Tolerance & Dependence
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Transcript Tolerance & Dependence
Tolerance
Definition: Diminished drug effectiveness or
potency resulting from repeated (chronic)
use.
Decreased efficacy
○ Downward shift
Decreased potency
○ Rightward shift
Cross Tolerance
When tolerance to one drug diminishes the
effects of another drug
Often observed between members of same
drug class
All opiates display cross-tolerance
Alcohol may exhibit cross-tolerance with other
substances with similar pharmacological actions,
such as the benzodiazepines (e.g., Valium, Xanax)
Mechanisms of Tolerance
Metabolic (dispositional) Tolerance
e.g., Alcohol and barbiturates increased liver
enzyme activity.
e.g., Amphetamine alters urine pH, making it more
acidic, which increases excretion of amphetamine.
Physiological (pharmacodynamic, cellular)
Tolerance
e.g., receptor affinity or number altered by drug
actions
disruption of homeostatic processes may be critical
Behavioral Tolerance
Learning to compensate for drug-induced
impairments
respondent or operant conditioning
Physical Dependence
Withdrawal symptoms
Physiological changes when chronic drug use is
stopped
Particular withdrawal symptoms depend on the
drug
○ Opiate withdrawal: flulike symptoms
○ Alcohol withdrawal: DTs, possible seizures
○ Many drugs do not produce PHYSICAL
dependence
○ Drugs with similar actions tend to produce similar
withdrawal symptoms
Cross Dependence
Drugs with similar actions will alleviate withdrawal
symptoms from another drug.
○ e.g., methadone for heroin dependence,
benzodiazepines for alcohol dependence
Tolerance and Respondent
Conditioning
Respondent Conditioning of Drug
Effects
Pavlov’s early work with apomorphine
Conditioned Compensatory Responses
the CR may not be opposite the UR
The body’s attempts to resist the drug’s
effects, rather than the drug effects
themselves may be what are conditioned.
Siegel’s research on respondent
conditioning of tolerance to the
analgesic effects of morphine in rats.
Tolerance and Respondent
Conditioning
Conditioned Compensatory Responses
May be difficult to extinguish
May persist long after physical withdrawal
symptoms no longer evident
Environmental cues may contribute to
relapse
Tolerance and Operant
Conditioning
Campbell and Seiden (1973)
Tolerance to amphetamine in rats treated
prior to DRL training sessions, not after.
Schuster et al. (1966)
Tolerance did not develop to rate-increasing
effects of amphetamine on an FI schedule.
Vogel-Sprott (1992)
role of reinforcement in conditioned
tolerance to alcohol in humans
Sensitization
Enhance effects of drug following
repeated exposure
Less common than tolerance
Most often studied in nonhuman species
○ Activating effects of drugs
Conditioned sensitization
Cross sensitization
Models of Addiction
Disease Model
Physical Dependence Model
Positive Reinforcement Model
Disease Model
Historical Background
Social reform of the 19th century
AA movement of the mid-20th century
Potential Strengths of Disease Model
Considers addictive behavior abnormal
Explains why only some develop addiction
Implications for Therapy vs. Punishment
Disease Model
Problems/Limitations of Disease Model
Mechanisms not well understood
Accepting “loss of control” as an explanation
may reduce the addicts accountability
Characterizing addiction as a disease
Predisposition Theories
Exposure Theories
Acceptance/rejection of the disease model
depends on the definition of “disease”,
more so than an understanding of
mechanisms responsible for addiction.
Physical Dependence Model
Historical Background
Drug seeking motivated by fear of
severe withdrawal symptoms.
What about drugs that don’t produce
physical dependence?
Defining Psychological Dependence
Problems/Limitations Dependence
Theories of Addiction
Positive Reinforcement Model
Modern Behavioral Neuroscience
Explanation for Addiction
Based on key findings that many drugs can
be established as positive reinforcers
Problems with Positive Reinforcement
Model
Drug Self-Administration
Similarities/Differences Between Human
and Nonhuman Species
Type of Drug
○ Most psychoactive drugs that are abused by
humans are also self-administered by
nonhumans.
○ Some drugs (e.g., LSD) are not selfadministered by nonhumans.
Patterns of Self-Administration
○ Patterns of use are comparable between
humans and monkeys (see figure 5-2)
Measuring Reinforcing Value of
Drugs
Rate: not an ideal measure
Progressive Ratio Schedules
Concurrent Schedules (choice)
Place Conditioning Procedures
Factors that Modulate
Reinforcing Value of Drugs
Dose Effects
Genetic Differences
Task Demands
Stress
Previous Drug Experience
Neuroanatomy of
Motivation/Reinforcement
Olds and Milner (1954)
Median Forebrain Bundle
Mesolimbic Dopamine
Pathways
VTA -> Nucleus Accumbens
Incentive Sensitization Theory
Robinson and Berridge (1993)
A model to explain drug craving
Craving is conceptualized as a manifestation
of incentive salience, which becomes
stronger with repeated drug use due to the
sensitization of the mesolimbic dopamine
system to drug effects.
Repeated presentation of a reinforcer causes
the stimuli associated with it to also have
greater incentive salience.
Repeated use of a drug increases its
reinforcing value and its capacity to control
behavior.
Behavioral Economics
Matching Law
Price and Demand
Marilyn Carroll (1993)
Generated demand curves from studies of
PCP consumption under different FR ratio
schedules in rhesus monkeys