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

Question 1

Tolerance

Answer 1

= Decreased effectiveness of a drug that results from repeated administrations
- This means a higher dose is required to elicit the same effect

Different effects of drugs undergo tolerance at different rates due to targeting different mechanisms in the brain and body

Many mechanisms likely involved in tolerance to different drug effects

Question 2

Acute tolerance

Answer 2

= a defined as a decreasing drug effect relative to drug-plasma levels (DPL) over a period of minutes to a few hours

This is rapid tolerance developing during a single session.

In this, during the rise of the drug curve, at a given blood level the effect of the drug is higher than when the blood level returns to the same level in the fall of the drug curve. So, the subjective experience of the drug, despite an identical blood profile has reduced with time

Question 3

Tolerance is

Answer 3

transient
Will disappear with time if drug use is discontinued

Question 4

Cross tolerance

Answer 4

= where use of one drug may also diminish the effects of other drugs

• Usually seen between members of the same drug class (e.g., opioids)
• Sometimes taken as evidence that effects are due to common mechanisms

Question 5

Pharmacokinetic tolerance

Answer 5

caused by an increase in the rate or ability of the body to metabolize the drug

Usually results from enzyme induction
resulting in less of the drug being available at the site of action.

Question 6

Pharmacodynamic tolerance

Answer 6

arises from adjustments made by the body to compensate for an effect of the drug
Homeostasis

This is believed to be on the basis of a physiological compensatory action used to reinstate homeostasis in the body and mitigate the effects of the drug. This homeostatic processes strengthen with repeated use

Question 7

Homeostasis and drugs

Answer 7

• Drug responses/mitigation much like many of the body’s physiological processes are controlled by feedback loops.
• with repeated administration, the homeostatic mechanisms used by the body to restore homeostasis adapt more quickly
• therefore, the drug has a smaller effect the more it is administered
• When drug administration is discontinued, the compensatory process weakens, but can take some time before disappearing completely

Question 8

One example of pharmacodynamic tolerance is …

Answer 8

upregulation and downregulation of neurotransmitter receptors

• This process may take a few weeks
  Partially responsible for the delayed effect of antidepressants

Question 9

Withdrawal

Answer 9

= Physiological changes that occur when use of a drug is stopped or the dosage is decreased

Different drugs produce different withdrawal symptoms, but drugs from the same family generally produce similar withdrawal

Withdrawal can be stopped almost immediately by giving the drug
Drugs from the same family often stop withdrawal as well= aka . Cross dependence

Degree of withdrawal varies across drugs
Some drugs you can only detect withdrawal with sensitive instruments
Some drugs withdrawal can be fatal

Withdrawal usually starts several hours after the drug has been discontinued

Can be produced in minutes if an antagonist drug is administered
Giving naloxone to morphine-dependent humans or nonhumans

Question 10

Cross-dependence

Answer 10

When there is dependence on a drug in the same class (as one where there is an existing dependence/addiction) and this second drug is used to mitigate the withdrawals from the first drug implicated in a dependence/addiction

Question 11

Dependence

Answer 11

This term is surrounded by confusion and misunderstanding

Historically, it has meant both:
A state in which discontinuation of a drug causes tolerance
A state in which a person compulsively takes a drug

The relationship between dependence and addiction is complex
People can take a drug compulsively in the absence of withdrawal
People can have withdrawal without taking a drug compulsively

Dependence, physical dependence, and physiological dependence
Used to describe a state where withdrawal will occur if use of a drug is discontinued

Question 12

Solomon and Corbit 1974 Opponent Process Theory

Answer 12

Suggests that when the body comes to learn that a drug produces a certain physiological effect, it’ll begin to introduce opponent compensensatory responses to reinstate homeostasis.

Eg. Instigated dysphoria to mitigate a euphoria inducing drug

eg. Drug A produces euphoria (high)

Process B which is compensatory, produces dysphoria

Question 13

Barret and Smith 2005 - study on opponent process theory for drug tolerance

Answer 13

1. Trained rats in a drug discrimination procedure (where the drug responds with a lever to indicate which drug they’re feeling the effects of)
   Chlordiazepoxide (CDP) – tranquilizer – anxiolytic
   Pentylenetetrazol (PTZ) – causes tension – anxiogenic
2. Once the discrimination was learned, tested rats with one injection of (Chlordiazepoxide) CDP then observed responses over time

Results;
- after 8 hours, the mice would respond using the lever that indicated they were feeling the effects of the anxiolytic drug (they didn’t have anxiety)
- After 16 hours, the mice would respond suggesting they were feeling very anxious as if under the influence of an anxiogenic drug.
This suggests their withdrawal produced an opponent experience (as they should’ve felt neutral without the drug)

Question 14

Opponent Process Theory and Withdrawal

Answer 14

If you take a drug continuously for weeks or months you:
Maintain enough of the drug in the body so that withdrawal symptoms never occur
The compensatory response, however, builds in strength (tolerance)

Question 15

Conditioning of drug effects

Answer 15

Principles of classical conditioning pertain to drug effects

Drug effects can be classically conditioned
Anything that reliably predicts drug administration can come to be a CS
Pavlov’s dogs (again)

Conditioned effects tend to be somewhat less in magnitude than when the drug is administered

Question 16

Classical Conditioning of Compensatory Responses

Answer 16

Sometimes the conditioned response to the drug is the same as the effect of the drug

Sometimes the conditioned response to the drug is the opposite of the drug (aka an opponent process)

In rats, the unconditioned response to morphine is analgesia; the conditioned response is hyperalgesia (as the body tries to maintain a pain threshold)

What is being conditioned is not the effect of the drug, but the body’s attempt to resist the effect of the drug; the compensatory response

Question 17

Classical conditioning of tolerance

Answer 17

= when the environment and preparations for drug administration become paired with the effects of the drug and become conditioned stimuli for opponent processes

eg. seeing a insulin needle, can produce an opponent process (ie. a spike in blood sugar) in preparation for the drop in blood sugar that occurs after drug administration.

Question 18

Siegel (1975) test of conditioned opponent processes driving drug tolerance

Answer 18

Aim: Siegal wanted to assess whether drug-associated environmental cues could come to produce tolerance

Method: Tested rats on the paw lick test

4 groups
S – received saline injections before hot plate test

M-HP – received morphine injections in the test room before hot plate test

M-CP – received morphine injections in test room before cold plate test

M-CAGE – received morphine injections in cage room before hot plate test

(so he manipulated the type of injection (Saline vs morphine) and the location for drug administration)

Results
S – no tolerance
-Day 4 paw-lick latency to the drug were the same. Aka low latency as no drug on board to mitigate discomfort from heat

M-HP – tolerance
- Day 4 paw-lick latency in response to drug was lower than at baseline - dropped to a level similar to controls. So, the effect of the morphine wained with multiple administrations

M-CP – tolerance
- Day 4 paw-lick latency in response to drug was lower than at baseline. So, the effect of the morphine wained with multiple administrations

M-CAGE – no tolerance!!
- The lick-latency was considerably higher. suggesting there were prominent analgesic effects of the morphine - and these hadn’t wained over time

Summary:
Tolerance did not develop when morphine was injected outside of the testing context

The environmental stimuli in the testing context become associated with the drug

These stimuli become CSs, capable of eliciting the compensatory responses on their own

Even though rats in group M-CAGE were exposed to the same injection schedule, tolerance did not develop because the injection occurred in a different room

Question 19

Conditioning and overdose

Answer 19

Classical conditioning of compensatory effects likely plays a role in some cases of overdose

Cues and stimuli associated with drug administration come to control compensatory responses
These responses get the body ready for drug administration

A significant number of cases of overdose involve death after administration of a well-tolerated dose

One common factor in some of these deaths is that they take place in a location that is different from usual

Question 20

Siegel et al. (1982) - Conditioned Tolerance and Overdose

Answer 20

Aim: Tested whether conditioned tolerance (or lack thereof) could play a role in overdose

Method
Injected different groups of rats with heroin or sugar in different rooms
Heroin dose was increased across days to produce tolerance to a large dose

3 groups
Control – injected with a sugar solution equally in both rooms
Group 1 – injected with sugar in Room 1 and heroin in Room 2
Group 2 – injected with sugar in Room 2 and heroin in Room 1

All rats then received a large dose of heroin

Results:
- The control group who had never received heroin had a much higher mortality rate (nearly all of them died) as they didn’t know how to handle the heroin
- When the drug was administered in a high dose in a different location to normal ~65% of mice died.
- When the drug was administered in a higher dose in the same location only around 30% died from the overdose

Question 21

Classical conditioning of withdrawal

Answer 21

Drug-associated stimuli become CSs

They elicit compensatory responses

In the absence of drug, these responses are withdrawal

Can produce relapse to drug use

The body had been free of the drug for months
Physiological withdrawal was not possible - as there is no drug for the ‘b/opponent’ process to occur

Conditioned withdrawal does not abate with time

The only way to get rid of it is for it to undergo extinction
The presentation of conditioned stimuli in the absence of drug administration

Question 22

O’Brien (1976) story about classical conditioning of withdrawal

Answer 22

“The patient was a 28-year-old man with a ten-year history of narcotic addiction. He was married and the father of two children. He reported that, while he was addicted, he was arrested and incarcerated for six months. He reported experiencing severe withdrawal during the first four or five days in custody, but later he began to feel well. He gained weight, felt like a new man, and decided he was finished with drugs. He thought about his children and looked forward to returning to his former job. On the way home after his release from prison, he began thinking about drugs and feeling nauseated. As the subway approached his stop, he began sweating, tearing from his eyes, and gagging. This was an area where he had frequently experienced narcotic withdrawal symptoms while trying to acquire drugs. As he got off the subway he vomited onto the tracks. He soon bought drugs and was relieved.”

Question 23

Cue exposure therapy

Answer 23

In this, you expose addicted individuals to drug cues while at the same time addressing withdrawal, craving, and anxiety that occur in their presence

The hope is that extinction will eliminate conditioned withdrawal and craving, allowing patients to return to normal life

Extinction = presentation of the conditioned drug stimulus (eg. environment or drug paraphernalia) without the drug to break the conditioning or association between the drug effect and the neutral stimulus

Question 24

Virtual Reality and Cue Exposure Therapy

Answer 24

Early treatments presented actual cues in the clinic. But, the context of a clinic is so different to real-life, this isn’t always effective.

Patients had trouble maintaining abstinence when they returned back to their original environments

More recently, clinicians have been using virtual reality to present more realistic cues and environments

In this, patients navigate a virtual reality with the help of their therapist, noting their craving levels and practising tools to help them overcome this and resist the craving.

So far results are promising

In a few studies, patients who have combined traditional therapy and VR treatment do better at maintaining abstinence than those who undergo only traditional therapy

This approach has great potential for future development

Question 25

Rewiring Drug Memories

Answer 25

Contemporary knowledge about memory processes is leading to potential treatment breakthroughs

Eg. Interfering with an active memory (by using retrieval cues) and making the most of the malleability of retreived/active memories to alter patterns of thinking (good diagram in notes)

Question 26

Xue et al. (2012) - Drug memories

Answer 26

Took advantage of the labile nature of recalled memories
Tested treatment efficacy in both rats and humans

Method:
1. Do a conditioned Place Preference test (for baseline)
2. 24 hrs later do a morphine-mediated CPP training
3. 24 hrs later do a CPP test
4. Split rats into one of four groups and perform relevant extinction training (eg. just a 55 min extinction paradigm where the rat is in morphine associated room without the drug, a 10 min memory retrieval task followed by a 10 min, 1 hr or 6 hr break, and then a 45 min extinction paradigm)
5. 24 hrs later, do a second CPP test.
5. 24 hrs later do a morphine primed reinstatement test

Results;
1. in the baseline CPP test, all rats showed no place preference
2. After CPP training (in CPP test 1), all rats preferred the morphine associated location
3. in CPP test 2 after the extinction paradigm, all 4 groups returned to baseline - with no preference for the room
4. In the reinstatement test, groups 2 and 3 continued to show no preference for either room (success) - this was the retrieval + 10 mins or 1 hr and extinction groups. The no retrieval and 6 hour group showed a morphine room preference

*May be worth looking at the diagram on the slides)

This study was repeated in a context more relevant to humans with heroin self-administration for 3hrs a day for rats.

Then was done in humans who had a history of heroin use. So, tried to reinstate a memory to alter it (aka extinguish the conditioned association to drug taking with the drug-related stimuli) whilst it was in a labile state. REsults were promising