Drug Tolerance, Withdraw,

Sensitization and Dependence

Drug Tolerance

Mithradates, 63 B.C., tries to commit suicide by

poisoning himself

He had been defeated by the Roman general Pompey and

his son led a successful revolt against him
The attempt fails
Why?
Out of fear of being poisoned to death, he had been
ingesting increasing amounts of poison until he could
tolerate them without ill effects
Drug tolerance

Drug Tolerance

Decreased effectiveness (potency) of a drug

that results from repeated administration
The necessity of increasing the dose of a
drug in order to maintain its effectiveness
Not all effects of a drug show tolerance at the
same rate, or at all
Develop tolerance to effects of drugs, not to
the drugs themselves

Mechanisms of Tolerance

Metabolic Tolerance

Increase in the rate at which the body

metabolizes and eliminates a drug
Usually enzymatic
Will diminish all drug effects

Mechanisms of Tolerance

Physiological Tolerance

Bodys response to drugs controlled by

homeostatic mechanisms
Processes initiated to maintain a set point
Adjustments made by the body to compensate for
the effects of the continued presence of a drug
May include entire systems particular to a single
drug effect (e.g., increased body temperature)
Or at the level of a single cell (e.g., increasing or
decreasing the number of receptors, or altering
the amount of neurotransmitter release)

Mechanisms of Tolerance

Tolerance will develop in a circumstance

where a drug places demand on an
organisms homeostatic mechanism
Tolerance to drug effects that are not
detected or that do not disrupt functioning
does not develop

Mechanisms of Tolerance

Behavioral Tolerance

Learned or conditioned tolerance through

experience with a drug

Behavioral Tolerance based on

Classical Conditioning

Classical Conditioning

An animal (including people) learn to produce

reflexive responses to previously neutral stimuli

i.e., stimuli that initially produce no observable response

Learning = a relatively permanent change in

behavior as the result of experience
If a neutral stimulus (in the past caused no
response) is paired with a stimulus that reflexively
causes a response, the neutral stimulus will come
to cause a similar response

The Terminology

Unconditioned (al) Stimulus (US)

It is the biologically significant event that

reflexively causes a response

Unconditioned Response (UR)

The reflexive response to the US

The Terminology

Conditioned Stimulus (CS)

The neutral stimulus to be paired with the US.

Does not produce any significant response at the start of
conditioning

Conditioned Response (CR)

A response often similar to the UR

Made to the CS even when US is not present

The Start of conditioning

The US produces a UR but CS produces

nothing
US (meat powder)
CS (tone)
Response
(salivation)
TIME

Acquisition trials

Also reinforced or training trials

The CS and US are repeatedly paired
US
CS
R
Question: Is the R a UR or a CR?
How can we find out?

Test trails

Present the CS ONLY on an occasional trial

intermixed among reinforced (CS-US) trials
If CS alone produces a response, it is a CR
Learning (conditioning) is measured as the strength
of the CR

Or as the percentage of test trials on which a CR occurs

What would happen if you presented a block of CS

only trials?

Extinction trials

Present the CS only for a BLOCK of trials

No CS-US pairings occur during the block

What will happen to the CR?

It will dissipate

Typical Findings
Asymptote

CR strength

80
70
60
50
40
30

Line 1

Spontaneous Recovery

20
10
0
acq

acq

acq

acq

ext

training

ext

ext

ext

More phenomenon

Subject makes a CR to
stimuli similar in some way
to the CS
Only one CS has ever been %CR
directly paired with the US (it
is the CS+)
All others are CSStrength of CR is a function
of similarity to original CS+
Called Stimulus
Generalization

60
40
20
0
CS-

CS+

CS-

similarity to CS+

More phenomenon

With repeated exposure

to CS+ (always paired
with US) and CS(never paired with US)
the subject learns to
discriminate between
the two
Stimulus Discrimination

80
70
60
50
40

% CR

30
20
10
0
CS-

CS+

Pavlovs Cerebral Conditioning

Theory

Pavlovs is a contiguity theory

Contiguous=next or near in time or sequence

a US and CS need only be contiguous for
conditioning (learning) to occur

It is also a stimulus substitution view

i.e, the CR is a weakly activated UR

The Nature of the CR

Is it just a weak UR?

US
UR

CR

Bright light

Pupil constriction

food

Salivation

same
same

shock

Muscle contraction

same

Air puff

eyeblink

same

shock

Increase HR

Decrease HR

The Nature of the CR

If mimicking the UR would be adaptive, the

CR will be the same
If mimicking the UR would be maladaptive,
the CR will be opposite
Consider morphine

US = drug
UR = analgesia (reduced sensitivity to pain) or
euphoria

The Nature of the CR

CR = Hypoanalgesia (Increased sensitivity to pain!!!)

or Dysphoria.
Opponent Process Theory

USs that produce opposite CRs tend to be emotional,

either positive or negative.
The body adapts to emotional stimuli by producing an
opposite reaction (an opponent process)
The idea is that the body is attempting to maintain a stable
emotional baseline (homeostasis)

Opponent Process Theory

180
160
140
120
100
80
60

UR
OP

40
20
0
1

Opponent Process Theory

Now suppose there is a stimulus that reliably

predicts the US
A CS? What might some of these be for morphine or
heroin?
What happens if the CS is presented without the
US?
Drug tolerance, overdose, craving, withdraw
What about diet coke?

Operant Conditioning

Not all behaviors are reflexive in nature

Some are ACTS ON THE ENVIRONMENT
These behaviors also change with
experience
i.e., learning

B.F. Skinner

There are 2 types of responses and therefore 2

types of learning
Operant behavior

Emitted responses
Operant = interaction with the environment in order to obtain
reinforcement
Learning associated with operants is Type R learning
Operant Conditioning

B.F. Skinner

DV = response rate, or operant strength

Reinforcement affects operant strength
Learning = changes in operant strength

B.F. Skinner

Skinner attempted to identify environmental

factors that influenced operant strength
Response rate
LEARNING

Cumulative recording of
responses
Min
1
2
3
4
5
6

BP
2
3
7
3
0
0

CBP
2
5
12
15
15
15

16
14
12
10

cbp
bp

8
6
4
2
0
1

Classifying Reinforcers

Primary

Things that are naturally reinforcing (no learning or

conditioning required)
Innate, biological significance
Food, water, shelter, sex

Secondary

Acquire reinforcing properties only through learning

(conditioning)
Not initially reinforcing themselves
Money, tokens, stars

Classifying Reinforcers

Positive

Negative

Causes an increase in operant strength when it occurs

Increases the probability of a response that precedes it
Causes an increase in operant strength when it is removed
Increases the probability of a response that precedes it
removal

As a model of drug taking

Drugs are self-administered because they act as reinforcers

Attempts to Decrease Operant Strength

Punishment

Causes a decrease in operant strength when it occurs

Decreases the probability of a response that precedes it

Omission Training

Causes a decrease in operant strength when it is removed

Decreases the probability of a response that precedes its
removal

Dependence and addiction

Addiction

The addicted individual has impaired control over the use of

the drug
The drug use has harmful consequences

Addiction as physical dependence

Dependence

Discontinuation of the drug causes withdraw symptoms, or

A person compulsively takes a drug
These are not the same
Physical vs Psychological dependence
Homeostatic theory vs reinforcement theory