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 classAll opiates display cross-toleranceAlcohol 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) Tolerancee.g., receptor affinity or number altered by drug

actionsdisruption of homeostatic processes may be critical

Behavioral ToleranceLearning to compensate for drug-induced

impairmentsrespondent 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 EffectsPavlov’s early work with apomorphine

Conditioned Compensatory Responsesthe CR may not be opposite the URThe 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 extinguishMay persist long after physical withdrawal

symptoms no longer evidentEnvironmental 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 exposureLess common than toleranceMost often studied in nonhuman species

○ Activating effects of drugsConditioned sensitizationCross sensitization

Models of Addiction Disease Model Physical Dependence Model Positive Reinforcement Model

Disease Model

Historical BackgroundSocial reform of the 19th centuryAA movement of the mid-20th century

Potential Strengths of Disease ModelConsiders addictive behavior abnormalExplains why only some develop addictionImplications for Therapy vs. Punishment

Disease Model Problems/Limitations of Disease Model

Mechanisms not well understoodAccepting “loss of control” as an explanation

may reduce the addicts accountability

Characterizing addiction as a diseasePredisposition TheoriesExposure 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 AddictionBased 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 SpeciesType of Drug

○ Most psychoactive drugs that are abused by humans are also self-administered by nonhumans.

○ Some drugs (e.g., LSD) are not self-administered 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 cravingCraving 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