Mechanisms of tolerance & models of Dependence
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Tolerance Definition: Diminished drug effectiveness or
potency resulting from repeated (chronic) use.Decreased efficacy
○ Downward shift Decreased potency
○ Rightward shift
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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)
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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
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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
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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.
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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
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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
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Sensitization
Enhance effects of drug following repeated exposureLess common than toleranceMost often studied in nonhuman species
○ Activating effects of drugsConditioned sensitizationCross sensitization
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Models of Addiction Disease Model Physical Dependence Model Positive Reinforcement Model
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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
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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.
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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
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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
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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)
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Measuring Reinforcing Value of Drugs
Rate: not an ideal measure Progressive Ratio Schedules Concurrent Schedules (choice) Place Conditioning Procedures
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Factors that Modulate Reinforcing Value of Drugs
Dose Effects Genetic Differences Task Demands Stress Previous Drug Experience
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Neuroanatomy of Motivation/Reinforcement
Olds and Milner (1954) Median Forebrain Bundle Mesolimbic Dopamine
Pathways VTA -> Nucleus Accumbens
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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.
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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