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.