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 Cross Dependence
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