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Pharmacology of Central Nervous System Section 1 The Functions of Neuron and Neuroglia General consideration 1.composition of nervous system (1)central and peripheral nervous systems (2)neuron and synapse* Neuron The elementary functions of neuron (1) Receive the excitations or inhibitions induced by internal or external stimulations. (2)Analyze and integrate the information from every organs. Neuron The elementary functions of neuron (3)Generate or carry the demands regulating the activities of the effectors. (4)Some neurons have neuroendocrine function. Neurons have 4 important zones • Soma and dendrites – receive the information,generate and integrate the local potential changes. • Initial segment - action potentials are generated. Neurons have 4 important zones • Axon process – transmits the impulses to the nerve endings. • Nerve endings - release the synaptic transmitters. • • • • • Neurotrophin Nerve growth factor(NGF) Brain-derived neurotrophin factor(BDNF) Neurotrophin 3 Neurotrophin 4/5 Neurotrophin 6 • Ciliary neurotrophin factor(CNTF) • Glial cell-derived neurotrophin factor(GDNF) • Insulin-like growth factorⅠ(IGF-Ⅰ) • Transforming growth factor(TGF) Neuroglia About 1.0×1012~ 5.0×1012 neuroglia cells , 10~50 fold of neurons Dendrites and axons can not be distinguished clearly No synapse formed and no AP produced The types of glial CNS - astrocyte oligodendrocyte microglia Functions of glial cells Astrocytes (Astroglia) - Support the neurons - Clean up brain "debris"( damaged material) and fill in the damaged area - Transport nutrients to neurons Functions of glial cells Astrocytes (Astroglia) - regulate the external chemical environment of neurons by removing excess ions and recycling neurotransmitters. Oligodendrocytes - myelinated axons (1) insulate the axons (2) facilitate the conduction of electrical impulses. Microglia - act as the immune cells of the CNS - remove most of the waste and cellular debris from the CNS - derivation,action in brain injury, action in other diseases. Section 2 General interactions between neurons Typical Synapses (chemical synapses) Synapse The small gap or space between the axon terminals of one neuron and the dendrites or cell body of the next neuron is called the Synapse . Structure of Synapse • Membrane of presynaptic neuron • Synaptic cleft • Membrane of postsynaptic neuron Major types of Synapses C B A A: axo-somatic synapse B:axo-dendritic synapse C:axo-axonic synapse Classifications of Synapses – Chemical synapses ▪Directed synapses (Typical synapses) ▪Non- directed synapses (Varicosity) – Electrical synapses Typical Synapses (chemical synapses) Synapse Process of Typical Synaptic Transmission Process of Typical Synaptic Transmission 1. An arriving action potential depolarizes the presynaptic membrane. 2. Calcium ions enter the cytoplasma of the synaptic knob 3. Neurotransmitters release. Process of Typical Synaptic Transmission 4. Neurotransmitters diffuse to and bind to the receptors on postsynaptic membrane. Process of Typical Synaptic Transmission 5. Receptors on the postsynaptic membrane are activated, producing a postsynaptic potential. 6. Neurotransmitters are broken down. Electrical Activities of Postsynaptic Neurons (Postsynaptic Potential) Forms of the postsynaptic potential • Excitatory postsynaptic potential (EPSP) • Inhibitory postsynaptic potential (IPSP) Postsynaptic Potentials Excitatory postsynaptic potential Inhibitory postsynaptic potential Postsynaptic Potentials •When a neuron responds to the neurotransmitter postsynaptically, it allows ions to move across its membrane. Postsynaptic Potentials •The movement of ions changes the membrane potential of the postsynaptic neuron. •It is called the “postsynaptic potential”. EPSP EPSP • Excitatory transmitters → Synaptic cleft → bind to receptors → ↑the postsynaptic membrane's permeability to Na+, Ca2+ → enter the postsynaptic neuron →produce a depolarizing potential. IPSP IPSP • Inhibitatory transmitters → Synaptic cleft → bind to receptors → the postsynaptic membrane’s permeability to Cl-(or K+ ) → Cl- enter the postsynaptic neuron →generate a hyperpolarizing potential. • The EPSP is produced by depolarization of the postsynaptic membrane. • During this potential, the excitability of the neuron to other stimuli is increased, • This the potential is called the EPSP. • The IPSP is produced by hyperpolarization of the postsynaptic membrane. • During this potential, the excitability of the neuron to other stimuli is decreased, • This the potential is called the IPSP. Neurotransmitters 40 Neurotransmitters Noradrenaline (NA) Dopamine (DA) 5-HT (5-hydroxytryptamine) monoamines Acetylcholine (ACh) Glutamate GABA (γ-aminobutyric acid) amino acids 41 Common features of neurotransmitters Synthesis Storage & release Interaction with target cell Termination of action 42 Synthesis -enzymes precursor uptake synthetic enzymes Neurotransmitters are synthesised from precursors by the action of enzymes e.g. DA synthesised from tyrosine by tyrosine hydroxylase and DOPA decarboxylase 43 Storage of transmitters- vesicles storage vesicles Neurotransmitters are stored in vesicles Protected from metabolic enzymes Ready for release 44 Release of transmitter-exocytosis Depolarization of the terminal causes Ca++ dependent exocytosis Action potential exocytosis • Voltage sensitive Ca++ channels open • Vesicles fuse with presynaptic membrane and empty into synaptic cleft 45 Interaction with target cell receptors** Presynaptic neurone Post-synaptic neurone 46 Termination of action-reuptake Monoamines & amino acids High affinity reuptake removes transmitter from the synaptic cleft Metabolic enzymes 47 Termination of action- metabolism Acetylcholine Extraneuronal metabolism inactivates transmitter choline is recycled Metabolic enzyme 48 Interaction with target cell-receptors Presynaptic neurone Post-synaptic neurone Receptors Excitatory/inhibitory Ligand-gated ion channel G-protein linked 49 Neurotransmitters and receptors (1) Neurotransmitter Identification of neurotransmitter Synthesis in ? Stored in terminal and can be released Binding to ? Removed quickly after action (2) Receptor Concept agonist, antagonist specific,saturation,reversible Classification and mechanisms a. ion channel coupling receptor b. metabotropic receptor (G-protein coupled receptor) Ligand-gated ion channels ion channel ION Allosteric change opens channel Ions can enter (or leave) cell 52 Ligand-gated ion channels • Receptor with binding site linked directly to an ion channel • Binding to the receptor opens the channel • Channels are ion selective • Ions enter or leave the cell altering membrane potential 53 Ligand-gated ion channels NMDA (glutamate) Ach 5-HT3 GABAA Na+ (Ca++) channels excitatory Cl- channel inhibitory 54 G-protein linked receptors Ions +/- G Changes in excitability Cellular effects G G +/- Enzyme Second messengers (cAMP, PI) Calcium release Protein phosphorylation Other 55 G-protein linked receptors • Receptor in which binding site is linked to a G protein • Binding to the receptor activates enzymes ‘second messengers’ opens ion channels • Effects are slow and often modulatory 56 Neurotransmitters Acetylcholine • first compound to be identified pharmacologically as a transmitter in the CNS. • Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors neostriatum A number of pathways contain medial septal nucleus acetylcholine the reticular formation • Cholinergic pathways play an important role in cognitive functions, especially memory. Amino acid and receptor Excitatory:glutamate, Inhibitory:GABA ,glycine Amino acid and receptor a. Glu in cerebral cortex and sensory afferents receptor:① ionotropic receptor: KA,AMPA,NMDA ② metabotropic receptor Glutamate • Excitatory synaptic transmission is mediated by glutamate, which is present in very high concentrations in excitatory synaptic vesicles . • Glutamate is released into the synaptic cleft by Ca2+-dependent exocytosis. Glutamate • The released glutamate acts on postsynaptic glutamate receptors • Cleared by glutamate transporters present on surrounding glia. Glutamate • In glia, glutamate is converted to glutamine by glutamine synthetase • Released from the glia, • taken up by the nerve terminal, • converted back to glutamate by the enzyme glutaminase. Glutamate • The high concentration of glutamate in synaptic vesicles is achieved by the vesicular glutamate transporter (VGLUT). • The ionotropic receptors divided into three subtypes : amino-3-hydroxy-5-methylisoxazole-4propionic acid (AMPA) • kainic acid (KA) • N -methyl-D -aspartate (NMDA). • A typical excitatory synapse contains AMPA receptors, which tend to be located toward the periphery, • NMDA receptors, which are concentrated in the center. • Kainate receptors • Kainate receptors being expressed at high levels in the hippocampus, cerebellum, and spinal cord b. GABA in cerebral cortex and cerebrum corpus striatum Receptor GABAA(ionotropic receptor) permeability for Cl-↑ GABAB(G-protein coupled receptor): permeability for K+↑and for Ca2+↓ • GABA pathways: The cerebellum - lateral vestibular nucleus; Striatum – substantia nigra c. Glycine in Renshaw cell of spinal cord but excitatory when combine with NMDA receptor Receptor(ionotropic ):permeability for Cl ↑ Dopamine Four pathway of dopaminergic neurotransmission 1.limbic system- mesencephalic pathway emotion 2.cortico- mesencephalic pathway thinking and motion Four pathway of dopaminergic neurotransmission 3.nigrostriatum pathway motion 4.hypothalamo-hypophysis pathway endocrine • DA receptor and neural illness • (1) DA of the substantia nigra striatum pathways can result in Parkinson's disease; • (2) D2 receptor of limbic systemmesencephalic pathway and corticomesencephalic pathway can lead to schizophrenia. 5-hydroxytryptamine, 5-HT distribution: raph nucleus in the middle of lower brain stem Receptor:5-HT1~7receptor 5 - HT : • to participate in the activities of cardiovascular • awakening - a sleep cycle • pain • mental emotional activities • the regulation of the hypothalamus pituitary neuroendocrine activity. Peptide and receptor a. Piptide hormone in hypothalamus b. Opium: β-endorphin μ enkephalin δ dynorphin κ c. Brain-gut peptide d. Cholecystokinin Other transmitters ① ② ③ ④ Histamin: located in hypothalamus NO CO Prostaglandin 4.Mechanism of drugs on CNS (1)axon: slow/block axonal electrical conduction e.g. antiepileptics anaesthetics 4.mechanism of drugs on CNS (2)synapse: most drugs ①affect transmitter: synthesis, storage, release, reuptake. e.g. antidepressants 4.mechanism of drugs on CNS (2)synapse: most drugs ②affect receptor: activation/inhibition(block) e.g. benzodiazepines, antipsychotics ③directly act on ion channels e.g. phenytoin 5.BBB (1) Structure barrier between blood and brain cell; 3 parts barrier between blood and cerebrospinal fluid barrier between brain cell and cerebrospinal fluid. (2)function: restrict passage of polar compounds and macromolecules from blood into brain (3)Pharmacological significance: prerequisite e.g. penicillin----meningitis • SUMMARY Activity of neuron(conduction of nervous impulse) (1) neurotransmitter: ①NA, ACh, DA, GABA, glutamate, glycine, 5HT, histamine, opioid peptides, (excitatory/ inhibitory). ②biosynthesis, storage, release, degradation, reuptake.* (2)receptor * (3)conduction of impulse cross synapse: presynaptic neuron release neurotransmitter synaptic cleft neurotransmitter interacts with receptor neurotransmitter-receptor complex initiates a sequence of events (open ion channel) modulate the electrical activity of the postsynaptic neuron (depolarization/ hyperpolarization). *