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Tolerance, withdrawal, sensitization and conditioned drug effects

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Title: Tolerance, withdrawal, sensitization and conditioned drug effects


1
Tolerance, withdrawal, sensitization and
conditioned drug effects
2
Tolerance
  • Tolerance can develop to different effects of a
    drug at different rates and disappear at
    different rates
  • Some effects may never develop any tolerance
  • It is better to think of tolerance developing to
    the effects of a drug rather than to the drug.

3
Tolerance
  • Decreased effectiveness (or potency) of a drug
    after repeated administrations
  • Increase in the dose in order to obtain the same
    effect after repeated administrations

ED50 increases with repeated administrations
4
Tolerance
Can apply to potency the ED50 is shifted to the
right with repeated administrations Or
effectiveness the maximum effect is
diminished Or both the ED50 is shifted to the
right and the maximum effect is lowered
5
Types of tolerance
  • Cross tolerance repeated administration of one
    drug diminishes the effect of another drug
  • Tachyphylaxis tolerance that develops after one
    or two administrations
  • Acute tolerance tolerance that takes place
    during a single administration.

6
Mechanisms of tolerance
  • Metabolic (dispositional) tolerance
  • Changes in the bodys ability to metabolize a
    drug
  • enzyme induction

7
Tolerance
  • Physiological tolerance (pharmacodynamic or
    cellular tolerance)
  • Arises from a homeostatic process
  • Set point
  • Compensatory mechanism
  • Compensatory mechanism gets stronger as the drug
    is taken and weakens when the drug is stopped

8
Tolerance
  • General or Nonspecific tolerance
  • Tolerance that takes place at a drugs only
    site of action or as a result of metabolic
    induction.
  • All drug effects diminish at the same time
  • Specific Tolerance
  • Tolerance that takes place in specific
    systems and may be independent of other drug
    effects

9
Tolerance
  • Behavioral tolerance Tolerance that arises from
    learning or conditioning mechanisms.

10
Tolerance
  • Because tolerance usually arises from a
    homeostatic mechanism, the drug must cause a
    functional disturbance for tolerance to occur.
  • Tolerance does not develop to the hypothermic
    effects of a drug if the animal is kept warm.
  • Tolerance to analgesia develops slowly in an
    animal that is not exposed to painful stimuli
    after being given an analgesic (morphine).

11
Withdrawal
  • Physical dependence the state where withdrawal
    or abstinence symptoms will occur when the drug
    is discontinued
  • Cross tolerance where Drug A will stop
    withdrawal symptoms caused by Drug B

12
Withdrawal
  • The word dependence should only be used to refer
    to the fact that a drug can cause withdrawal
    symptoms, not to the state of compulsive use or
    addiction.
  • Physical dependence is not the crucial factor in
    addiction.
  • There is no way of knowing if psychological
    dependence exists. It is therefore not a useful
    explanatory concept for addiction.

13
Withdrawal and Tolerance
  • Solomon and Corbits opponent process theory
  • A-process euphoria
  • B-process compensatory response - disphoria

14
Withdrawal and tolerance
15
Withdrawal and Tolerance
  • Hangover expression of compensatory response
    after a single administration
  • Withdrawal expression of a compensatory response
    after repeated administrations

16
Wothdrawal and Compensatory Responses
17
CDP lever
Barrett and Smith Experiment Rats were trained
to discriminate between CDP (an anxiolytic) and
PTZ (an anxiogenic). They were then given a
single administration of CDP. At first they
responded on the CDP lever (meaning they felt
calm), but later they responded on the PTZ lever
(meaning that they felt agitated). Finally, this
effect went away and they responded equally on
both levers.
PTX lever
18
Tolerance and Conditioning
  • Pavlov experiment
  • Tone CS apomorphine UCS
  • salivation UCR (drug effect)
  • Tone salivation CR (same as UCR)

19
Tolerance and Conditioning
  • Tone CS Morphine UCS
  • analgesia UCR ( pain sensitivity)
  • Tone hyperalgesia CR ( pain
    sensitivity)
  • The UCR is the opposite of the CR!! WHY?

20
Tolerance and Conditioning
  • Morphine has two effects
  • A process analgesia
  • B process (compensatory response) hyperalgesia

TONE CS
Most of the time the B process becomes the CR
21
Tolerance and Conditioning
  • Most of the time a conditioned drug effect will
    be opposite of the drug effect, i.e. the
    compensatory response.
  • The withdrawal response is the compensatory
    response.
  • Therefore drug withdrawal is usually conditioned
    to stimuli associated with the drug.

22
Siegel - conditioned compensatory response and
tolerance
  • Rats showed increases in paw lick latency when
    given morphine - analgesia
  • Rats developed tolerance to the analgesic effect
    of morphine, paw lick latency decreases to normal
    with repeated exposure.
  • Tolerance to morphine disappeared when rats were
    tested in a new environment.
  • Rats given a placebo in test environment showed
    hyperalgesia.

23
Tolerance and Withdrawal
  • Withdrawal will be intensified in the presence of
    stimuli that usually signal that the drug is
    coming because the subject will experience both
    unconditioned and conditioned compensatory
    responses.
  • Because of absorption, low blood levels always
    signal high blood levels of a drug. For this
    reason, low doses of a drug can cause withdrawal
    symptoms.

24
Siegel experiment on heroin withdrawal
Group 1 morphine and withdrawal in same test
environment Group 2 morphine in home cage and
withdrawal in test environment Group 3 no
morphine
25
Tolerance and Withdrawal
  • When a drug is taken in a new environment, there
    will be less conditioned compensatory response
    and the drug will have an enhanced effect.
  • Might explain mysterious OD in heroin users.

26
  • Siegel Experiment
  • Tolerance phase
  • Rats were given 30 daily injections of either
    heroin or placebo
  • Group 1 Heroin in Room A and placebo in Room B
    alternately
  • Group 2 Placebo in Room A and Heroin in Room B
    alternately
  • Group 3 Placebo in both room A and B
    alternately
  • Testing Phase
  • All rats were given lethal dose of heroin (15
    mg/Kg)
  • ST rats were given Heroin in the same room they
    had received heroin previously
  • DT rats were given Heroin in a different room
    from which they had received heroin
  • Control rats were given Heroin in either room.

27
  • Siegel Experiment
  • Results
  • Control group - 96 died of overdose
  • no tolerance
  • ST group 32 died of an overdose
  • tolerance
  • DT group 64 died of overdose
  • partial tolerance no conditioned tolerance

28
Tolerance and Operant Conditioning
  • Campbell and Seiden experiment
  • Training 28 sessions on DRL
  • Group 1 amphetamine DRL
  • Group 2 DRL - amphetamine
  • Day 29 all got amphetamine before DRL
  • Results
  • Group 1 showed tolerance to amphetamine on day 29
  • Group showed no tolerance to amphetamine on day
    29

29
Tolerance and Operant conditioning
  • Animals can learn to alter their behavior to
    overcome the effect of a drug if they are
    reinforced for doing so.
  • Tolerance develops to the effects of amphetamine
    on DRL faster than it does to the effects of
    amphetamine on FI

30
Sensitization
  • The effects of a drug increase when administered
    repeatedly
  • Not mirror image of tolerance
  • only some drugs and some effects
  • measures of activity and stereotypy
  • lasts a long time and may increase with time

31
Sensitization
  • Usually self-administered drugs such as cocaine,
    amphetamine, nicotine, heroin and morphine.
  • Cross sensitization between drugs and other
    conditions like stress. Eg stress increases the
    effect of these drugs.
  • Can be conditioned to environments. Drug-like
    effect is conditioned
  • Brain mechanisms that are sensitized control
    activation and motivation and may play a part in
    drug addiction.

32
Expectancy and Context
  • Placebo effect If we know we are getting a drug
    we will experience the effect we expect. There is
    an expectation pathway in the brain. It is a
    top down mechanism that modifies the effect of
    drugs on pain (Benedetti experiment).
  • Volkow experiment. PET scans showed stronger
    response to methylphenidate if the participants
    were expecting the drug and reported a stronger
    high.

33
Expectancy and Context
  • Drugs have a greater activating effect when given
    in a novel environment
  • Drug sensitization is faster and stronger when
    the drug is administered in a novel environment.
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