Transcript No Slide Title

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)
Name of Behaver:
Movement Cycle:
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)
Name of Behaver:
Movement Cyc
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)
Name of Behaver:
Movement Cycle:
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)
Name of Behaver:
Moveme
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