Control

bioavailability of
drugs
→ measures of
behavioural
effects

Research methods in
psychopharmacology
 Validity in research.

“anxiety, mood,
disordered thoughts”

“anxiety, mood, Parallel or predict

disordered thoughts” Clinical tests

Important to apply findings in lab animals to humans: if claiming to study pain relief
(content validity) the drug use should predict pain relief (predictive validity)
especially in humans (face validity)

Face validity→ for pain: rat grimace scale vs humans communication

For depression: Forced swim test vs human survey . Eg. may have predictive validity
without strong face validity
Reliability in research: valid research must be
reliable
• Reliably get same result every time test is done
• Otherwise cannot generalize findings
• not useful - especially common when studies move from animal to human
• Different techniques vary in reliability and validity
• Use Convergent findings
Optimal animal behaviour tests
have predictive validity AND:
• Specific
• to the drug type (eg. anticonvulsant)
• to the Behaviour (eg. seizure onset)
• Sensitive
• Physiologically relevant
• within a safe dose of drug (based on TI)
• Dose-response curve!!!!
• show a dose-response relationship

• Rank order of potency → ?

• Ranking drugs by efficacy
• Rank drugs by therapeutic action
• by dose that is effective

Anticonvulsants; % increase in time until seizure onset

Neurobiological techniques (review)
• In vivo vs in vitro
• Stereotaxic surgery
• Lesion, microinjection, electrode record or stimulate (see ICSS),
microdialysis, voltammetry (real time measurements)
• Histology for proteins, receptors, or ligands
• Quantify, activity, tissue distribution
• Human and animal Brain imaging
• PET*, fMRI, MRI, EEG,
• *pre and post drug
Running studies--- In glass ---or ---in the living
system

Tracking delivery and

distribution of
nanoparticles

Less variables, but

Poorer predictive
validity in vitro
 Neurobiological techniques
• Stereotaxic surgery allows for direct manipulation or drug delivery to brain areas
• Lesion, microinjection, electrode record or stimulate (see ICSS), microdialysis, voltammetry
(real time measurements)
Collection is slower 1- 5 min

MFB stim
increase DA
release

Collection is fast 1- 5 msec MFB stim the LH →VTA

 Neurobiological techniques (review)
• Histology for proteins, receptors,
or ligands
• Quantify, activity, tissue
distribution
• Provide clues about drug mechanism
or expected drug effects

Need longitudinal
measures, using
single time point
can cause gross
• Human and animal Brain imaging
misinterpretation • PET*, fMRI, MRI, EEG,
• *pre and post drug
 Compare cocaine to bathsalts

Behavioural techniques Similar mechanism of action: DAT

blocker

• Help identify
• Neurochemical basis of behaviour
• Dopamine and movement
• Drug induced changes in behaviour
• Cocaine and locomotion
• Develop animal models of psychiatric disorder
• Screening newly synthesized drugs preclinical
• Which is more potent?
• …can we expect the same effects in humans?
Translational research: Translating animal models
to humans Most drugs fail here

• Cannot easily mimic many

human conditions
• Normally requires genetic
mutation
• Unclear how animal
findings translate to human
condition
• Use Tasks that map onto
both human and non human
behaviours
• Eg. Stop-signal task:
Measures impulsivity
• Or inhibition?
• Or both?
• Need for specificity
simple behaviours are useful and easy to
measure
• Tremor, defecation, reflex, feeding or drinking, sedation,
anaesthetic plane, eyelid drooping, toe pinch
• Catalepsy
• Motor side effect of antipsychotic
• Motor activity (assess sleep vs locomotion)
• Photo beams, video tracking, open field test
• Analgesia
• grimace scale
• Tail flick test
• Avoidance of pain (negative reinforcement)
• Learning and memory
• Water and land Mazes spatial
• Anxiety
• EPM, conflict test (approach-avoidance), ultrasonic
vocalization,open field test
• Fear
• Conditioned; potentiated startle
Delayed response task
• Measure of PFC damage
• assess working memory
• Altered in addicts
• Chicken-egg
• Match to place (location) or visual cue (sample)
Measuring reward: evaluate reinforcing
(“euphoric”)effects
Assess rewarding or
Often several aversive effects
pairings

• Conditioned place preference (CPP)

• classical conditioning of associating drug effect (UCR)
with drug context (CS)
• Associate drug effect with environment/ no drug with
other neutral environment
• Testing under no drug
• Study mechanism by treating with antagonist, lesion,
neurotoxin, etc.
• Measure of addiction potential?
• certainly discriminate aversion vs reward from
drug
• Most addictive drugs show CPP
 Measuring reward: evaluate reinforcing
(“euphoric”)effects
• Operant conditioning (RL)
• Consequences control behaviour
• Response to Obtain reward or avoid punishment
• Eg. Press lever=reward
• Often use Skinner box (operant chamber)
• Establish behaviour alter reinforcement
schedule (see next slide)
• Can assess drug preference by including 2
levers
• Iv. Self administration by lever press
Schedules of reinforcement controls rate and
pattern of
• Fixed ratio
behaviour
• Reward after fixed number of responses
• Eg. “FR-3”
• many drugs administered on a variable ratio
schedule (VR-3)
• Increasing ratio indicates reward value
• Breaking point
• Higher=more reinforcing; greater abuse
potential
• Self-administration method
• Assess abuse potential in humans
• most valid model
• Can assess drug preference by having different
drugs on different levers Dose response curve;
comparing drugs of same class
• Fixed Interval (appetite suppressant)
• Reward after fixed time period
• Scalloped responding
 Use schedules of reinforcement to study
neurobiological mechanism of “reinforcement”
• Electrical self-stimulation of “reward
circuit” (MFB stimulation)\
• Intracranial self stimulation (ICSS)
• Change in activity→ change
neurotransmission→ reward
• First assess current needed to produce
ICSS
• Then provide drug and reduce current ,
if Drug+low level stim=ICSS suggest
drug interacts with circuit
• Drug acting to produce same effect as
high stim
• Useful to understand reward circuit and
how drugs affect it
 discriminative stimuli indicate possibility of
reinforcement
• Sd=any stimulus that signals reinforcement possible in operant task
• Chamber lights
• Tones
• Vibrations
• Lever extension
 Drugs effects, and their internal cues, can act
like discriminative stimuli Higher THC
lever selection=
• When under influence of drug- acts as Sd feels more like
that a behaviour will be THC
reinforced/punished
• Approach lever for internal cues associated with
drug state; but not cues unassociated
• Can assess similarities and differences in internal
states produced by drugs of similar or different
class
• Eg. THC vs cocaine All still have lots of
lever presses, just
AMPH and coc
animals do not
press THC
associated lever
 Behavioural techniques in the scope of drug
use and addiction
• Environmental stimuli reliably associated with
reward
• Predict reward S→ R
• Eg. See chips→ nom nom
• Can arouse motivation (incentive)
• Eg. See chips, crave jube jubes→ walk to Mac’s
Most self-administration techniques use both operant
and classical conditioning

• Operant learning: Behaviours that result in reward

(incentive value) OR ESCAPE PUNISHMENT
• Drug taking behaviours
• Drug seeking behaviours
• Classical conditioning: relationships between
drug-related stimuli and rewards
• Stimuli provide predictive value
• Stimuli can also provide incentive value (induce craving)
• Difficult to disentangle incentive from predictive
value of cues
Pavlovian conditioned
approach (PCA)
• Valuable for studying addiction vulnerability
• Measure incentive motivation cues
• Currently no test for humans
• Uses operant chambers, no drug- just food reward, in a
classical conditioning task
• Incentive stimuli (lever) and predictive stimuli (food
magazine) dissociated
• by seeing where CR is directed
PCA shows rats are learning the
CS is predictive or CS is
incentive
• Autoshaping
• Always get 1 banana pellet (US) when well-lit, vibrating lever
(CS) extends
• CS=predictive value
• Variable interval schedule
• Sign tracker (ST)
• Direct CR towards lever
• CS predictive and incentive
• DA release to lever
• More vulnerable to cue-induced reinstatement of drug use
• Goal tracker (GT)
• Direct CR toward reward magazine
• CS predictive
• Intermediate
• Unbiased
• CS not always predictive or incentivized
• Shows predictive value of reward-related cue is not always
incentive
• in GT vs in ST
 incentive stimuli as the generators of
motivational states and elicitors of actions
• Incentive:
1. Attractive, eliciting approach, multimodality of sensory experience
important
2. Motivate or support ongoing operant actions
3. Acts as a Conditioned reinforcer: Reinforce learning new actions

They want you to interact!!!

 incentive stimuli as the generators of
motivational states and elicitors of actions
• an Incentive stimulus Acts as a
Conditional reinforcer: Reinforce
learning new actions
1. reMove magazine and move lever
2. Introduce nose poke holes
3. Active vs inactive port causes retraction
of lever
4. ST see lever as incentive stimulus
• Learned new behaviour to access it
• Still interacted with lever even though
limited availability
• Ineffective incentive for GT
Incentive stimuli Can be the drug itself or the
stimuli associated with the drug taking
• EX .The coffee addiction Starbuck’s wants you to have
• Approach, gift cards, buy beans, make own, buy mugs
• Capitalism wants us all to be Sign trackers
• Incentivized by this brand but not competing brands

They want you to interact!!!

 Individual differences in attributing incentive
salience to environmental cues
• Early life stress→ increase ST
• Increase propensity to attach incentive
salience to stimuli
• Different breeding colonies
• ST more impulsive
• Poor at delay discounting
• Incentive=DA response
• CS=larger DA response in ST
Addiction is a drug “habit”? Not necessarily, get
addicted without acquiring habit
• Animal studies model addiction using S-R paradigms
• Reinforced for interacting with drug-related stimuli
• Real-world addicts do more than S-R; must be flexible and
relational to acquire drugs
• Cannot form a habit
• Drug seeking=incentive=dopamine
• Closer to accessing drug more incentivizing
Mimicking flexible drug seeking behaviours in
animals
• Puzzle self-administration procedure (PSAP)
• Signal that can acquire (light)
• Drug available; puzzle off/light off
• Solve puzzle→ cocaine
• Repeating behaviours (habits) would not gain access
 • Repeating behaviours (habits) in PSAP would not allow drug access but still get “addiction “

• Still get “addiction”

• Increased intake
• Increased seeking in lights on
• Sensitized motivation
• Continued drug use despite aversion
• Therefore can develop addiction in
absence of drug habit
• Seeking behaviour is mediated by
consequences
A rest stop. un repose. ᓇᑮᐏᐣ (nakîwin)