Chapter 3

• Drug tolerance


  Decrease in effect with repeated doses of a drug OR the necessity of increasing the dose to maintain the same effect of a drug if it is repeatedly administered
• Tolerance develops to the effects of a drug, not to the drug
• Tolerance develops and disappears to effects at different rates
• Mithridatism


  Developing tolerance to poisons or drugs
• Cross-tolerance


  Tolerance to one drug will diminish the effect of another drug
• Acute tolerance


  Tolerance that develops to the effect of a drug during a single administration
• Mechanisms of tolerance


  • Pharmacokinetic (metabolic tolerance) - increased metabolism due to enzyme induction
  • Pharmacodynamic (physiological tolerance) - adjustment in the physiology of the body to compensate for the effect of the drug (e.g. down-regulation)
• Homeostasis


  Maintains a physiological "set point" by feedback from receptors to controlling mechanism
• Functional disturbances


  • Tolerance only develops to the effects of a drug that create a functional disturbance, i.e. effects that activate homeostatic feedback (e.g. anorexic, hypothermic, analgesic)
• Behavioural tolerance


  Tolerance that develops through learning and conditioning
• Withdrawal symptoms


  Changes that occur when the use of a drug is stopped or the dosage is reduced
• Dependence


  The state where discontinuing a drug will cause withdrawal symptoms
• Psychological dependence


  Dependence on a drug due to psychological factors
• Cross dependence


  Dependence on one drug that can be relieved by another drug
• Opponent process theory


  The 'A' process is the direct effect of the drug and the 'B' process is the compensatory effect of the body
• Withdrawal symptoms reflect homeostatic changes that arise from the development of tolerance
• Withdrawal symptoms are often the physiological opposite of the drug effect
• The 'B' process grows with repeated use of the drug
• Classical conditioning of drug effects

  Drugs can be classically (respondent) conditioned
• Often the unconditioned response (UR) and the conditioned response (CR) are opposite
• The physiology "learns" to alter itself in anticipation of certain drug effects
• Experiment: Paw lick test (hot-plate)

  1. Morphine increases latency to lick

  2. Tolerance develops and latency shortens

  3. Latency shortens only if morphine-paw lick test given in same room where tolerance developed

  4. Different room, longer latencies like early morphine
• The room becomes the conditioned stimulus (CS) and the compensatory response is the conditioned response (CR)
• Giving saline instead of morphine after tolerance develops in the same room causes the rats to become hyperalgesic (increased sensitivity to pain)
• This explains why drug addicts can have withdrawal symptoms in the environment where they normally take the drug
• This also explains why patients can develop tolerance to pain medication and why drug addicts may die from overdose in a novel environment
• Siegel experiment


  1. Tolerance phase: Rats given 30 daily injections of either heroin or placebo in different rooms

  2. Testing phase: All rats given lethal dose of heroin in either the same or different room
• Control group had 96% mortality, ST group had 32% mortality, and DT group had 64% mortality
• Operant conditioning of drug effects

  Animal learns through operant conditioning to change behaviour to compensate for drug effects
• Experiment: DRL schedule (fixed interval, but not reinforced later if press early i.e. clock is reset)

  1. Animals given amphetamine either before or after operant task

  2. Pretask amphetamine group does better than post-task amphetamine group, therefore due to behavioural tolerance, not metabolic or physiological
• When favourable consequences result from displaying unimpaired (i.e., tolerant) behaviour after drinking, a drinker learns to develop behavioural strategies to compensate for alcohol's effects
• Sensitization


  An effect of a drug increases with repeated administrations
• Stereotyped behaviours


  Repeated movements like head bobbing or sniffing
• Cross sensitization


  Sensitization to one drug that can affect the response to another drug
• Expectancy


  The placebo effect - if we know we are getting a drug we will experience the effect we expect
• There is an "expectation pathway" in the brain that is a "top down" mechanism that modifies the effect of drugs on pain
• Placebos can be as effective as real treatments, e.g. sham surgery and osteoarthritis of the knee
• Nocebo effect


  Negative expectations can actually cause harm