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Behavioral Pharmacology • Studying drug effects on behavior – Objectively defined behavior – Objective measurement system – Dose range – Control conditions (placebo) – Each subject gets all doses – Visual inspection of data Behavioral Pharmacology Behavioral Pharmacology # aggressions/day Chronic Effects of Drug on Aggression Drug 45 40 35 30 25 20 15 10 5 0 1 2 3 Placebo 4 5 6 7 8 Day Drug 9 10 11 12 13 14 Acute Effects of Thorazine on responding under FR 50 140 120 Resp/min 100 80 60 40 20 0 P 10 mg/kg 20 mg/kg 40 mg/kg Dose NOTE: Single sessions at each dose in BBCD sequence. BBC 10mg BBC 40mg BBC 20 mg BBC 40 mg BBC 10 mg BBC 20 mg BBC 10mg BBC 20mg BBC 40 mg BBC 40 mg BBC 20 mg BBC 10 mg Assays: DMTS Choice stimuli Sample stimulus DMTS: Start FR 5 Delay with no stimuli Delay = 0”, 4”, or 8” Snack Repeat trial % correct DMTS as a Function of Drug and Delay 90 85 80 75 70 65 60 55 50 45 40 0" 4" 8" P 5 mg/kg 10 mg/kg 15 mg/kg Delay NOTE: BBCD Exercises • In DMTS, what is presented first? • Then... • Then... • Then... • DMTS is a study of …. Repeated Acquisition Solution on Day “x”: L R C Reinf Repeated Acquisition: Measures • Rate of response • % correct • # trials to mastery • # minutes to mastery # trials to mastery Repeated Acquisition Data 50 45 40 35 30 25 20 15 10 5 0 Placebo Determination 1 Determination 2 P 1 mg/kg 3 mg/kg 9 mg/kg Dose NOTE: BBCD with 2 determinations at each dose Exercises • Giving drugs during repeated acquisition is an assay of drug effects on _______ • Participants learn to _________ • One dependent variable in repeated acquisition is ___________ • BBCD stands for _________ Drug Discrimination • Initial Training: – Train S to press right button if experiencing d-amphetamine – Train S to press left button if experiencing placebo FR 20 if placebo day FR 20 if drug day Choice Drug Discrimination • Testing: – Give test drugs at various doses to test for similar stimulus properties – If FR 20 (right button) is pressed, then the drug “feels similar” Drug Discrimination • Testing: – Give test drug – See what key is pressed Does not “Feel like” training drug Choice “Feels Like” training drug Exercises • The purpose of a drug discrimination study is to: • The SD in drug discrimination studies is: • Training: Drug is d-amphetamine Testing: Drug is cocaine If chooses the drug button: Conclusion? Phase Years Population Purpose Success Rate PreClinical 3.5 Lab and animals Safety and bio activity 5000 tested Phase 1 1 20-80 Healthy Volunteers Safety and dose 5 enter Phase 2 2 100-300 patient volunteers Efficacy and side effects 5 enter Phase 3 3 1000-3000 Efficacy & adverse reactions to longer term use 5 enter FDA 2.5 Review and approval Phase 4 Additional post marketing study required by FDA 1 approved 10 mg 15 mg 5 mg 5 mg Poling • 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 Poling • 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 Poling 3 design factors – Single vs repeated observations Pre-post testing vs daily recording – Between subject vs within subject Between – either Tx or P Within – each subject gets all conditions – Stats vs visual T tests, F tests vs visual inspection Poling Fig 9-3. Use of anti-psychotics w/MR Many drug studies not well done – Measurement – Design – Dose range Data recording methods –See Fig 95. Poling MPH study – Fig 9-4 – – – – DV Design concerns Results Inter-subject replication Poling • Clozaril study Fig 9-6 – Random assignment to 1 or 2 groups; Clozaril vs Thorazine. Rating scales used. – Other studies are correlational – take people with drug and those without, and then compare behavior. Poling • Between vs within subject designs – Depends on the kind of question – Predictions of % affected – Nature of effects • Behavioral mechanisms of drugs – All behavioral functions of other stimuli – MO, SD, CS, US, reinforcers, punishers Poling Review 3 design factors: – Single vs repeated observations – Between vs within – Stats vs visual Poling Review • Difference between typical and atypical – Affinity for D1/D2 vs D3/D4 • Behavioral mechanisms of drugs – – – – – MO SD Reinforcer/punisher CS US McKim: Cannabis McKim: Cannabis • • • • Source- plants Active ingredient - THC Hashish - dried resin from top Hash oil? – Boil hash in alcohol, filter out residue, allow alcohol to evaporate (cannabinoids are soluble in alcohol) • Thai sticks: buds bound with string onto short sections of bamboo or stems • Spread by Scythians in 200 BC • Also known in China 6000 years ago 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 McKim • Kinetics – Administration/Absorption: • Slow absorption orally • Fast if inhaled – Distribution • Lipid soluble so goes everywhere • Collects in liver, lungs, intestines – Metabolism • Liver • Many metabolites: some are active – Excretion • T ½ - biphasic: 30 min then 20-30 hours McKim • Neuropharmacology – – – – CB1 found in CNS CB2 found in spleen and immune system Endogenous cannibinoids – THC is stronger Potentiate NE, DA, SE, ACH, endogenous opiates • Effects on body – – dilation of eye vessels, hunger, dry mouth, increase in HR • Medicinal uses – decrease in intraocular pressure, antiemetic, movement disorder, spasticity, analgesia McKim • Other effects – Sleep – will increase, but can disrupt on high doses – Perceptual effects – can disrupt time discrimination, decrease pain – Many things appear funny, dreamy state – Memory problems – disrupts short term memory – Attention – disrupts attention – Driving – problems with attention – Aggression decrease – Immune system – may depress McKim • Relation to Korsakoff’s syndrome? – Korsakoff’s is seen in alcoholics and has memory problem and disorientation. – Caused by damage to hippocampus, which has CB receptors – Cannabis may block functions of hippocampus • Tolerance – Non-humans – yes – Humans –sensitization? some tolerance • W/D syndrome – Increase in anxiety, restlessness, irritability; AO for food McKim • Health risks – Will not produce psychosis. But, will increase intensity of schiz symp or paranoia • Effects on brain or “intellectual” functioning? – Rats – yes – Monkeys – no – Humans – no. But might be problems in memory and attention. • Amotivational syndrome? – NH – some evidence in PR schedules – Humans – none. McKim • Gateway drug? – No. • Lung cancer? – There are 50-70% more carcinogenic material. • Decrease in testosterone • It may potentiate cigarette smoke • Weakens immune system McKim • Study by Kelly et al. wherein participants smoked placebos as often as 2.3% THC. – Single access vs choice – What was the reason for this outcome? – What is more sensitive procedure was for assessing preference Poling Review • Source of cannibis – Marijuana plant • Receptors – CB1 & CB2 • Effects – – – – Dilation of capillaries in eyes EO for food Dry mouth Increase HR McKim: Hallucinagens • LSD: – Hallucinogen class – similar to serotonin – Source – synthetic drug, but similar chemicals exist in ergot fungus that infects grains – SE agonist/antagonist • Kinetics – Oral administration; absorbed in stomach – Metabolized? – Liver – T ½ - 2 hours – Typical dose – 300 mics or less – Effects – dilation of pupils, hallucinations, early sweating, nausea, jaw grinding – Not lethal McKim • Psilocybin – – – – – – Hallucinogen class – similar to serotonin Source – mushrooms Duration of action – 4-6 hours Dose – 4-8 mg Mechanism – SE agonist/antagonist Not lethal McKim • Mescaline – – – – – – Hallucinogen class – similar to NE Source – cactus called peyote Ceremonies by Native American Church Usual dose – 200 mg Effects – nausea, dilation, hallucinations Not lethal McKim • MDMA/MDA (ecstasy) – – – Hallucinogen class – similar to NE Usual dose – 100 mg Effects – euphoria, state of well being, talkative, EO for everything High dose may deplete serotonin – • Sleep problems, anxiety, hostility, impulsiveness, selective impairment of memory/attention, depression, heat regulation – – Typical use – rave drug Mechanism – causes release and blocks reuptake of SE, NE, DA – heart, liver damage, hyponatremia (low blood NA from drinking excessive water) McKim • Atropine – Similar to ACH – – – – Anticholinergic Dilates pupils Used pre-surgically to reduce drooling/secretions Increase HR for bradychardia McKim • PCP – Source – synthesized; “angel dust” – Use – originally an anesthetic and analgesic – Effects -trancelike state, disorientation, fear/anxiety, some psychosis – Blocks NMDA receptor, which is excitatory – resp for reinforcing effects – PCP has its own receptor on the NMDA receptor – When PCP occupies, it blocks the ion channel NE, DA, ACH, SE – Lethality problem: TI of 10 – Long term psychosis Poling Review • 3 classes of hallucinogens – SE – LSD/psilocybin – NE – Mescaline/Ecstasy – ACH - atropine • Effects of LSD – Hallucinations – Pupil dilation • Sources – LSD – synthetic – Mescaline – peyote – Psilocybin - mushroom Poling • Health risks Review – Ecstasy • Serotonin depletion • Dehydration • Heart trouble – PCP • Psychosis • Lethal Count Per Minute 07-Mar 14-Mar-04 21-Mar 28-Mar 04-Apr 11-Apr-04 18-Apr 25-Apr 02-May 09-May-04 16-May 23-May 30-May 06-Jun-04 0.001 29-Feb 0.01 0.005 22-Feb 0.1 0.05 15-Feb-04 0.5 08-Feb 1 01-Feb 10 5 25-Jan 100 50 18-Jan-04 1000 500 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 Successive Days (Per Week) Standard Chart 10 behaviors in 10 minutes Count Per Minute 07-Mar 14-Mar-04 21-Mar 28-Mar 04-Apr 11-Apr-04 18-Apr 25-Apr 02-May 09-May-04 16-May 23-May 30-May 06-Jun-04 0.001 29-Feb 0.01 0.005 22-Feb 0.1 0.05 15-Feb-04 0.5 08-Feb 1 01-Feb 10 5 25-Jan 100 50 18-Jan-04 1000 500 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 Successive Days (Per Week) Standard Chart 100 behaviors in 50 minutes Count Per Minute 07-Mar 14-Mar-04 21-Mar 28-Mar 04-Apr 11-Apr-04 18-Apr 25-Apr 02-May 09-May-04 16-May 23-May 30-May 06-Jun-04 0.001 29-Feb 0.01 0.005 22-Feb 0.1 0.05 15-Feb-04 0.5 08-Feb 1 01-Feb 10 5 25-Jan 100 50 18-Jan-04 1000 500 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 Successive Days (Per Week) Standard Chart 5/minute and observed for 1 minute Count Per Minute 07-Mar 14-Mar-04 21-Mar 28-Mar 04-Apr 11-Apr-04 18-Apr 25-Apr 02-May 09-May-04 16-May 23-May 30-May 06-Jun-04 0.001 29-Feb 0.01 0.005 22-Feb 0.1 0.05 15-Feb-04 0.5 08-Feb 1 01-Feb 10 5 25-Jan 100 50 18-Jan-04 1000 500 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 Successive Days (Per Week) Therapeutic and Toxic Effects 100 Therapeutic 80 % Responding Toxic 60 40 ED99 20 TD50 TD1 ED50 0 70 80 90100 200 Dose 300 Indices Lidocaine Quantal Dose-Effect 100 80 % 60 Achieving Complete 40 Analgesia ED90 = 490 mg ED50 = 400 mg 20 0 100 1000 Total Lidocaine Dose (mg) Ferrante et al. Anesth Analg 82:91-7, 1996 SIB – Naltrexone effects SIB – Naltrexone effects SIB – Naltrexone effects SIB – Naltrexone review • Criteria for inclusion – Primary focus was the effect of naltrexone – Ss were diagnosed with ID – SIB was measured – Peer refereed English language journal – Results were in a quantitative format – Short-term or acute trials SIB – Naltrexone effects SIB – Naltrexone effects D-Amphetamine as SD/SDP Risperdal: Effects on matching MPH: FA Results Neurogenesis: Factors