Intro To Neuro PDF

Introductory Neuropharmacology Robert Peter Biney, PhD School of Pharmacy and Pharmaceutical Sciences University of Cape Coast Ghana 1  Learning Objectives Describe how...

Introductory Neuropharmacology Robert Peter Biney, PhD School of Pharmacy and Pharmaceutical Sciences University of Cape Coast Ghana 1  Learning Objectives Describe how neurochemical imbalance may Explain lead to neurologic importance of disorders specific neurotransmitte rs in health and Identify major disease neurotransmitt Describe specific er types and events at neuronal receptors synapse relating to synthesis, storage and2 release of  Neuropharmacology How drugs influence behavior by affecting cellular function and neural mechanisms in the nervous system CNS Drugs Cross the BBB into the CNS to affect brain function Can selectively modify CNS function  May stimulate and/or depress the CNS Alter Mood, Pe rce ption , Con sciou sn e ss, Cognition, Psychotropic drugs – used toBehaviour stabilize or improve mood, mental status or behaviour https://www.dreamstime.com/stock-photo-pills-head-human-hand- drawing-colored-brain-image59667696  Goals of Neuropharmacology 1. To develop drugs to correct pathophysiological changes in the abnormal CNS. 2. To develop/use drugs as probe compounds to both elucidate and manipulate the normal CNS  Neuropharmacology – Issues and Challenges CNS functionally most complex system Understanding of drug effects very much more difficult Relationship between individual cellular behaviour and whole organ behaviour not direct CNS-active drug may act at multiple sites with disparate and even opposing effects. Many CNS disorders involve multiple brain regions and pathways, which can frustrate efforts to use a single therapeutic agent.  Classification of CNS Drugs - WHO ATC, 1976 Mainly an Indication-based Classification https://www.whocc.no/atc/structure_and_principles/ Classificatio n of CNS Drugs Drugs that influence behaviour and improve functional status of patients with neurological or psychiatric diseases typically act by enhancing or blunting neurotransmission in the CNS  Neurochemical Messengers 1. Neurotransmitters Cause electrophysiological changes in the postsynaptic cell. Cause: Excitation by depolarization OR inhibition by hyperpolarization E.g. Acetylcholine 2. Neuromodulators In contrast neuromodulators have effect on a large population of neurons but have slow synaptic actions Enhance or blunt the effects of classical neurotransmitters E.g. Histamine 9 1/20/2025  Neurochemical Messengers 3. Neurohormones Neuroendocrine cells receive inputs from neurons like neurotransmitters but in response release messenger molecules (hormones) into the blood stream Travel in circulation to act at a site distant from release site E.g. Oxytocin 4. Neurotrophic factors Assist neurons in attempts to repair damage Produced within the CNS by neurons, astrocytes, microglia, or immune cells Useful adjuncts to rehabilitative treatment E.g. Brain 10 derived neurotropic 1/20/2025 factor One minute paper Why do neurons communicate via chemical means 11  Neurotransmitters Endogenous chemicals in the brain that act to enable signalling across a chemical synapse Carry and modulate signals between neurons or other cell types Act on a variety of targets to elicit biological functions Cause electrophysiological changes in the postsynaptic cell.  Excitation by depolarization OR  Inhibition by hyperpolarization 12  History Otto Loewi and “vagusstuff” Nobel Prize in 1936 together with Henry Dale 13  Neurotransmitters Conventional  Stored in synaptic vesicles  Released on Ca2+ entry into axon terminal in response to an action potential  Act by binding to receptors on the membrane of the postsynaptic cell Unconventional Endocannabinoids and gasotransmitters (nitric oxide)  Not stored in synaptic vesicles  May carry messages from the postsynaptic neuron to the presynaptic neuron (retrograde)  Can cross the cell membrane and act directly on molecules inside the cell 14  Identification as a neurotransmitter Localization: must reside in the “presynaptic” terminal of the pathway of interest. Release: must be released from a neuron in response to neuronal activity and in a calcium-dependent manner. Synaptic mimicry: should produce a response that mimics the action of the transmitter released by nerve stimulation and application of a selective antagonist should block the response. Exceptions Nitric oxide is not stored in neurons and released by exocytosis  synthesized when needed and readily diffuses across membranes. 15  Synthesis and Storage Two main categories of neurotransmitters 1. Small molecule transmitters  Synthesized and stored in the terminal (fast release)  Enzymes in presynaptic terminal catalyse synthesis 2. Peptide transmitters (Neuropeptides)  Synth e size d in th e ce ll bod y and must be transported to the terminal (slower release) A neuron typically will synthesize and release only one type of small molecule neurotransmitter but can synthesize and release 16 more than one neuropeptide  Release Translocation/mobilization Ca2+ influx phosphorylate synapsin promotes translocation Fusion and Release SNARE proteins guides and promotes fusion with cell membrane Synaptobrevin SNAP-25 Syntaxin Synaptotagmin – Ca2+ sensing Target for neurotoxins 17 Neurotransmitter Actions 18  Neurotransmitter Clearance Should the action of neurotransmitters be terminated after acting on its postsynaptic receptors? Think – Pair – Share Clearance achieved through 1. Neuronal transport and/or 2. Degradation - break down by enzymes. 19  Learning Objectives Appreciate how neurochemical imbalance may Explain lead to neurologic importance of disorders specific neurotransmitte rs in health and Identify major disease neurotransmitt Describe specific er types and events at neuronal receptors synapse relating to synthesis, storage and 20 release of  Small molecule neurotransmitters 2 Cl a s s e s – ba s e d on c h e m ic a l Biogenic Amines structure Amino acids Glutamate Histamine Serotonin Catecholamines GABA Dopamine Glycine Noradrenaline Acetylcholine Adrenaline 21  Glutamate Primary excitatory neurotransmitter in the CNS  Excitatory synaptic transmission is mediated by glutamate  Important neurotransmitter in synaptic plasticity 22  Glutamate Acts on 3 ionotropic receptors subtypes. 1. AMPA - (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 2. Kainate 3. NMDA (N-methyl-D-aspartate) NMDAR also has Glycine binding site Also act on 8 metabotropic receptor subtypes 23 Effects may be excitatory or inhibitory (pre-synaptic or post-synaptic) Read Synaptic plasticity Excitotoxicity  Glutamate 8 metabotropic receptors (mGlu1-8) Widely distributed throughout the CNS, on neurons & glia; regulate cell excitability and synaptic transmission. Group I: typically located postsynaptically largely excitatory; ↑Gq-PLC-IP3-Ca2+; modify responses through ionotropic GluRs by raising [Ca2+]i Group II & III: mostly presynaptic ↑ Gi/o-AC (↓cAMP) activation tends to reduce synaptic transmission and neuronal excitability. May be autoceptors, involved in reducing glutamate release, or heteroceptors  One minute paper Metabotropic glutamate receptors can be excitatory or inhibitory. How is this possible? 26  GABA Primary inhibitory neurotransmitter in the CNS  Release from local interneurons  Ubiquitous 27  GABA Gamma Amino Butyric acid – Main inhibitory NT Acts on 2 receptor subtypes GABAA  Ionotropic – gates Cl-  Fast IPSP  Selectively inhibited by picrotoxin and bicuculline (convulsants) GABAB  Metabotropic  localized to perisynaptic regions GABAA target of several pharmacological agents  Inhibit Ca2+ channels or activate K+ channels  Also inhibits adenylyl cyclase  Selectively inhibited by baclofen - spasmolytic 28 GABAA receptor  Acetylcholine 1st compound to be identified pharmacologically as a transmitter in the CNS Primary role in the autonomic nervous system Has wide application in the PNS  Main neurotransmitter at the neuromuscular junction An important neurotransmitter in memory Degeneration of cholinergic pathways is hallmark of Alzheimer disease 30  Acetylcholine Acts on 2 types of receptors 1. Nicotinic (ionotropic)  Skeletal muscle (Nm)  CNS, autonomic ganglia, and adrenal gland (Nn) 2. Muscarinic (metabotropic)  Most CNS responses to acetylcholine are mediated by muscarinic receptors  M1, M3, M5 receptors expressed in the brain  In PNS has effect on smooth muscle contraction – wide effects Muscarinic receptors appear to mediate the main behavioural effects associated with acetylcholine Effects on arousal & on learning and short-term memory Muscarinic antagonists (e.g. hyoscine) cause amnesia 31  Dopamine Dopamine generally exerts a slow inhibitory actions Four main dopaminergic pathways Nigrostriatal pathway — important in motor control Me s ol im b ic p a t h wa y — i n v o l v e d i n emotion and drug- induced reward Mesocortical pathway — involved in emotion Tuberoinfandibular pathway — regulate neuronal secretions The predominant catecholamine in the CNS 32  Dopamine Acts on 5 receptor subtypes (all metabotropic)  D1-like – D1 and D5  D2-like – D2, D3, D4 Dopamine receptor activation leads to  Opening of potassium channels  Inhibition of Ca2+ channels  Inhibition of adenylyl cyclase Dopamine receptors implicated in symptoms of both Parkinson's disease and schizophrenia (positive and negative symptoms) Dopamine acts on the chemoreceptor trigger zone to cause nausea and vomiting – dopamine antagonists used in management of vomiting 33 Have you been listening? Which of these pathways is most likely implicated in cocaine’s reward enhancing effects A. Tuberoinfandibular pathway Orange B. Mesolimbic pathway Yellow C. Mesocortical pathway Green D. Nigrostriatal pathway Pink  Serotonin MAO Inhibitors 5-HT is involved in various neurologic Reserpine responses: Depletes Behavioural responses (e.g. hallucination) 5-HT stores Feeding behaviour Triptans Control of mood 5-HT 1D agonists Sleep/wakefulness Vomiting Release SSRI Enhacers  Triptans – Sumatriptan Fenfluramine Inhibits 5- HT reuptake Antidepressants  SSRI = Se le ctive Se rotonin Reuptake Inhibitor  Fluoxe tine , se r traline , clomipranil  M O A = M o n o a m i n e o5-HT x i d3a s e A Antagonists inhibitors Ondansetron, Still listening? Stimulating 5-HT autoreceptors will Orange A. reduce breakdown of 5-HT at the synapse cleft. B. generate an EPSP. Yellow C. reduce 5-HT release into synapse. Green D. inhibit 5-HT storage in synaptic vesicles. Pink  Noradrenaline Noradrenaline transmission is important in: the 'arousal' system, controlling wakefulness and alertness control of mood (functional deficiency contributing to depression) Psychotropic drugs that act partly or mainly on NA transmission in the CNS include antidepressants, cocaine and amphetamine. Some antihypertensive drugs (e.g. clonidine, methyldopa) act mainly on noradrenaline transmission in the CNS. 37  Cannabinoids Endocannabinoids (anandamide and 2-arachidonoylglycerol) act as retrograde synaptic messengers synthesised and secreted in response to a rise in intracellular Ca2+ Two receptor types, both linked to Gi and inhibition of adenylyl cyclase activity  CB1 – mainly CNS - basal ganglia, hippocampus, cerebellum, and cerebral cortex, leukocytes and testis o Activation of CB1 receptors results in inhibition of glutamate release  CB2 – periphery - spleen, tonsils, bone marrow, peripheral blood leukocytes  Cannabinoids Δ9-tetrahydrocannabinol is a CB agonist derived from marijuana CB 1 agonists - therapeutic potential for treatment of vomiting, pain (CB 2 as well), muscle spasms, multiple sclerosis, anxiety, Alzheimer's disease and tardive dyskinesia Cannabinoids Cannabinoids  The ‘Brain Balance’ Brain neuronal function is a controlled balance between excitatory and inhibitory neurotransmission Over excitation = anxiety, epilepsy and convulsions Over inhibition = depression, anaesthesia and coma. Excitatio Inhibitio Chemical Imbalances in result in Neurological Disorders n n γ -Amimobutyric acid (GABA) Serotonin  CNS depression, resp. depression,  Sleep, hallucinations, decreased sedation appetite, anxiety  seizures, movement disorders  depression, OCD, pain sensitivity Glutamate  seizures, neuronal degeneration  schizophrenia, cognitive impairment 42  End... 43