CNS Intro Pt1 BMS2047 - Updated PDF

BMS2047 Introduction to Pharmacology of the Central Nervous System Dr Sarah Trinder [email protected] http://www.cvr.org.au/ Tuesday, 27 February 2024 1 Outline Central nervous system (CNS) disorders Anatomy & major functions of the brain Types of chemical signalling in the brain Important term...

BMS2047 Introduction to Pharmacology of the Central Nervous System Dr Sarah Trinder [email protected] http://www.cvr.org.au/ Tuesday, 27 February 2024 1 Outline Central nervous system (CNS) disorders Anatomy & major functions of the brain Types of chemical signalling in the brain Important terms to describe said signalling Amino acid transmitters Monoamines Other CNS mediators http://www.cvr.org.au/ Tuesday, 27 February 2024 2 Can you list some CNS conditions? www.hounslowiapt.nhs.uk http://www.tenninetyblog.co.uk/ en.wikipedia.org seizures.dolyan.com Richard Hess Tuesday, 27 February 2024 neurosciencefundamentals.unsw.wikispaces.net The NHS and CNS drugs In 2022/3 CNS drugs* were the 2nd most prescribed class of drugs to cardiovascular drugs, in England. 230 million prescription items, 19% of all prescriptions equivalent ~4 prescribed items/person Cost to the NHS? £1.59 billion, 15% of total costs www.hseni.gov.uk *CNS drugs as defined by the British National Formulary (BNF); includes analgesics, does not include anaesthetics. Tuesday, 27 February 2024 4 Anatomy of the brain Mid brain Cerebellum Pons Tuesday, 27 February 2024 Medulla Adapted from http://schoolworkhelper.net/brain-imaging-anatomy-lateralization/ 5 Major functions of the brain Cerebellum Motor – movement/co-ordination Basal ganglia (striatum, substantia nigra) Motor - movement Limbic system Amygdala & cingulate gyrus – emotion & memory Hippocampus – learning & memory Thalamus Sensory neurotransmission Hypothalamus & pituitary gland Endocrine control Tuesday, 27 February 2024 6 Cerebral cortex Higher brain functions Tuesday, 27 February 2024 From Human physiology: an integrated approach, Silverthorn 7 The brain and transmission The brain is a chemical machine Controls main functions of higher animals over wide timescales Fast and slow transmission, controlled by chemical mediators molecular mechanisms Photo credit: Lightspring/Shutterstock http://bgr.com/2016/01/21/brain-memory-capacity-petabyte/ Tuesday, 27 February 2024 8 Chemical signalling in the CNS Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 9 Important terms (can be confusing)! Neurotransmitters – released presynaptically and generate rapid excitatory/inhibitory responses postsynaptically. Fast – act via ligand-gated ions channels (glutamate, GABA) Slow – mainly by G protein-coupled receptors (GPCR; dopamine, peptides) Neuromodulators – released by neurons and astrocytes, generate slower responses both pre- and postsynaptically mainly by GPCRs (NA, dopamine) Neurotrophic factors – often released by non-neuronal cells often kinase-linked receptors regulating gene expression Number of chemicals are both neurotransmitters and neuromodulators – ACh, dopamine, 5-HT….. AND can act via ligand-gated ion channels and GPCRs! Tuesday, 27 February 2024 10 Quick bit of revision neurotransmission Tuesday, 27 February 2024 11 What happens during an action potential? What happens during an action potential? Vm (mV) +30 Depolarisation Na+ channels open Na+ enters the cell 0 Repolarisation Na+ channels close (refractory) K+ channels open K+ leaves the cell Hyperpolarisation Some K+ channels remain open ATP-Na+/K+ pump restores resting potential Threshold potential -50 -70 Resting potential Tuesday, 27 February 2024 Resting potential Na+ channels at rest 12 Neurotransmitter release Tuesday, 27 February 2024 13 Not just neurons! Glial cells Non neuronal cells out number neurons 10 to 1 Non-conducting cell Provide metabolic support for neurons BUT…. NIH/National Instititute of Neurological Disorders and Stroke (NINDS) Have a communication role express receptors and transporters release mediators, often in a Ca2+-dependent manner Tuesday, 27 February 2024 14 Amino acid transmitters Tuesday, 27 February 2024 15 Amino acid transmitters Two key systems Glutamate (Glu) γ-Aminobutynic acid (GABA) Common principles Ubiquitous across the CNS and PNS Key excitatory & inhibitory neurotransmitters Tuesday, 27 February 2024 16 Amino acid transmitters Glutamate Main excitatory transmitter in CNS Stored in synaptic vesicles released by Ca2+ -dependent exocytosis Comes from glucose (Kreb’s cycle) or synthesised from glutamine (pharmacologically inactive) via glial cells Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 17 Amino acid transmitters Glutamate receptors 3 main inotropic receptors NMDA – pre- & postsynaptic, glial cells AMPA - postsynaptic Kainate - pre- & postsynaptic 8 metabotropic receptors (GPCRs) mGlu1-8, classified into 3 groups found on neurons and glial cells Located most abundantly in cortex, basal ganglia and sensory pathways Tuesday, 27 February 2024 18 Amino acid transmitters NMDA receptor Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 19 Amino acid transmitters Pharmacological intervention of glutamate receptors? Ketamine Mematine Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 20 Amino acid transmitters Pharmacological potential for glutamate receptors? NDMA antagonists and channel blockers strokes, epilepsy, schizophrenia disappointing clinical trials, why? Positive AMPA modulator agonists cognitive enhancement, schizophrenia, depression, ADHD disappointing clinical trials, why? How could we get around this? Tuesday, 27 February 2024 21 Amino acid transmitters γ-Aminobutynic acid - GABA Main inhibitory transmitter in the brain Widespread distribution in the brain highest density in the nigrostriatal system synthesised in GABAergic neurons majority short interneurons Glu GABA GABAergic neuron Inhibition Tuesday, 27 February 2024 Glu 22 Amino acid transmitters GABA synthesis and deactivation GABA is synthesised from glutamate by glutamic acid decarboxylase (GAD) GABA deactivation: re-uptake by specific transporters GABA transporter 1 (GAT1) – GABAergic nerve terminals GAT3 – astrocytes and GABAergic synapse degradation – GABA transaminase (GABA-T) found in mitochondria of astrocytes and neurons Gln Glutaminase GlnT Glutamine synthetase Gln Glu GAD Glu GAT1 GABA-T GABA GAT3 GABAergic neuron Tuesday, 27 February 2024 GABA Astrocyte GABA 23 Amino acid transmitters How can we increase GABA function? Gln Tiagabine Glutaminase GlnT Glutamine synthetase Gln Glu Glu GABA-T GAT1 GAD GABA GAT3 GABAergic neuron GABA Astrocyte Vigabatrine GABA Tuesday, 27 February 2024 24 Amino acid transmitters GABA receptors GABAA receptor ligand gated Cl- channel - neurotransmitter hyperpolarisation = reduces excitability mainly located postsynaptically pentamer GABAB receptor GPCR - neuromodulator inhibits voltage gated Ca2+ channels and adenylate cyclase (AC) opens K+ channels located pre- and postsynapically dimer Tuesday, 27 February 2024 25 Amino acid transmitters Barbiturates Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 26 Monoamines Tuesday, 27 February 2024 27 Monoamines The diffuse modulatory systems of the brain Four main systems Noradrenergic - NA Dopaminergic - DA Serotonergic - 5-HT Cholinergic - ACh Common principles Small populations of neurons at core Cell bodies in brain stem and basal forebrain Release transmitter molecules diffusely Associated with high level behaviours Tuesday, 27 February 2024 28 Monoamines Noradrenaline (NA) Locus coeruleus – NA system (LC-NA system) Function Arousal Attention/memory Stress Cognitive control Emotions Neuroplasticity Posture & balance Blood pressure Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 29 Monoamines Adrenoceptors All adrenoceptors expressed in CNS α1 receptors - Gq coupled – poorly understood α2 receptors Gi/o coupled, inhibits AC and Ca2+ channels, activates K+ channels located on NAergic neurons – act as inhibitory autoreceptors located postsynaptic non NAergic neurons blood pressure control sedation – anaesthetics analgesia β1 receptors Cortex, striatum and hippocampus β2 receptors Cerebellum β3 receptors Locus coeruleus, hippocampus All β receptors - Gs coupled, activates adenylate cyclase Tuesday, 27 February 2024 30 Monoamines Cocaine, Tricyclic antidepressants Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 31 Monoamines Dopamine (DA) Endocrine control Motor control - Parkinson’s disease Behavioural Behavioural - emotion, memory and learning Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 32 Monoamines Dopamine receptors D1 type – consists of D1 and D5 Gs coupled, activates adenylate cyclase Mainly postsynaptic D2 type – consists of D2, D3 and D4 Gi/o coupled, inhibits AC and Ca2+ channels, activates K+ channels Found pre- and postsynaptically D2 D3 D1 D5 D2 D3 D4 D1 D2 D4 D1 D5 D2 D3 D4 Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 33 Monoamines Dopamine (DA) TH = Tyrosine hydroxylase L-tyrosine TH L-dopa metabolites MAO DA DAergic neuron Gi/o D2 DAT D2 Gi/o Gs AC Tuesday, 27 February 2024 D1 cAMP 34 Monoamines 5-hydroxytryptamine/serotonin (5-HT) Function Mood Memory processing Sleep Cognition Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 35 Monoamines 5-hydroxytryptamine/serotonin (5-HT) Trp Trp = tryptophan 5-HTP = 5-hydroxytryptophan TH = Tryptophan hydroxylase TH 5-HTP metabolites 5-HT MAO 5-HT neuron Gi/o 5-HT1B/D Tuesday, 27 February 2024 SERT 36 Monoamines 5-HT receptors Inhibitory Inhibitory/Excitatory Receptor Location Signalling system Gi/o = ↓cAMP, may modulate Ca2+ channels Gi/o = ↓cAMP, may modulate Ca2+ channels Gi/o = ↓cAMP, may modulate Ca2+ channels Gi/o = ↓cAMP, may modulate Ca2+ channels Gi/o = ↓cAMP, may modulate Ca2+ channels 5-HT1A CNS 5-HT1B CNS & periphery 5-HT1D Behaviour: locomotion, CNS & blood vessels Cerebral vasoconstriction 5-HT1E CNS Unknown 5-HT1F CNS & periphery 5-HT2A CNS & periphery Unknown Neuronal excitation, Behaviour, Smooth muscle etc Gq/11 = ↑IP3 & Ca2+ 5-HT2B Gastric fundus Contraction Gq/11 = ↑IP3 & Ca2+ 5-HT2C CNS & lympocytes Unknown Neuronal excitation, Behaviour: CNS & periphery anxiety, Emesis CNS & periphery Neuronal excitatio, GI motility Modulation of exploratory CNS behaviour (rats)? CNS & leukocytes Learning memory? Thermoregulation? Circadian CNS & periphery rhythm? Gq/11 = ↑IP3 & Ca2+ 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7 Tuesday, 27 February 2024 Main function Neuronal inhibition Behaviour: sleep, feeding thermoregulation, anxiety Presynpatic inhibition, Behaviour, pulmonary vasoconstriction Ligand-gated cation Gs = ↑cAMP Gs = ↑cAMP Gs = ↑cAMP Gs = ↑cAMP 37 Monoamines Acetylcholine (ACh) Motor control - Parkinson’s disease - Huntington’s chorea Arousal - Alzheimer’s disease Learning & short term memory Tuesday, 27 February 2024 From Rang and Dale’s Pharmacology 38 Monoamines ACh receptors Muscarinic (mAChR) – GPCRs M1 – excitatory, Gq = ↑IP3, ↓K+ conductance M2 – inhibitory, Gi/o = ↑cAMP, ↓Ca2+ & ↑K+ conductance – presynaptic inhibition M3 – excitatory, Gq – glandular/smooth muscle M4 & M5 – function not well know Nicotinic (nAChR) – inotropic Mainly presynaptic – facilitate release of Glu, DA & GABA When postsynaptic - mediate fast excitatory transmission Tuesday, 27 February 2024 39 Other CNS mediators Purines Adenosine (A1 & A2A) – inhibitory: sedative, neuroprotective ATP (P2X) Histamine H1-3 widespread in brain Anti-histamine used to control nausea/vomiting (motion sickness), induce sleep Tuesday, 27 February 2024 40 Learning Outcomes To describe & explain the mechanism of action of the main transmitter systems in the CNS: Amino acid transmitters Glu GABA Monoamines NA DA 5-HT ACh Tuesday, 27 February 2024 41