2. The Bridge Between Neuronal
Communication and
Tolerance, Sensitization, Dependence &
Withdrawal
Repeated exposure to a drug causes changes to the
structure and functioning of neurons of the CNS.
3. Tolerance
• Tolerance: diminished response to administration of
drug after repeated exposure to that drug
– What should be considered when a drug has more than
one effect?
• Therapeutic Index (ED/ LD)
• Mragin of Safety
– How quickly can tolerance develop?
• Tachyphylaxis (psychadelics like LSD)
• Acute Tolerance
– What happens when a person stops taking the drug?
• Abstinence Syndrome, Withdrawal
• Is tolerance reversible?
– Other considerations regarding tolerance?
• Compulsive drug taking and addiction?
4. Tolerance
• Tolerance: diminished response to administration of
drug after repeated exposure to that drug
– 3 Major Types of Tolerance
– PK: metabolic Concentration
and
– PD: functional, non-associative Exposure Time
– Behavioral: context-specific, learned, associative
• Behavioral and Environmental Manipulations
• Learning and Memory
5. Tolerance
• Drug Disposition Tolerance a.k.a. Metabolic Tolerance or PK
Tolerance: usually enzyme induction
– A drug can produce effects that reduce its own bioavailability (i.e.,
concentration at target site)
– How might the appearance of drug disposition tolerance in tolerant
and non-tolerant subjects change based on route of administration?
• Peak effect and duration of action
• Non-tolerant & Tolerant Animals
– I.V. administration of ED50 and LD50
– Sub-Q administration of ED50 and LD50
• Slow absorption routes vs. fast absorption route (I.V.)
6. Tolerance
• PK Cross-tolerance: the development of tolerance
to one drug can diminish pharmacological
effectiveness of a second drug based on enzyme
actions.
– Which drugs might you expect to show cross-
tolerance?
7. Tolerance
• Pharmacodynamic Tolerance: compensatory
mechanisms; cellular tolerance
– Two types: General or Non-Specific and Specific
» General: all effects of drug are diminished to the same
extent
» Specific: specific to a particular drug effect
• develops independently of other tolerance mechanisms
• appearance or disappearance of specific tolerance may occur at different
rates
» We can relate PD tolerance to homeostatic
mechanisms because of its compensatory nature (i.e.,
system is trying to regain balance)
8. Tolerance
• General or Nonspecific Type: all effects of drug
are diminished to the same extent
• When might we expect “up-regulation” mechanisms to occur?
– i.e. receptor up-regulation, increased pre-synaptic neurotransmitter
release
– Sensitization: increased activity at receptor
• When might we expect “down-regulation” mechanisms to occur?
– i.e. receptor down-regulation, decrease in pre-synaptic
neurotransmitter release
– Desensitization: decrease in receptors ability to elicit cellular changes
upon agonist binding
9. Tolerance
• Specific Tolerance
– Effect of drug must lead to functional disturbances,
placing demand on homeostatic mechanism.
» Return to set-point:
» Amphetamine-Anorexia
» Alcohol-Hypothermia
» Morphine-Analgesia
10. Tolerance
• PD Cross-tolerance: the development of tolerance
to one drug can diminish pharmacological
effectiveness of a second drug based on receptor-
neurotransmitter interaction changes.
– Which drugs might you expect to show PD
cross-tolerance?
11. PK and PD Tolerance Wrap Up
• Purely physiological mechanisms
• Rate at which tolerance develops is dependent upon
drug dose and frequency of use (dosage)
– Large doses administered in short intervals of time
– Moderate doses administered in moderate intervals of time
– Smaller doses administered in longer intervals of time
• Threshold dose for each drug, below which
tolerance would not be expected to develop
– No induction of metabolic or cellular changes
12. Behavioral Tolerance
• Behavioral Tolerance (a.k.a. context-specific
tolerance): experience with a drug leads to decrease in
effect drug is having
• Three Processes of Behavioral Tolerance
– Habituation (S-R)
– Pavlovian Conditioning (Classical)
– Instrumental Conditioning (Operant)
13. Behavioral Tolerance
• Habituation
S R
• Stimulus: any event, external or internal that is
capable of activating receptors in sensory system
• Response: measurable reaction in organism; i.e.
NT release, heart rate, etc…
• Why is this NOT the same as PD tolerance?
14. Behavioral Tolerance
• Pavlovian Conditioning & Conditioned Compensatory
Response
UCS UCR
CS CR
• Unconditioned Stimulus: UCS like heroin
• Unconditioned Response: UCR is a variety intended + unintended effects
• Conditioned Stimulus: CS like environmental cue (or psychological state)
• Pairing of 2 Stimuli (UCS + CS)
• Conditioned Compensatory Response: a response elicited that is opposite to
the drug induced effects; reduced effectiveness of UCS
• What happens when you change the environment?
– Rat Paw-Lick Test
– Human Heroin Overdose
15. Behavioral Tolerance
• Instrumental Conditioning (in Skinner Box)
Drug Behavior Reward
Behavior Reward Drug
• Instrumental: behavior is necessary for conditioning process to occur
• Consequences: reinforcers or punishers
• DRL schedule: differential reinforcement of low-rates (low rates of responding get reinforced)
• Amphetamine will stimulate responding behavior; reinforcement will decrease
• Animals pretreated with amphetamine showed tolerance to its stimulant effects, whereas
animals treated after session did not show tolerance
• Rats developed behavioral strategy for overcoming the effect of amphetamine when the
behavior was rewarded
16. Behavioral Tolerance
• General Implications
– In order for tolerance to develop, the organism must perform the task under
the influence of the drug
– Behaviors not affected detrimentally by drug, or those that are enhanced, will
show no tolerance
– Tolerance developed is task-specific
• i.e., alcohol and driving vs. alcohol and typing
– Tolerance developed can generalize
• i.e., learning to maintain balance on bicycle or motorcycle while intoxicated
– Rate of development of tolerance can be altered with task-difficulty
• i.e., humans and alcohol (walking vs. driving)
– Behavioral cross-tolerance can occur when drugs produce similar behavioral
effects
• i.e., overcoming slurred speech with barbiturate may transfer to alcohol
– Tolerance should last relatively long time because learning is defined as a
relatively permanent change
17. Sensitization or Reverse Tolerance
• Occurs when the effect of a drug increases with
repeated administrations
– Ex: cocaine, amphetamines, nicotine, alcohol, opiates
in animal models
• With low dose, first administration causes activating
responses such as motor activity and rearing behavior
– Repeated administration of low dose causes progressive
increase in these behaviors
18. Sensitization or Reverse Tolerance
• Context Specific
– Put animal in new context and sensitization does not
appear
• Environment where drug administration occurs
can become a CS for sensitization, eliciting the
CR
– Placebo injection
19. Sensitization or Reverse Tolerance
• Cross-sensitization can occur
– Morphine, cocaine, amphetamine
• Sensitization has greater persistence than
tolerance
– In rats, lasts up to 1 year
– Can increase with time
