certain brain regions.[Stahl, 2013] Furthermore, many addictive substances work by altering the effect of dopamine within the brain.[Purves et al., 2008] For instance, the drug cocaine appears to act by inhibiting the reuptake of dopamine, which leads to an increased concentration of dopamine in the synapse, prolonging its action.[Purves et al., 2008] Delusion – a disturbance in thought leading to false beliefs. Hallucination – a false sensory perception, such as hearing voices or seeing things that are not there. Prolactin – a hormone, produced and released into the bloodstream by the pituitary gland, that is involved in the secretion of milk and breast growth; unusually high amounts are responsible for impotence and loss of libido in both men and women. References: Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000. Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.