Week 3 Reading : How we Adapt to Drugs - Tolerance, Sensitization and Expectation

Question 1

Drug Tolerance

Answer 1

As the decreased effectiveness (or potency) of a drug that results from repeated administrations or as the necessity of increasing the dose of a drug in order to maintain its effectiveness after repeated administrations

Question 2

Tolerance effects

Answer 2

o Some effects of a drug may develop tolerance quickly and others may show tolerance more slowly and some not at all. The effects of a drug do not diminish at the same rate.
o Amount the effect of morphine for example are nausea and vomiting which show rapid tolerance but the ability of morphine to constrict the pupils shows no tolerance
 Because of this, different mechanisms must be responsible for tolerance

Question 3

What is the main cause of tolerance

Answer 3

Mainly it results from adaptation at the site of action

Question 4

Example of tolerance; King Mithridates

Answer 4

• Examples: King Mithridates who was a good pharmacologist was afraid of being poisoned throughout his life so took increasing doses of poison until he could tolerate large amount without ill effects. He ended up having his Gallic mercenaries dispatch him as he wanted to die. This tolerance effect was called mithridatism (lankester, 1889).

Question 5

• Tachyphylaxis

Answer 5

= a synonym for tolerance, particularly in medical literature. It’s derived from Latin tachy meaning accelerated and phylaxis meaning protection and is sometimes used to designate a rapidly developing tolerance aka acute tolerance

Question 6

• Acute Tolerance

Answer 6

o It is possible for tolerance to develop during a single administration of a drug.
o With some drugs and depending on the effect being measured, the drug effect can be greater at a specific blood level during absorption than it is at the same blood level during elimination, showing that tolerance has developed. Aka acute tolerance
o With some drugs and depending on the effect being measured, the drug effect can be greater a specific blood level during absorption than it is at the same blood level during elimination, showing that tolerance has developed during a single administration
 The effect will peak before the blood levels peak and the effect will be gone before all of the drug is elimination from the body. Thus, if you measure the effect of the drug at time A as the blood level is rising and again at time B when the blood level is exactly the same but falling, you will bee that the effect at time B is much less.

Question 7

example of acute tolerance = alcohol

Answer 7

• As blood alcohol level rises, you feel increasingly intoxicated but the subjective effect peaks before blood level and the subjective effect disappears before the alcohol does.

Question 8

Waning of Tolerance effects

Answer 8

o Tolerance may disappear after a time without drug use
o Tolerance to one drug may well diminish the effect of another drug. This is called cross-tolerance and is usually seen between two members of the same drug class

Question 9

2 key mechanisms behind tolerance

Answer 9

o Pharmokinetic tolerance
o Pharmacodynamic tolerance

Question 10

o Pharmokinetic tolerance

Answer 10

(aka metabolic tolerance or dispositional tolerance) arises from an increase in the rate or ability of the body to metabolize a drug, resulting in fewer drug molecules reaching their sites of action
 This results mostly from enzyme induction – or an increase in the level of an enzyme in the body to breakdown the drug thus increasing the rate of metabolism
 When this occurs, all effects of the drug are reduced due to the reduced concentration of the drug at it’s site of action. This will also create cross-tolerance with drugs that may be metabolized by the same enzyme

Question 11

o Pharmacodynamic tolerance

Answer 11

 Also known as physiological or cellular tolerance
 A type of tolerance that arises from adjustments made by the body to compensate for an effect of the continued presence of a drug. It’s generally believed these adjustments are the result of homeostasis . When a drug is taken it alters some aspect of the bodies functioning so the bodies response is controlled by a homeostatic mechanism – the body gets better at restoring homeostasis with repeated drug taking such that the drug has a smaller and smaller effect.
 When a drug is not used for a long period of time this strengthening of the homeostatic mechanism will weaken
 Eg. Upregulation (when a receptor blocks drug action) or downregulation (when drugs activate a receptor) of neurotransmitter receptors. This is responsible in part for the delay in therapeutic effects of anti-depressants which have to be taken for weeks to show effects

Question 12

The role of Functional Disturbances in Tolerance

Answer 12

o Disruptions in physiology alone are not always sufficient to cause tolerance
o A drug induced change needs to be of some significance to the animal.
 Eg. Amphetamine causes anorexia in rats and this effect shows tolerance when the drug is repeatedly administered to hungry rats in the presence of food.
* However, the rats won’t form a tolerance to the anorexic effects of amphetamine if the drug is administered in the absence of food. This is because it has no interaction with the animals food eating behavior so th ehomeostatic mechanism doesn’t kick in.
 Eg. Tolerance to hypothermic (body-cooling) effect of Alcohol does not develop in rats in a very warm environment where alcohol does not have a hypothermic effect, and tolerance to the analgesic effect of morphine develops faster in rats subjected to painful stimuli after drug administration.

Question 13

• Behavioural Tolerance

Answer 13

o With experience, an organism can learn to decrease the effect that the drug is having = behavioural tolerance.
o This learning can involve operant and classical conditioning processes.

Question 14

• Withdrawal

Answer 14

o = the physiological changes that occur when the use of a drug is stopped or the dosage is decreased
o Different drugs produce different withdrawal symptoms but drugs of the same family tend to produce similar withdrawal symptoms.
o Withdrawal can be stopped by administering the drug again
o It can also be stopped by taking a different drug of the same family – doing so is called cross-dependence
o Withdrawal usually begins some hours after cessation of drug use. But it can be increased in onset with the use of a drug antagonist. Eg. Naloxone is a powerful antagonist to morphine and rapidly blocks all morphine effects. – producing withdrawal in minutes

Question 15

Drug Dependence

Answer 15

o The word previously has been used in two ways
 To describe a state in which discontinuation of a drug causes withdrawal symptoms, and
 To describe a state in which a person compulsively takes a drug (aka addiction)
* It was believed that dependence and addiction were the same and that if you took a drug enough to produce withdrawal symptoms when you stopped you were dependant and would seek out the drug compulsively – therefore being addicted
o Now dependence (physical dependence and/or physiological dependence) = the state in which withdrawal symptoms will occur when the drug use stops

Question 16

Opponent Process Theory

Answer 16

o Tolerance and Dependence are believed to be closely related. Withdrawal symptoms are often seen as a compensatory adjustment to the homeostatic mechanisms that have been made to the effects of a drug after repeated use.
o The dynamics of this process were intro’d by Solomon and Corbit (1974) who suggested the theory or acquired motivations, a theory that also applies to drug use.
o They suggested that abused drugs to stimulate a process (eg. Create euphoria) introduce a compensatory process (eg. Intro-ing a dysphoric state) – so when the drug wears of the compensatory process endures for a while after – producing a negative affective state

Question 17

Example of opponent process theory

Answer 17

With alcohol, whilst in the hangover you feel negative symptoms due to stomach irritation, dehydration etc. The elements like light sensitivity and noise can be thought of as a brief withdrawal symptoms that is a compensatory response to the effects of alcohol.

Question 18

Withdrawal and compensatory effects

Answer 18

o If withdrawal is an expression of compensatory effects that cause tolerance to drugs, you might expect there to be a strong correlation between tolerance and withdrawal symptoms – but thi s is not the case. It’s unusual for someone to show considerable tolerance but have no withdrawal effects .
 This is because there’s effects from say behavioural tolerance – which wouldn’t have a physiological compensatory effect so would produce no physiological withdrawal.

Question 19

Conditioning of Drug Effects

Answer 19

Operant and classical conditioning can alter the effects of drugs and can explain phenomena like tolerance and withdrawals

Question 20

Classical Conditioning and Drug Effects

Answer 20

o In one of pavlovs early classical conditioning studies, a dog was given a small dose of apomorphine subcutaneously and after one to two minutes a note of a specific pitch was sounded for some time. Whilst the note was playing, the drug began to take effect making the dog restless, salivating and vomiting. After some time, the tone was able to elicit the active symptoms of the drug without the drug being administered. In this way the stimulus preceding the drug (aka the tone and drug administration tools) became conditioned producing the conditioned respone (nausea and salivation)
o However, the conditioned response to a drug and the effect of a drug are not always the same. Some stimuli when presented alongside a drug (the conditionined stimulus) produce a compensatory physiological response (conditioned response) that opposes the actions of the drug itself.
o Eg. Rats show an unconditioned response to morphine (aka analgesia) but the conditioned response to stimuli repeatedly paired with morphine is hyperalgesia. This is the body’s attempt to resist the effect of the drug – a compensatory effect.
o The body resists drug-induced changed by making adjustments or compensatory changes in its physiology in an attempt to restore normal functioning. These are in part responsible for tolerance and they make the body less susceptible to the drug when it is given later.

Question 21

o Siegal, 1975

Answer 21

 In a paw lick test after a morphine injection, the paw-lick latency increases suggesting morphine reduced pain sensitivity
 With repeated exposure, the latency gets shorter as a tolerance to the morphine develops
 The M-HP group were injected with morphine in a testing room where the hot plate test was done . These rats showed an analgesic effect from morphine on the first day, but day 3 their responding was the same as the control rats given saline
 Rats in the M-CAGE group were injected with morphine in the colony room and returned to their home cage without testing in training.
 2 days later both groups of rats were given morphine in the test room and did the hot plate test. The M-HP group continued to show tolerance but the M-CAGE group showed a large analgesic effect, indicating no tolerance on morphine.
 In this study, Siegal was able to demonstrate that rats would show tolerance to the analgesic effects of morphine only if they were given the paw lick in the same room where repeated morphine injections had been experienced earlier. – this is conditional tolerance.
 Siegal proposed that the environment repeatedly associated with a drug acts like a conditioned stimulus – but rather than becoming conditioned for the effect the drug is having, it becomes a conditioned stimulus for the physiological changes the body is making to compensate for the drug’s effect. Thus, the environment associated with the administration of the drug elicits physiological responses opposite to the effect of the drug. This helps prepare the rat.

Question 22

• Classical Conditioning of Withdrawal

Answer 22

o When compensatory responses to a drug occur (due to the presentation of a conditioned stimulus that has been repeatedly paired with the drug, eg. A location or stimuli) but no drug is received, the symptoms are withdrawal symptoms

Question 23

• Sensitization

Answer 23

o Reverse tolerance = sensitization
 Most of the time, when a drug is repeatedly administered, tolerance developes to the many effects of the drug. However, sometimes, the effect of a drug can increase with repeated administrations this is reverse tolerance
 This is less common than tolerance
 This effect is characterized by increased motor activity and rearing behavior in rates – this is an activating effect of a drug
 Stereotyped behavior is invariable repetitive movements like head bobbing or sniffing which are engaged with for extended periods.
 Repeated administration of higher doses of certain drugs will cause stereotyped behavior where only activation behavior was caused in lower doses.
 Like tolerance sensitization can be conditioned to an environment
* This mirrors the conditioning of tolerance however, this effect mirrors a drug-like response.

 Sensitization is believed to persist over long periods and can even increase over time.

Question 24

REgions of the brain involved in sensitization

Answer 24

 Sensitization doesn’t involve one neural effect – but involves the general motivation control system of the brain responsible for arousal and approach to both conditioned and natural incentives like food and receptive sexual partners.
 The part of the brain that becomes sensitized is believed to be the mesolimbic dopamine system

Question 25

Sensitization in humans

Answer 25

 Sensitivation of drug-induced actiation hasn’t been demonstrated in humans but is commonly observed with cocaine, and amphetamine – where at low doses they produce psychosis and even convulsions in heavy users but not in beginning users

Question 26

The placebo and Nocebo effect

Answer 26

 The placebo effect = a contextual effect, where the expecataion of a drug can alter the effect you have.
* It may be responsible for up to 70% of the effectiveness of antidepressants and 50% of pain relievers
 The nocebo effect – caused by expectations that can arise from patient instructions and from other sources like package inserts or ads on television etc