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