神經(jīng)科學講座

PsychopharmacologyCarmelaM.Reichel,PhDAssociateProfessorMedicalUniversityofSouthCarolinaFall2022Objectivesofthislecture.BriefintroductionPharmacokinetics–understandthecomponentsofpharmacokineticsPharmacodynamics–understandthecomponentsofpharmacodynamicsPsychopharmacologyissues–tolerance,dependence,withdrawalNon-associativeandassociativelearning–usingpsychopharmacologyinneurosciencelaboratoriesPsychopharmacologyPsychopharmacologyisthestudyoftheeffectsofdrugs(illicitandprescribed)onmood,sensation,thinking,andoverallbehavior.Thestudyofhowdrugscanbeusedtotreatmentalillness.Psychopharmacologyencompassesawiderangeofsubstanceswithmultiplepsychoactiveproperties,focusingprimarilyonchemicalinteractionsinthebrain.1.IntroductionPharmacologyPharmacokineticsMovementofthedrugthroughthebodyDrugdoseAbsorptionDistributionMetabolismExcretionPharmacodynamicsEffectsofthedrugonthebodyReceptorbindingDoseresponserelationshipsDruginteractionsTolerance1.IntroductionDrugDoseDrugeffectsareprimarilyinfluencedbytheamountofdrugtakenDoseistypicallycalculatedaccordingtoapersonsbodyweight Formula:(desireddosemg/kg)(bodyweightkg)=mgofdrugneededDosageNumberofadministrationsofthedrugperday2.PharmacokineticsDrugmustcrosstheBBBMusttravelfromthesiteofentryintothebodytothebrainviathecirculatorysystemHowmuchofthedrugthatgetstothebraindependsonhowwellthedrugtravelsthroughthebodyandreachesthebrainintact2.Pharmacokinetics-absorptionPharmacokineticsMovementofthedrugthroughthebodyFactorsofpharmacokineticsDrugabsorption GettingthedrugintothebloodstreamDistributionTransportofdrugthroughthebloodtothesiteofactioninthebodyMetabolismThewaythebodybreaksdownthedrugExcretion/elimination2.Pharmacokinetics-absorptionDrugAbsorptionReferstogettingthedrugfromwhereitisadministeredintothebloodstreamTransportacrosscellmembranesPassivediffusionFacilitateddiffusionActivetransportPinocytosis2.Pharmacokinetics-absorptionPassiveDiffusionDiffusionfromhighconcentrationtolowconcentrationatarateproportionaltothegradientdependingon:LipidsolubilityandsizeDegreeofionizationProportionofun-ionizedformandpHoftheenviornment(pKa=aciddissociationconstant)pKa=thepHwhenhalfthedrugisionizedandhalfun-ionizedUn-ionized=lipophilic=readilycrossesIonized=hydophilic=difficultycrossing2.Pharmacokinetics-absorptionFacilitatedDiffusionAcarriermoleculeinthemembranecombinesreversiblywiththedrugoutsidethecellmembraneallowingthedrugtodiffusethroughthemembrane.LimitedbythemolecularconfigurationofthedrugandavailabilityoftransportersDoesnotrequireenergyCannotgoagainsttheconcentrationgradient2.Pharmacokinetics-absorptionActivetransportThemovementofadrugacrossacellmembraneagainsttheconcentrationgradient.Requiresenergy(AdenosineTriphosphate,ATP)Drugssimilartoendogenoussubstances(ions,vitamins,sugars,aminoacids)2.Pharmacokinetics-absorptionPinocytosisThecellmembraneinvaginatestheparticleformingavesiclethatlaterdetachesandmovestothecellinterior.EnergyexpenditureisrequiredMainlytransportproteins2.Pharmacokinetics-absorptionAnotherfactorthateffectsabsorptionRouteofadministrationOral=buccal,sublingual,GIInjection=IV,IP,IM,SCInhalationandintranasalTopical/absorbedthroughskinormembrane2.Pharmacokinetics-absorptionPlasmaConcentrationsofCocaineNotethatthepeakamountsofcocaineandthetimecoursediffersdependingontherouteofadministration2.Pharmacokinetics-absorptionDistributionOncea

drug

entersintosystemiccirculationbyabsorptionordirectadministration,itmustbe

distributed

intointerstitialandintracellularfluids.Thevolumeofdistributionisaproportionalityfactorthatrelatestheamountofdruginthebodytotheconcentrationofdrugmeasuredinabiologicalfluid.

Theextentofdistributionintotissuedependsonplasmaproteinandtissuebinding.2.Pharmacokinetics-distributionReversibleproteinbindingofdrugsInthebloodstream,drugsaretransportedinsolutionasfree(unbound)drugandpartlyreversiblyboundtoplamsaorbloodcells(bound).Albumin(acidicdrugs),alpha-1acidglycoproteinandlipoproteins(basicdrugs)Onlytheunbounddrugisavailableforpassivediffusion,whichdeterminesthedrugconcentrationsattheactivesite.Athighconcentrations,bindingsitescanbecomesaturated.Drugscanbindtoothersubstancesdependingonlipidsolubility.2.Pharmacokinetics-absorptionThiopentalThiopentalishighlylipidsoluble,rapidlyentersthebrainafterasingleIVinjection,producesrapidanestheticeffectslastingonlyafewminutes.Thedrugisredistributedtomoreslowlyperfusedfattytissue.Thiopentalisthenslowlyreleasedfromtheadiposetissuemaintainingasubanestheticplasmalevels.Administrationofmoredrugwillincreasetheamountofdrugstoredinfat.Storageinfatmayinitiallyshortenadrugseffect,butthenprolongsdrugactionbyredistributionintocirculation.2.Pharmacokinetics-absorptionBloodbrainbarrierRegardlessofthelevelsofthedruginsystemiccirculation,adrugcanonlyenterintobraintissueifitcancrossthisbarrier.Theblood-brainbarrierischaracterizedbytightjunctionsbetweenendothelialcellsofthecapillaries,makingitunusuallydifficultforadrugtoexitacapillaryandenterthesurroundingtissue.Theevolutionarysignificanceofthisbarrieristoprotectthebrainfromblood-borneinfectionsandchemicals,whichunfortunatelytranslatesintoaprotectionsystemagainstdrugsaswell.Ifadrug’sdesiredtargetisthebrain,themoleculemustbehighlyhydrophobictoensurepenetrationofthecapillarywall.Serlin,Y.,Shelef,I.,Knyazer,B.,&Friedman,A.(2015).AnatomyandPhysiologyoftheBlood-BrainBarrier.

SeminarsinCell&DevelopmentalBiology,

38,2–6.2.Pharmacokinetics-absorptionProtectivebarriersofthebrain(i)Theblood-brainbarrierproperformedbytightjunctionsbetweentheendothelialcellsofthecerebralvasculature.Itisthoughtthatpericytes(peri.)aresufficienttoinducesomebarriercharacteristicsinendothelialcells,whileastrocytes(astro.)areabletomaintaintheintegrityoftheblood-brainbarrierpostnatallySerlin,Y.,Shelef,I.,Knyazer,B.,&Friedman,A.(2015).AnatomyandPhysiologyoftheBlood-BrainBarrier.

SeminarsinCell&DevelopmentalBiology,

38,2–6.2.Pharmacokinetics-absorptionProtectivebarriersofthebrain(CSF)(ii)Theblood-CSFbarrierformedbytightjunctionsbetweenepithelialcellsofthechoroidplexusepithelialcells.(iii)TheouterCSF-brainbarrierandthelevelofthepiaarachnoid,formedbytightjunctionsbetweenendothelialcellsofthearachnoidvessels(iv)TheinnerCSF-brainbarrier,presentonlyinearlydevelopment,formedbystrapjunctionsbetweentheneuroependymalcellsliningtheventricularsurfaces.Intheadultthisbarrierisnolongerpresent.Boththeblood-brainandCSF-brainbarriersextenddownthespinalcord.TheCSF-filledventricularsystemisdepictedinblue,whileCNSbraintissueisinbrown.Thelateralventricularchoroidplexusesareshowninred.Abbreviations:astro,astrocyte;bv,bloodvessel;cpec,choroidplexusepithelialcell;csf,cerebrospinalfluid;peri,pericytes.Serlin,Y.,Shelef,I.,Knyazer,B.,&Friedman,A.(2015).AnatomyandPhysiologyoftheBlood-BrainBarrier.

SeminarsinCell&DevelopmentalBiology,

38,2–6.2.Pharmacokinetics-absorptionMetabolismThemetabolicbreakdownofthedrugbylivingorganisms,usuallythroughspecializedenzymaticsystemssotheycanbeexcretedinbodyfluids.Liveristhemajorsiteofdrugmetabolism.Firstpasseffect.Mostmetabolitesareinactive,butsomemetabolitesturnintotheactivecompoundorprodrug.Phase1=involvesachemicalreactionsuchasoxidation,reduction,hydrolysis.Phase2=modifiedcompoundsfromphase1areconjugatedtopolarcompoundstobeexcretedfromthekidneyandliver(urineandbile,respectively).2.Pharmacokinetics-metabolismCytochromeP-450ThemostimportantenzymesystemofphaseImetabolismiscytochromeP-450(CYP450),amicrosomalsuperfamilyofisoenzymesthatcatalyzestheoxidationofmanydrugs.CYP450enzymescanbeinducedorinhibitedbymanydrugsandsubstancesresultingindruginteractionsinwhichonedrugenhancesthetoxicityorreducesthetherapeuticeffectofanotherdrug.2.Pharmacokinetics-metabolismRateofMetabolism/ExcretionFirstOrderKinetics-Highconcentrationareexcretedfasterthanlow:smallfractionofthemetabolizingenzyme’ssitesareoccupied,andthemetabolismrateincreaseswithdrugconcentration.Themetabolismrateisaconstantfractionofthedrugremaininginthebody(ie,thedrughasaspecifichalf-life).ZeroOrderKinetics–Contantrate:mostoftheenzymesitesareoccupied,metabolismoccursatitsmaximalrateanddoesnotchangeinproportiontodrugconcentration;instead,afixedamountofdrugismetabolizedperunittime(nospecifichalf-life).Asdrugconcentrationincreases,metabolismshiftsfromfirst-ordertozero-orderkinetics.2.Pharmacokinetics-metabolismElimination/ExcretionLivermetabolizesdrugsintowatersolublemetabolitesThesearethenpassedintourineKidneyremovesdrugsfromthebodymostefficientlywhenconcentrationsarehighEliminationisslowinpsychoactivedrugsbecausethearelipidsolubleExcretiondependsonacidityofurineandacidityofthedrugAcidicdrugs(aspirin)canbeenhancedbymakingurinemorebasic(bicarbonateinsoda)Basicdrugs(morphine)canbeenhancedbymakingurinemoreacidic(vitaminC)Inadditiontourinedrugsandtheremetabolitescanbeexcretedthrough:Feces(oral)LiverbileBreastmilkLungsPerspiration2.Pharmacokinetics-ExcretionSummaryofpharmacokineticsPharmacokineticsMovementofthedrugthroughthebodyDrugdoseAbsorptionDistributionMetabolismExcretionSubjecttoindividualvariables:SexBodyfatHealthAgeMetabolicenzymes2.PharmacokineticsPharmacodynamicsPharmacodynamics(sometimesdescribedaswhatadrugdoestothebody)isthestudyofthebiochemical,physiologic,andmoleculareffectsofdrugsonthebodyandinvolvesreceptorbinding

(includingreceptorsensitivity),postreceptoreffects,and

chemicalinteractions.Pharmacodynamicscombinedwithpharmacokinetics,helpsexplaintherelationshipbetweenthe

doseandresponse.Thepharmacologicresponsedependsonthedrugbindingtoitstarget.Theconcentrationofthedrugatthereceptorsiteinfluencesthedrug’seffect.ReceptorbindingDoseresponserelationshipsDruginteractionsTolerance3.PharmacodynamicsReceptorInteractions3.PharmacodynamicsReceptorInteractions3.PharmacodynamicsDose-ResponseRelationshipsTherelationshipbetweendrugconcentrationatthesiteofactionandtheresponsetothedrugwhichmaybequantifiedatthelevelofmolucule,cell,tissue,organ,organsystem,ororganism.Theserelationshipscanbeusedtoidentifypopulationtrendsfortherequireddoseandfrequency,therapeuticwindows,anddruginteractions.3.PharmacodynamicsEffectincreasesasdrugdoseincreases,thendecreasesasmoredrugisgiven.DoseResponseBi-phasicDoseResponseEffectincreasesasdrugdoseincreases3.Pharmacodynamics100755025DrugEffectDose,mg110100100010,000SomedosesproducenoeffectCharacteristicsDerivedfromDoseResponseFunctionsThresholddose:minimallyrequireddosetoelicitaresponseMaximalresponse:greatestdegreeofagivenresponsethatcanbeachievedwiththatdrugED50=100mgEffectiveDose(ED)50:

?effectivedoseforhalfofthesubjectstested3.PharmacodynamicsLethalorToxicEffect100755025Dose,mg0.010.1110100100010,000TherapeuticorDesiredeffect%PeoplewithDrugResponse

ED50LethalDose50:lethalortoxicdoseforhalfofthesubjectstestedCharacteristicsDerivedfromDoseResponseFunctionsTherapeuticindex:ED50/LD50TherapeuticWindow:Arangeofdosedthatproducearesponsewithoutanadverseeffect.Rangebetweentheminimaleffectiveconcentrationandtheminimaltoxicconcentration.TherapeuticWindowSideEffect:unintendedeffectsthataccompanytherapeuticeffects.3.PharmacodynamicsAffinity,Specificity,andSelectivityAffinity:thestrengthofbindingbetweenthedruganditsreceptorquantifiedbythedissociationconstantkD.Drugconcentrationatwhichreceptoroccupancyishalfofmaximum.HighkD=lowaffinity,rapiddissociation,LowkD=highaffinity,slowdissociationSpecificity:drugactionrelatestothenumberofdifferentmechanismsinvolved.Selectivity:drugsabilitytopreferentiallyproduceaneffectandisrelatedtostructurallyspecificityofdrugbindingtoreceptors.Actsonmorethanonereceptorciteastheconcentrationincreases.3.PharmacodynamicsDrugsdifferintheirefficacyandtheirpotencyEfficacyvs.PotencyEfficacy:Themaximumeffectofwhichthedrugiscapableofproducing.AKA:maximalefficacyorintrinsicactivity.Potency:thedoserequiredtoproduceaspecificintensityofthedesiredeffect

WhichdrughasgreaterEfficacy?

WhichdrugismorePotent?3.PharmacodynamicsDrugpotencycanbealteredbythepresenceofanotherdrugDrug-interactionsCompetitiveantagonist:anantagonistthatwillbindtobutnotactivatethereceptorNonCompetitiveantagonist:anantagonistthatbindstoanallostericsiteonthereceptorpreventingactivationbytheagonistPartialAgonist:Acompoundthatcanactivatereceptorsbutareunabletoelicitthemaximalresponse3.PharmacodynamicsPharmacologyPharmacokineticsMovementofthedrugthroughthebodyAbsorptionDistributionMetabolismExcretionPharmacodynamicsEffectsofthedrugonthebodyDoseeffectcurvesEffectiveandlethaldoseDruginteractionsCharacteristicsofusersBiologicalCharacteristicsInitialsensitivityGeneticallybasedGenderFat/waterratioDrugbindstofat,slowingmetabolismLesswatermeansdrugismoreconcentratedWeightMorefluidandfatAgeIntegrityofenzymesystemsPsychologicalCharacteristicsPersonalitycharacteristicssensationseekingAddictivepersonalityDrugexpectancySocialandenvironmentalfactorsPeoplereportdifferentfeelingsfromalcoholwhendrinkingaloneorwithothersSmokingpotwithsomeone“acting”highvs.notactinghigh,influencedselfreportofmarijuanaeffects4.PsychopharmacologyissuesIssuesinpsychopharmacologyTolerance-

repeatedexposuretothesamedoseofadrugresultsinalessereffect.Therefore,increasinglylargerdosesarerequiredtoachievethesameeffect.Insomecases,theoriginaleffectcanneverbeachievedDependence-

drugusethatresultsinuncontrollablemoodsthatleadtheusertousedrugscompulsivelydespiteobviousadverseeffectsdifferentfromdrugabuse:useofdrugsindosesorwaysthatresultinadverseconsequencesWithdrawal-

Withdrawalisduetochangesinthenervoussystemthatareinplaceinresponsetothechronicpresenceofthedrug5.PharmacodynamicissuesDefinition:repeatedexposuretothesamedoseofadrugresultsinalessereffect.Therefore,increasinglylargerdosesarerequiredtoachievethesameeffect.Insomecases,theoriginaleffectcanneverbeachievedCrosstolerance

?developmentoftolerancetoonedrugresultsinadecreasedsensitivitytoanothertypeofdrugbarbituates/alcoholcocaine/amphetamineToleranceDrugEffectDose(mg)FirstuseLateruseDrugEffectDose(mg)FirstuseLateruse4.Psychopharmacology-ToleranceTypesofTolerancepharmacokinetic(metabolic)tolerance:changesinapharmacokineticparameter(absorption,metabolism,distribution,etc).AdaptationsincytochromeP450changesabsorptionandmetabolismpharmacodynamictolerance:adaptivechangestakingplacewithinthesystemsaffectedbythedrug.Receptorupordownregulationlearnedtolerance:areductionofthedrugseffectduetopastexperienceDrugeffectsareintensifiedwithinaspecificcontext4.Psychopharmacology-ToleranceLearnedTolerance4.Psychopharmacology-Tolerancedrugdependence:drugusethatresultsinuncontrollablemoodsthatleadtheusertousedrugscompulsivelydespiteobviousadverseeffectsdifferentfromdrugabuse:useofdrugsindosesorwaysthatresultinadverseconsequencesDependencepsychologicaldependence:compulsionordesiretoexperienceeffectsofadrugbecauseitproducespleasureorreducesdiscomfortInfluencedbythecontextthepersonisin-resultoflearningandmemoryComesaboutbecauseoftherewardingeffectsofdrugAllabuse-pronedrugsenhancebrainrewardorlowerthethresholdforrewardComesaboutbecausedrug?takingbehaviorisregularlyfollowedbytherewardingeffectsofthedrug.ThedrugreinforcesthebehaviorPsychologicaldependencemayalsoberelatedtoanindividual'sfearsaboutgoingintowithdrawalphysicaldependence:definedbytheoccurrenceofawithdrawalsyndromeWithdrawalsyndrome?setofdefinedsymptomsassociatedwithadecreaseinthebloodlevelsofaparticulardrugUsuallytheeffectsofwithdrawalareoppositefromtheeffectsofthedrugWithdrawalsyndromevariesfromdrugtodrug4.Psychopharmacology-DependenceWithdrawalisduetochangesinthenervoussystemthatareinplaceinresponsetothechronicpresenceofthedrugWhenthedrugisremoved,thecompensatorymechanismsareexposedandanimbalanceresultsChronicuseofadrugwithashortplasmahalflifewillinducearelativelyintensebutshortlastingwithdrawalsyndrome(acuteuseofthisdrugisunlikelytoproduceanysignificantwithdrawaleffects)Conversely,chronicuseofadrugwithalongplasmahalflifewillresultinarelativelyweakabstinencesyndromethatdissipatesslowlyWithdrawalSyndrome4.Psychopharmacology-WithdrawalTypesofbehaviorsinpsychopharmacologyUnlearned–unconditionedReflectivebehaviors–orienting,gag,hotstoveComplexelicitedbehaviors–kinesis,taxisNon-associativeHabituation,sensitizationLearnedPavlovianInstrumentalOverlap5.Non-associativeandassociativelearningTypesofbehavior:UnlearnedUnlearnedReflective–smallestunitofanunconditionedbehaviorWithdrawalfromahotstoveOrientingtoloudnoiseGagreflexComplexelicitedbehaviorsKinesis,taxis,modalactionpatternsCanbemodifiedbyexperience5.Non-associativeandassociativelearningTypesofbehavior:non-associativeNon-associativeHabituation:responsedecreaseswithrepeatedpresentationofthestimulustimestimulusonoffonoffonoffonoffRRRR5.Non-associativeTypesofbehavior:non-associativeNon-associativeSensitization:responseincreaseswithrepeatedpresentationofthestimulustimestimulusonoffonoffonoffonoffRRRR5.Non-associativeUnconditionedbehaviorsNormalgripstrengthHomecageactivityDigging,grooming,thigmotaxis,explorationBeamwalkingBalanceandcoordinationTimetocrossbeam,Falls,slipsPre-trainingeffectsandmotivationalfactorsRotorodRotatingbarrevolvesatconstantorincreasingspeedsLatencytofall–endpointModifiedbyexperience–performancegetsbetterwithpractice5.Non-associativeMotorActivityDruginducedincreasesordecreasesinactivityLocomotionvs.StereotypiesBothhavepurposesBlockadeofapomorphine-inducedsteotypiesbyneurolepticsAntidepressantreversalofreserpinesyndrome10mintimeblocksMcDougalletal.,2008DistanceTraveledStereotypies5.Non-associativeConditionedbehaviors-RelativelypermanentchangeinbehaviorduetopastexperiencePavlovianconditioningClassicalconditioning–IvanPavlovStimulus-stimuluslearningInstrumentalconditioningOperantconditioning–BFSkinnerStimulus-responselearning5.AssociativelearningClassicexample5.AssociativelearningClassicalconditioningdependsonthedegreetowhichtwostimuliarecorrelated.Inthisexperimentonratsatone(theconditionedstimulusorCS)waspairedwithanelectricshock(theunconditionedstimulusorUS)infouroutof10ofthetrials(redticks).Insometrialblockstheshockwaspresentedwithoutthetone(greenticks).Thedegreeofconditioningwasevaluatedbydetermininghoweffectivethetonealonewasinsuppressinglever-pressingtoobtainfood.Suppressionoflever-pressingisasignofaconditioneddefensiveresponse,freezing.(Adapted,withpermission,fromRescorla1968.)A.MaximalconditioningoccurredwhentheUSwaspresentedonlywiththeCS.B–C.Littleornoconditioningwasevidentwhentheshockoccurredwithoutthetoneasoftenaswithit(40%).Someconditioningoccurredwhentheshockoccurred20%ofthetimewithoutthetone.Citation:LearningandMemory,KandelER,SchwartzJH,JessellTM,SiegelbaumSA,HudspethAJ,MackS.PrinciplesofNeuralScience,FifthEdition;2014.Availableat:/content.aspx?bookid=1049§ionid=59138701Accessed:April03,2019Copyright?2019McGraw-HillEducation.Allrightsreserved5.AssociativelearningPavlovianConditioningOperant(instrumental)conditioningresponse/outcomelearningAbehaviorisfollowedbyaresponsesuchthatthefrequencyofthebehaviorchangesPossibleoutcomesofbehaviorPositivereinforcementNegativereinforcementPositivepunishmentNegativepunishmentSchedulesofreinforcementextinction5.AssociativelearningOperant(instrumental)conditioningIncreaseBehaviorDecreaseBehaviorReceivesomethingPositivereinforcement-behavioralstrengtheningprocedureinwhichtheoccurrenceofabehaviorresultsinpresentationofthedesiredstimulusorreinforcerPunishment-behavioralreductionprocedureinwhichtheoccurrenceofthebehaviorisfollowedbyanaversivestimulusLosesomething

Negativereinforcement-behavioralstrengtheningprocedureinwhichanaversivestimulusisremovedoromittedifthebehavioroccursNegativepunishment-behavioralreductionprocedureinwhichtheoccurrenceofbehaviorresultsinremovalofthedesiredstimulus5.Associativelearning5.AssociativelearningConditionedemotionalresponseProcedureinwhichtheCSsignalsanaversiveeventisabouttohappenDependentmeasureistypicallyasuppressionratioAlsocalledconditionedsuppression5.AssociativelearningPhase1Establishbarpressresponseforsucrose(operant)Phase2Introduceaversivestimuli(US)pairedwithaCS(Pavloviandefenseconditioning)ConditionedemotionalresponseSHOCK5.AssociativelearningCond