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Introduction to the pharmacology of CNS drugs

Introduction to the pharmacology of CNS drugs

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Introduction to the pharmacology of CNS drugs

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  1. Introduction to thepharmacologyof CNS drugs Domina Petric, MD

  2. I. Ion channelsandneurotransmitterreceptors

  3. Themembranesof nerve cellscontaintwotypesofchannels:

  4. Voltage-gatedchannels • Voltage-gatedchannelsrespond to changesinthe membrane potentialofthecell. • In nerve cells, voltage-gatedsodiumchannels are concentrated on theinitial segment and on theaxon. • Thesechannels are responsible for thefastactionpotential, whichtransmitsthe signal fromcellbody to nerve terminal.

  5. Voltage-gatedchannels • There are manytypesofvoltage-sensitivecalciumandpotassiumchannels on thecellbody, dendritesandinitial segment, whichact on a muchslower time scaleandmodulatethe rate at whichthe neuron discharges.

  6. Voltage-gatedchannels • Some typesofpotassiumchannelsoponedbydepolarizationofthecellresultinslowingoffurtherdepolarizationandact as a brake to limit furtheractionpotentialdischarge.

  7. Neurotransmittersbind on:

  8. Ionotropicreceptors • The receptor consistsofsubunits. • Bindingofliganddirectlyopensthechannel. • Channel is an integral partofthe receptor complex. • Thesechannels are insensitive or onlyweaklysensitive to membrane potential.

  9. Ionotropicreceptors • Activationofionotropicreceptorsresultsin a brief (afewmilliseconds to tensofmilliseconds) openingofthechannel. • Ligand-gatedionotropicchannels are responsible for fastsynaptictransmissiontypicalofhierarchicalpathwaysinthe CNS.

  10. Metabotropicreceptors • These are seven-transmembrane G protein-coupledreceptors. • Binding to the receptor engages a G protein, whichresultsintheproductionofsecondmessengersthatmodulatevoltage-gatedchannels.

  11. Membrane-delimitedpathways

  12. Diffusiblesecondmessengers

  13. Metabotropicreceptors • Membrane-delimitedactionsoccurwithinmicrodomainsinthe membrane. • Secondmessenger-mediatedeffectscanoccuroverconsiderabledistances. • Theeffectsofmetabotropic receptor activationcanlasttensofseconds to minutes.

  14. Metabotropicreceptors

  15. II. Thesynapseandsynapticpotentials

  16. Synapses • Thecommunicationbetweenneuronsinthe CNS occursthroughchemicalsynapsesinthemajorityofcases. • Electricalcouplingbetweenneuronsmayplay a role insynchronizingneuronaldischarge.

  17. Propagationofactionpotential • Anactionpotentialinthepresynapticfiberpropagatesintothesynaptic terminal andactivatesvoltage-sensitivecalciumchannelsinthe membrane ofthe terminal. • Calciumflowsintothe terminal. • Theincreaseinintraterminalcalciumconcentrationpromotesthefusionofsynapticvesicleswiththepresynaptic membrane.

  18. Propagationofactionpotential • Thetransmittercontainedinthevesicles is releasedintothesynapticcleftanddiffuses to thereceptors on thepostsynaptic membrane. • Bindingofthetransmitter to its receptor causes a brief change in membrane conductance (permeability to ions) ofthepostsynapticcell.

  19. Propagationofactionpotential

  20. EPSP

  21. IPSP

  22. IPSP • Theopeningofthechloridechannelduringtheinhibitorypostsynapticpotentialmakesthe neuron leaky. • Changesin membrane potential are more difficult to achieve. • Thisshuntingeffectdecreasesthe change in membrane potentialduringtheexcitatorypostsynapticpotential.

  23. Presynapticinhibition • Axoaxonicsynapsesreducetheamountoftransmitterreleasedfromtheterminalsofsensoryfibers. • Presynapticinhibitoryreceptorsare present on almost all presynapticterminalsinthebrain. • Axoaxonicsynapses are restricted to thespinalcord.

  24. III. Cellularorganizationofthebrain

  25. Cellularorganizationofthebrain

  26. Hierarchicalsystems

  27. Hierarchicalsystems • Informationinhierarchicalsystems is typicallyphasicandoccursinburstsofactionpotential. • Insensorysystems, theinformation is processedsequentiallybysuccessiveintegrations at eachrelaynucleus on itsway to thecortex: a lesion at any link incapacitatesthesystem.

  28. Twotypesofcells are:

  29. Projectionneurons • Theprojectionneuronsformtheinterconnectingpathwaysandtransmitsignalsoverlongdistances. • Thecellbodies are relativelylarge. • Theiraxonsemitcollateralsthatarborizeextensivelyinthevicinityofthe neuron. • Theseneurons are excitatory.

  30. Projectionneurons

  31. Localcircuitneurons • Localcircuitneurons are smallerthanprojectionneurons. • Theiraxonsarborizeintheimmediatevicinityofthecellbody. • Most oftheseneurons are inhibitory: theyreleaseGABA or glycine.

  32. Localcircuitneurons • Theysynapseprimarilyon thecellbodyoftheprojectionneurons. • Theycanalsosynapse on thedendritesofprojectionneuronsas wellaswitheachother. • Twocommontypesofpathways are recurrentfeedbackpathwaysandfeed-forwardpathways.

  33. Localcircuitneurons • A specialclassoflocalcircuitneurons are axoaxonicsynapseson theterminalsofsensoryaxonsinthespinalcord. • Intheretina andolfactorybulb, localcircuitneuronsmaylackanaxonandreleaseneurotransmitterfromdendriticsynapsesin a gradedfashion, intheabsenceofactionpotential.

  34. Nonspecific (diffuse) systems Neuronalsystemsthatcontain one ofthemonoamines: • norepinephrine • dopamine • 5-hydroxytryptamine (serotonin)

  35. Example: noradrenergicneurons

  36. Noradrenergicneurons • Theseaxons are fine andunmyelinated. • Theyconductveryslowly at about 0,5 m/s. • Theaxonsbranchrepeatedlyand are extraordinarilydivergent. • Branchesfromthe same neuron caninnervateseveralfunctionallydifferentpartsofthe CNS.

  37. Noradrenergicneurons • Intheneocortex, thesefibershave a tangentialorganizationandcanmonosynapticallyinfluence largeareasofcortex. • Thepatternofinnervationbynoradrenergicfibersinthecortexandnucleiofthehierarchicalsystem is diffuse.

  38. Literature • Katzung, Masters, Trevor. Basicandclinicalpharmacology.