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CHAPTER 6.docx

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Suzanne Erb

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mmCHAPTER 6: TOLERANCE, SENSITIVE, DEPENDENCE AND ADDICTION TOLERANCE AND SENSITIZATION Drug tolerance: reduction in potency or efficacy of a drug with repeated administration -increasingly larger doses of the drug are required to induce the same behavioural effect -tolerance due to drug exposure is different from genetic or dispositional tolerance> individual isn’t affected by the drug as much as others bc of genetic or dispositional factors Tachyphylaxis or acute tolerance: same amount of drug administered on two separate occasions a couple of hours apart may induce greater effects with the first dose than with the second dose Cross-tolerance: development of tolerance for one type of drug results in decreased sensitivity to effects of another type of drug -once tolerance to a drug develops, larger and more frequent doses that do become toxic are often administered -tolerance to the effects of drugs do not develop uniformly Drug sensitization: increase in potency or efficacy with repeated administration -drug produces greater effects at the same dose with repeated administration and the same effect can be produced by lower doses -i.e. DA antagonist induces catalepsy sensitization & locomotor effects of stimulants and morphine and ethanol TORELANCE AND SENSITIZATION MECHANISMS -Three types of drug tolerance and sensitization: pharmacokinetic, pharmacodynamic, & context-specific -pharmacokinetic and pharmacodynamic forms of tolerance are produced by exposure to high concentrations of a drug generally with a certain minimum exposure time required and are not affect by environmental/ behavioural manipulations of the organisms -context-specific tolerance due to behavioural and environmental manipulations that involve learning/memory PHARMACOKINETIC AND PHARMACODYNAMIC MECHANISMS Pharmacokinetic- ability of liver to synthesize more drug-metabolizing enzymes than normal when exposed to a drug -repeated exposure, liver metabolize drug at faster rate than it could previously, and decreases duration of action -may not be reduced very much if administered other than oral route -responsible for cross-tolerance between drugs Pharmocodynamic- leads to a depletion of neurotransmitters critical to the drug’s effects -drug’s action lead to depletion of transmitter bc transmitters used faster than they can be replenished or because actual synthesis of transmitters decreased -fewer transmitter available= larger drug dose administered, larger drug dose must be administered -can be due to cross tolerance -finally depletion of neurotransmitters can lead to the person experiencing symptoms that are opposite those experience with the drug; .:. where the drug initially induces effects by amplifying a neurotransmitter’s activity, absence of the drug results in reduction in the neurotransmitter’s activity Homeostasis: processes that maintain a state of equilibrium Down-regulation/receptor subsensitivity: continuous exposure to drugs that mimic or amplify the action of neurotransmitters’ at their receptors tends receptors tends to decrease receptor activity -can occur due to: reductions in receptor number, reductions affinity of receptors for its ligands or reductions in signal transduction activity -reduction in receptor number can occur bc: - the receptors dissociate from neuronal membrane & sequestered inside cytoplasm inaccessible for activation -short-lived as receptors can be recycled to neuronal membrane and accessible for activation OR - receptors degrade and aren’t replaced by synthesis of new protein fast enough -persists for some length of time bc neuron would need to synthesize new replacement receptors -can also be a decrease in receptor’s ability to elicit cellular changes when agonist binds but no change in receptor # -occur with metabrotopic receptors that become uncoupled from g-protein Up-regulation/supersenstivity repeated exposure to drugs that act as antagonists or dampen the action of neurotransmitters’ at their receptors -greater population of receptors, higher doses of antagonist are needed to block them -explains cross-tolerance between different classes -intracellular proteins associated with second-messenger systems show adaptive up-regulation i.e. enhanced levels of gene transcription factors i.e. delta FosB in orbitofrontal cortex implicated w sensitization -sensitization = increase in dendritic spines in cocaine DEPENDENCE ABUSE AND ADDICTION Drug abuse: drug taking behaviour can result in adverse consequences Drug dependence: real or perceived need of drug for normal physiological or psychological function and the deleterious consequences of drug withdrawal -used as a synonym for drug addiction 1. tolerance, as defined by either: a. need for markedly increased amounts of the substance to
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