The Bridge Between Neuronal Communication andTolerance, Sensitization, Dependence & WithdrawalRepeated exposure to a drug causes changes to the structure and functioning of neurons of the CNS.
Tolerance• Tolerance: diminished response to administration of drug after repeated exposure to that drug – What should be considered when a drug has more than one effect? • Therapeutic Index (ED/ LD) • Mragin of Safety – How quickly can tolerance develop? • Tachyphylaxis (psychadelics like LSD) • Acute Tolerance – What happens when a person stops taking the drug? • Abstinence Syndrome, Withdrawal • Is tolerance reversible? – Other considerations regarding tolerance? • Compulsive drug taking and addiction?
Tolerance• Tolerance: diminished response to administration of drug after repeated exposure to that drug – 3 Major Types of Tolerance – PK: metabolic Concentration and – PD: functional, non-associative Exposure Time – Behavioral: context-specific, learned, associative • Behavioral and Environmental Manipulations • Learning and Memory
Tolerance• Drug Disposition Tolerance a.k.a. Metabolic Tolerance or PK Tolerance: usually enzyme induction – A drug can produce effects that reduce its own bioavailability (i.e., concentration at target site) – How might the appearance of drug disposition tolerance in tolerant and non-tolerant subjects change based on route of administration? • Peak effect and duration of action • Non-tolerant & Tolerant Animals – I.V. administration of ED50 and LD50 – Sub-Q administration of ED50 and LD50 • Slow absorption routes vs. fast absorption route (I.V.)
Tolerance• PK Cross-tolerance: the development of tolerance to one drug can diminish pharmacological effectiveness of a second drug based on enzyme actions. – Which drugs might you expect to show cross- tolerance?
Tolerance• Pharmacodynamic Tolerance: compensatory mechanisms; cellular tolerance – Two types: General or Non-Specific and Specific » General: all effects of drug are diminished to the same extent » Specific: specific to a particular drug effect • develops independently of other tolerance mechanisms • appearance or disappearance of specific tolerance may occur at different rates » We can relate PD tolerance to homeostatic mechanisms because of its compensatory nature (i.e., system is trying to regain balance)
Tolerance• General or Nonspecific Type: all effects of drug are diminished to the same extent• When might we expect “up-regulation” mechanisms to occur? – i.e. receptor up-regulation, increased pre-synaptic neurotransmitter release – Sensitization: increased activity at receptor• When might we expect “down-regulation” mechanisms to occur? – i.e. receptor down-regulation, decrease in pre-synaptic neurotransmitter release – Desensitization: decrease in receptors ability to elicit cellular changes upon agonist binding
Tolerance• Specific Tolerance – Effect of drug must lead to functional disturbances, placing demand on homeostatic mechanism. » Return to set-point: » Amphetamine-Anorexia » Alcohol-Hypothermia » Morphine-Analgesia
Tolerance• PD Cross-tolerance: the development of tolerance to one drug can diminish pharmacological effectiveness of a second drug based on receptor- neurotransmitter interaction changes. – Which drugs might you expect to show PD cross-tolerance?
PK and PD Tolerance Wrap Up• Purely physiological mechanisms• Rate at which tolerance develops is dependent upon drug dose and frequency of use (dosage) – Large doses administered in short intervals of time – Moderate doses administered in moderate intervals of time – Smaller doses administered in longer intervals of time• Threshold dose for each drug, below which tolerance would not be expected to develop – No induction of metabolic or cellular changes
Behavioral Tolerance• Behavioral Tolerance (a.k.a. context-specific tolerance): experience with a drug leads to decrease in effect drug is having• Three Processes of Behavioral Tolerance – Habituation (S-R) – Pavlovian Conditioning (Classical) – Instrumental Conditioning (Operant)
Behavioral Tolerance• Habituation S R• Stimulus: any event, external or internal that is capable of activating receptors in sensory system• Response: measurable reaction in organism; i.e. NT release, heart rate, etc…• Why is this NOT the same as PD tolerance?
Behavioral Tolerance• Pavlovian Conditioning & Conditioned Compensatory Response UCS UCR CS CR• Unconditioned Stimulus: UCS like heroin• Unconditioned Response: UCR is a variety intended + unintended effects• Conditioned Stimulus: CS like environmental cue (or psychological state)• Pairing of 2 Stimuli (UCS + CS)• Conditioned Compensatory Response: a response elicited that is opposite to the drug induced effects; reduced effectiveness of UCS• What happens when you change the environment? – Rat Paw-Lick Test – Human Heroin Overdose
Behavioral Tolerance• Instrumental Conditioning (in Skinner Box) Drug Behavior Reward Behavior Reward Drug• Instrumental: behavior is necessary for conditioning process to occur• Consequences: reinforcers or punishers• DRL schedule: differential reinforcement of low-rates (low rates of responding get reinforced)• Amphetamine will stimulate responding behavior; reinforcement will decrease• Animals pretreated with amphetamine showed tolerance to its stimulant effects, whereas animals treated after session did not show tolerance• Rats developed behavioral strategy for overcoming the effect of amphetamine when the behavior was rewarded
Behavioral Tolerance• General Implications – In order for tolerance to develop, the organism must perform the task under the influence of the drug – Behaviors not affected detrimentally by drug, or those that are enhanced, will show no tolerance – Tolerance developed is task-specific • i.e., alcohol and driving vs. alcohol and typing – Tolerance developed can generalize • i.e., learning to maintain balance on bicycle or motorcycle while intoxicated – Rate of development of tolerance can be altered with task-difficulty • i.e., humans and alcohol (walking vs. driving) – Behavioral cross-tolerance can occur when drugs produce similar behavioral effects • i.e., overcoming slurred speech with barbiturate may transfer to alcohol – Tolerance should last relatively long time because learning is defined as a relatively permanent change
Sensitization or Reverse Tolerance• Occurs when the effect of a drug increases with repeated administrations – Ex: cocaine, amphetamines, nicotine, alcohol, opiates in animal models • With low dose, first administration causes activating responses such as motor activity and rearing behavior – Repeated administration of low dose causes progressive increase in these behaviors
Sensitization or Reverse Tolerance• Context Specific – Put animal in new context and sensitization does not appear• Environment where drug administration occurs can become a CS for sensitization, eliciting the CR – Placebo injection
Sensitization or Reverse Tolerance• Cross-sensitization can occur – Morphine, cocaine, amphetamine• Sensitization has greater persistence than tolerance – In rats, lasts up to 1 year – Can increase with time