Mechanisms of tolerance & models of Dependence

1. Mechanisms of tolerance & models of Dependence

2. Tolerance • Definition: Diminished drug effectiveness or potency resulting from repeated (chronic) use. • Decreased efficacy • Downward shift • Decreased potency • Rightward shift

3. 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)

4. 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

5. 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

6. 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.

7. 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

8. 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

9. 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

10. Models of Addiction • Disease Model • Physical Dependence Model • Positive Reinforcement Model

11. 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

12. 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.

13. 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

14. 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

15. 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 self-administered by nonhumans. • Patterns of Self-Administration • Patterns of use are comparable between humans and monkeys (see figure 5-2)

16. Measuring Reinforcing Value of Drugs • Rate: not an ideal measure • Progressive Ratio Schedules • Concurrent Schedules (choice) • Place Conditioning Procedures

17. Factors that Modulate Reinforcing Value of Drugs • Dose Effects • Genetic Differences • Task Demands • Stress • Previous Drug Experience

18. Neuroanatomy of Motivation/Reinforcement • Olds and Milner (1954) • Median Forebrain Bundle • Mesolimbic Dopamine Pathways • VTA -> Nucleus Accumbens

19. 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.

20. 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