behavioral pharmacology studying drug effects on behavior studying drug effects on behavior...

Behavioral PharmacologyBehavioral Pharmacology

• Studying drug effects on behaviorStudying drug effects on behavior– Objectively defined behaviorObjectively defined behavior– Objective measurement systemObjective measurement system– Dose rangeDose range– Control conditions (placebo)Control conditions (placebo)– Each subject gets all dosesEach subject gets all doses– Visual inspection of dataVisual inspection of data

Behavioral Behavioral PharmacologyPharmacology

Chronic Effects of Drug on Chronic Effects of Drug on AggressionAggression

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Acute Effects of Thorazine Acute Effects of Thorazine on responding under FR on responding under FR 5050

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Assays: DMTSAssays: DMTS

Sample stimulus

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ExercisesExercises

• In DMTS, what is presented first?In DMTS, what is presented first?

• Then...Then...

• Then...Then...

• Then...Then...

• DMTS is a study of ….DMTS is a study of ….

Repeated AcquisitionRepeated Acquisition

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• % correct% correct

• # trials to mastery# trials to mastery

• # minutes to mastery# minutes to mastery

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NOTE: BBCD with 2 determinations at each dose

ExercisesExercises

• Giving drugs during repeated acquisition Giving drugs during repeated acquisition is an assay of drug effects on _______is an assay of drug effects on _______

• Participants learn to _________Participants learn to _________

• One dependent variable in One dependent variable in repeated acquisition is ___________repeated acquisition is ___________

• BBCD stands for _________BBCD stands for _________

Drug DiscriminationDrug Discrimination• Initial Training:Initial Training:

– Train S to press right button if Train S to press right button if experiencing d-amphetamineexperiencing d-amphetamine

– Train S to press left button if Train S to press left button if experiencing placeboexperiencing placebo

FR 20 if drug day

FR 20 if placebo day

Choice

Drug DiscriminationDrug Discrimination

• Testing:Testing:– Give test drugs at various doses to test Give test drugs at various doses to test

for similar stimulus propertiesfor similar stimulus properties– If FR 20 (right button) is pressed, then If FR 20 (right button) is pressed, then

the drug “feels similar”the drug “feels similar”

Drug DiscriminationDrug Discrimination• Testing:Testing:

– Give test drugGive test drug– See what key is pressedSee what key is pressed

“Feels Like” training drug

Does not “Feel like” training drug

Choice

ExercisesExercises• The purpose of a drug discrimination The purpose of a drug discrimination

study is to:study is to:

• The SD in drug discrimination studies The SD in drug discrimination studies is:is:

• Training: Drug is d-amphetamineTraining: Drug is d-amphetamineTesting: Drug is cocaineTesting: Drug is cocaineIf chooses the drug button: If chooses the drug button: Conclusion?Conclusion?

PhasePhase YearsYears PopulationPopulation PurposePurpose Success Success RateRate

PreClinicalPreClinical 3.53.5 Lab and Lab and animalsanimals

Safety and Safety and bio activitybio activity

5000 tested5000 tested

Phase 1Phase 1 11 20-80 20-80 Healthy Healthy VolunteersVolunteers

Safety and Safety and dosedose

5 enter5 enter

Phase 2Phase 2 22 100-300 100-300 patient patient volunteersvolunteers

Efficacy Efficacy and side and side effectseffects

5 enter5 enter

Phase 3Phase 3 33 1000-30001000-3000 Efficacy & Efficacy & adverse adverse reactions to reactions to longer term longer term useuse

5 enter5 enter

FDAFDA 2.52.5 Review and Review and approvalapproval

1 approved1 approved

Phase 4Phase 4 Additional post marketing study required by FDAAdditional post marketing study required by FDA

10 mg 15 mg 5 mg 5 mg

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• Behavior change meds mechanism not well understood

• We know about NT, but not link with behavior.

• 4 essential features of a drug evaluation?

• DV

• Meds given according to protocol

• Design

• Data analysis must be adequate

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• Prescribing drugs to special populations in need of protection should involve safeguards. • Goals are clear with specific targets and in P interests

• Tx decisions made on basis of drug effects

• Flexible and integrated with beh Tx.

• 3 design factors

• Single vs repeated observations

• Between vs within

• Stats vs visual

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3 design factors 3 design factors – Single vs repeated observations Single vs repeated observations

Pre-post testing vs daily recordingPre-post testing vs daily recording

– Between subject vs within subjectBetween subject vs within subject Between – either Tx or PBetween – either Tx or P Within – each subject gets all conditionsWithin – each subject gets all conditions

– Stats vs visualStats vs visual T tests, F tests vs visual inspectionT tests, F tests vs visual inspection

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Fig 9-3. Fig 9-3. Use of anti-psychotics w/MRUse of anti-psychotics w/MR Many drug studies not well doneMany drug studies not well done

– Measurement Measurement – DesignDesign– Dose rangeDose range

Data recording methods –See Fig 9-Data recording methods –See Fig 9-5.5.

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MPH study – Fig 9-4MPH study – Fig 9-4– DVDV– Design concernsDesign concerns– ResultsResults– Inter-subject replicationInter-subject replication

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• Clozaril study Fig 9-6Clozaril study Fig 9-6– Random assignment to 1 or 2 Random assignment to 1 or 2

groups; Clozaril vs Thorazine. groups; Clozaril vs Thorazine. Rating scales used.Rating scales used.

– Other studies are correlational – Other studies are correlational – take people with drug and those take people with drug and those without, and then compare without, and then compare behavior.behavior.

• Between vs within subject Between vs within subject designs designs

– Depends on the kind of question Depends on the kind of question – Predictions of % affectedPredictions of % affected– Nature of effectsNature of effects

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• Behavioral mechanisms of drugsBehavioral mechanisms of drugs– All behavioral functions of other All behavioral functions of other

stimulistimuli– MO, SD, CS, US, reinforcers, MO, SD, CS, US, reinforcers,

punisherspunishers

3 design factors:3 design factors:– Single vs repeated observations Single vs repeated observations – Between vs within Between vs within – Stats vs visualStats vs visual

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• Difference between typical and Difference between typical and atypicalatypical

– Affinity for D1/D2 vs D3/D4Affinity for D1/D2 vs D3/D4

• Behavioral mechanisms of drugsBehavioral mechanisms of drugs– MOMO– SDSD– Reinforcer/punisherReinforcer/punisher– CSCS– USUS

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McKim: Cannabis

• Source- plantsSource- plants

• Active ingredient - THCActive ingredient - THC

• Hashish - dried resin from topHashish - dried resin from top

• Hash oil?Hash oil?– Boil hash in alcohol, filter out residue, Boil hash in alcohol, filter out residue,

allow alcohol to evaporate allow alcohol to evaporate (cannabinoids are soluble in alcohol)(cannabinoids are soluble in alcohol)

• Thai sticks: buds bound with string Thai sticks: buds bound with string onto short sections of bamboo or onto short sections of bamboo or stems stems

• Spread by Scythians in 200 BCSpread by Scythians in 200 BC

• Also known in China 6000 years Also known in China 6000 years agoago

McKim: Cannabis

McKim: Cannabis

Scythians: “There is nothing new or strange in what we do. We follow our mode of life in peaceful times. We have neither towns nor cultivated lands in these parts which might induce us, through fear of their being ravaged, to be in any hurry to fight you. But if you must needs come to blows with us speedily, look about you, and behold our fathers' tombs. Attempt to meddle with them and you shall see whether or not we will fight with you."

McKim: Cannabis

• KineticsKinetics– Administration/Absorption: Administration/Absorption:

• Slow absorption orallySlow absorption orally

• Fast if inhaledFast if inhaled

– DistributionDistribution• Lipid soluble so goes everywhereLipid soluble so goes everywhere

• Collects in liver, lungs, intestinesCollects in liver, lungs, intestines

– MetabolismMetabolism• LiverLiver

• Many metabolites: some are activeMany metabolites: some are active

– ExcretionExcretion• T ½ - biphasic: 30 min then 20-30 hoursT ½ - biphasic: 30 min then 20-30 hours

McKim

• NeuropharmacologyNeuropharmacology– CB1 found in CNSCB1 found in CNS– CB2 found in spleen and immune CB2 found in spleen and immune

systemsystem– Endogenous cannibinoids – THC is Endogenous cannibinoids – THC is

stronger stronger – Potentiate NE, DA, SE, ACH, Potentiate NE, DA, SE, ACH,

endogenous opiatesendogenous opiates

• Effects on body – Effects on body – – dilation of eye vessels, hunger, dry dilation of eye vessels, hunger, dry

mouth, increase in HRmouth, increase in HR

• Medicinal usesMedicinal uses– decrease in intraocular pressure, anti-decrease in intraocular pressure, anti-

emetic, movement disorder, spasticity, emetic, movement disorder, spasticity, analgesia analgesia

McKim

• Other effectsOther effects– Sleep – will increase, but can disrupt Sleep – will increase, but can disrupt

on high doseson high doses– Perceptual effects – can disrupt time Perceptual effects – can disrupt time

discrimination, decrease paindiscrimination, decrease pain– Many things appear funny, dreamy Many things appear funny, dreamy

statestate– Memory problems – disrupts short Memory problems – disrupts short

term memoryterm memory– Attention – disrupts attentionAttention – disrupts attention– Driving – problems with attentionDriving – problems with attention– Aggression decreaseAggression decrease– Immune system – may depressImmune system – may depress

McKim

• Relation to Korsakoff’s syndrome?Relation to Korsakoff’s syndrome?– Korsakoff’s is seen in alcoholics and Korsakoff’s is seen in alcoholics and

has memory problem and has memory problem and disorientation. disorientation.

– Caused by damage to hippocampus, Caused by damage to hippocampus, which has CB receptorswhich has CB receptors

– Cannabis may block functions of Cannabis may block functions of hippocampushippocampus

• ToleranceTolerance– Non-humans – yesNon-humans – yes– Humans –sensitization? some Humans –sensitization? some

tolerancetolerance

• W/D syndrome W/D syndrome – Increase in anxiety, restlessness, Increase in anxiety, restlessness,

irritability; AO for foodirritability; AO for food

McKim

• Health risksHealth risks– Will not produce psychosis. But, will Will not produce psychosis. But, will

increase intensity of schiz symp or increase intensity of schiz symp or paranoiaparanoia

• Effects on brain or “intellectual” Effects on brain or “intellectual” functioning?functioning?

– Rats – yesRats – yes– Monkeys – noMonkeys – no– Humans – no. But might be problems Humans – no. But might be problems

in memory and attention.in memory and attention.

• Amotivational syndrome?Amotivational syndrome?– NH – some evidence in PR schedulesNH – some evidence in PR schedules– Humans – none.Humans – none.

McKim

• Gateway drug?Gateway drug?– No.No.

• Lung cancer?Lung cancer?– There are 50-70% more carcinogenic There are 50-70% more carcinogenic

material.material.

• Decrease in testosteroneDecrease in testosterone

• It may potentiate cigarette smokeIt may potentiate cigarette smoke

• Weakens immune systemWeakens immune system

McKim

McKim

• Study by Kelly et al. wherein Study by Kelly et al. wherein participants smoked placebos as participants smoked placebos as often as 2.3% THC. often as 2.3% THC.

– Single access vs choice Single access vs choice – What was the reason for this outcome? What was the reason for this outcome?

– What is more sensitive procedure was What is more sensitive procedure was

for assessing preferencefor assessing preference

• Source of cannibisSource of cannibis– Marijuana plantMarijuana plant

• ReceptorsReceptors– CB1 & CB2CB1 & CB2

• EffectsEffects– Dilation of capillaries in eyesDilation of capillaries in eyes– EO for foodEO for food– Dry mouthDry mouth– Increase HRIncrease HR

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• LSD:LSD:– Hallucinogen class – similar to serotoninHallucinogen class – similar to serotonin– Source – synthetic drug, but similar Source – synthetic drug, but similar

chemicals exist in ergot fungus that chemicals exist in ergot fungus that infects grainsinfects grains

– SE agonist/antagonistSE agonist/antagonist

• KineticsKinetics– Oral administration; absorbed in stomachOral administration; absorbed in stomach– Metabolized? – LiverMetabolized? – Liver– T ½ - 2 hoursT ½ - 2 hours– Typical dose – 300 mics or lessTypical dose – 300 mics or less– Effects – dilation of pupils, hallucinations, Effects – dilation of pupils, hallucinations,

early sweating, nausea, jaw grindingearly sweating, nausea, jaw grinding– Not lethalNot lethal

McKim: Hallucinagens

• PsilocybinPsilocybin– Hallucinogen class – similar to Hallucinogen class – similar to

serotoninserotonin– Source – mushroomsSource – mushrooms– Duration of action – 4-6 hoursDuration of action – 4-6 hours– Dose – 4-8 mgDose – 4-8 mg– Mechanism – SE agonist/antagonistMechanism – SE agonist/antagonist– Not lethalNot lethal

McKim

• MescalineMescaline– Hallucinogen class – similar to NEHallucinogen class – similar to NE– Source – cactus called peyoteSource – cactus called peyote– Ceremonies by Native American Ceremonies by Native American

ChurchChurch– Usual dose – 200 mgUsual dose – 200 mg– Effects – nausea, dilation, Effects – nausea, dilation,

hallucinationshallucinations– Not lethalNot lethal

McKim

• MDMA/MDA (ecstasy)MDMA/MDA (ecstasy)– Hallucinogen class – similar to NEHallucinogen class – similar to NE– Usual dose – 100 mgUsual dose – 100 mg– Effects – euphoria, state of well being, Effects – euphoria, state of well being,

talkative, EO for everythingtalkative, EO for everything– High dose may deplete serotoninHigh dose may deplete serotonin

• Sleep problems, anxiety, hostility, Sleep problems, anxiety, hostility, impulsiveness, selective impairment of impulsiveness, selective impairment of memory/attention, depression, heat memory/attention, depression, heat

regulationregulation – Typical use – rave drugTypical use – rave drug– Mechanism – causes release and blocks Mechanism – causes release and blocks

re-uptake of SE, NE, DAre-uptake of SE, NE, DA– heart, liver damage, hyponatremia (low blood NA heart, liver damage, hyponatremia (low blood NA

from drinking excessive water)from drinking excessive water)

McKim

• Atropine – Similar to ACHAtropine – Similar to ACH– AnticholinergicAnticholinergic– Dilates pupilsDilates pupils– Used pre-surgically to reduce Used pre-surgically to reduce

drooling/secretionsdrooling/secretions– Increase HR for bradychardiaIncrease HR for bradychardia

McKim

• PCPPCP– Source – synthesized; “angel dust”Source – synthesized; “angel dust”– Use – originally an anesthetic and Use – originally an anesthetic and

analgesicanalgesic– Effects -trancelike state, Effects -trancelike state,

disorientation, fear/anxiety, some disorientation, fear/anxiety, some psychosispsychosis

– Blocks NMDA receptor, which is Blocks NMDA receptor, which is excitatory – resp for reinforcing effectsexcitatory – resp for reinforcing effects

– PCP has its own receptor on the NMDA PCP has its own receptor on the NMDA receptor receptor

– When PCP occupies, it blocks the ion When PCP occupies, it blocks the ion channel NE, DA, ACH, SEchannel NE, DA, ACH, SE

– Lethality problem: TI of 10Lethality problem: TI of 10– Long term psychosisLong term psychosis

McKim

• 3 classes of hallucinogens3 classes of hallucinogens– SE – LSD/psilocybinSE – LSD/psilocybin– NE – Mescaline/EcstasyNE – Mescaline/Ecstasy– ACH - atropineACH - atropine

• Effects of LSDEffects of LSD– HallucinationsHallucinations– Pupil dilationPupil dilation

• SourcesSources– LSD – syntheticLSD – synthetic– Mescaline – peyoteMescaline – peyote– Psilocybin - mushroomPsilocybin - mushroom

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• Health risksHealth risks– EcstasyEcstasy

• Serotonin depletionSerotonin depletion

• DehydrationDehydration

• Heart troubleHeart trouble

– PCPPCP• PsychosisPsychosis

• LethalLethal

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Therapeutic and Toxic Therapeutic and Toxic EffectsEffects

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Lidocaine Quantal Dose-Lidocaine Quantal Dose-EffectEffect

% % Achieving Achieving Complete Complete AnalgesiaAnalgesia

Total Lidocaine Dose (mg)Total Lidocaine Dose (mg)Ferrante et al. Anesth Analg 82:91-7, 1996Ferrante et al. Anesth Analg 82:91-7, 1996

EDED5050 = 400 mg = 400 mg

EDED9090 = 490 mg = 490 mg

SIB – Naltrexone effectsSIB – Naltrexone effects

SIB – Naltrexone reviewSIB – Naltrexone review

• Criteria for inclusionCriteria for inclusion– Primary focus was the effect of Primary focus was the effect of

naltrexonenaltrexone– Ss were diagnosed with IDSs were diagnosed with ID– SIB was measuredSIB was measured– Peer refereed English language Peer refereed English language

journaljournal– Results were in a quantitative Results were in a quantitative

formatformat– Short-term or acute trialsShort-term or acute trials

SIB – Naltrexone effectsSIB – Naltrexone effects

D-Amphetamine as SD/SDP

Risperdal: Effects on matching

MPH: FA Results

Neurogenesis: Factors

behavioral pharmacology studying drug effects on behavior studying drug effects on behavior...

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