Psy 134 Lecture 6 - Tolerance, Sensitization, and Withdrawal

Describe the 3 major mechanisms that underlie the development of tolerance/sensitization to a drug effect

1) Changes in drug pharmacokinetics can increase or decrease the rate at which the drug is broken down. Specifically, more/less enzymes may be produced to breakdown the drug. 2) Changes in the body to compensate for some of the effects of drug will lead to sensitization of some drug effects and tolerance of others. This can come in the form of changes in of feedback loops, receptor density or intracellular coupling, neurotransmitter release, etc. 3) Behaviorally, you can learn to compensate for drug effects (tolerance; ex: learning how to drink and drive) or to compensate for the lack of a drug effect (sensitization; ex: after a bad experience with weed, lower doses become sensitized to you).

Explain how conditioned sensitization could account for drug overdose

For this scenario, we will pretend the intoxication effects of alcohol are sensitized over time. Rina only drinks at Michael's house, and she always only drinks five shots. Her sensitization to alcohol is conditioned to Michael's house. One day, Rina decides to drink alone at her own house because she is sad Zobabe broke up with her. She drinks 5 shots like usual, but does not feel it. Therefore, she drinks more to achieve the same level of intoxication as before. However, because the other depressant effects of alcohol have not been tolerated or sensitized, Rina ODs and has to get her stomach pumped.

Explain how shifts in a DRC function could indicate tolerance or sensitization

If the DRC function shifts to the right, then tolerance is indicated. If the DRC function shifts to the left, then sensitization is indicated.

Describe a behavioral experiment that one could conduct to determine whether or not pharmacokinetic tolerance or sensitization developed to a drug and explain how one could definitively prove that pharmacokinetic changes have in fact occurred

In a model animal, you could administer a certain dose of drug daily to one group. After a month, you could start a second group on the drug at the same dose as well. We can then perform behavioral assays that are known to change in output when a drug is administered on both groups and see how long the drug effects will affect behavioral assay results. An example would be measuring locomotor activity when the drug being studied is cocaine.

Explain why it is incorrect to say: "Bob developed morphine tolerance" or "Sally developed cocaine sensitization"

It is incorrect to say this because tolerance and sensitization is specific to certain effects of a drug. Some effects of a drug might be sensitized, while others might not be tolerated, and still others might not be tolerated or sensitized. For example, tolerance will develop towards intoxication effects of alcohol, but not the decreasing body temperature effects. Therefore, you will still die if your BAC is too high despite not feeling intoxicated.

Explain how conditioned tolerance could account for drug overdose

Johnny only does heroin at Chad's house, and he does the same dose everytime. His tolerance to heroin becomes conditioned to Chad's house. One day, Johnny, being the dumb mofo he is, decides to do the same dose of heroin at his own house. Because his tolerance is not conditioned to his own house, he dies. I wish I was Johnny.

Explain how one might demonstrate acute tolerance to a drug

Acute tolerance is defined as a lessening of the drug's effect on the descending limb of the dose-time curve and it only occurs during the first time of drug administration. An example of acute tolerance is that we will feel super drunk well before the plasma concentration of alcohol peaks. Therefore, we will also sober up by the time the plasma concentration peaks, and the intoxication effects will disappear before ethanol has left the body.

Define drug withdrawal and describe it mechanistically.

Biologically, drug withdrawal is defined as the aversive effects experienced by a dependent drug user when they are no longer on the drug. These effects develop due to the opponent process effect, which strengthens the bodies response to the drug. In the absence of the drug, the opponent processes linger, causing withdrawal symptoms. For example, if you're dependent on alcohol, the depressive effects counter the stimulatory response your body produces. However, once you're not on alcohol anymore, the stimulatory effects still persist, and you could get a seizure.

Define conditioned tolerance and conditioned sensitization and describe an experiment that one could conduct to determine whether or not such adaptations have occurred in response to repeated drug exposure

Conditioned tolerance is when tolerance has been associated with certain stimuli while conditioned sensitization is when sensitization has been associated with certain stimuli. They both tend to occur when the drug is often administered at the same place. To test for either, you could administer a drug to a model animal in condition A for a month and test them weekly using a behavioral assay, such as locomotor activity recording, to get baseline behavioral information. Afterwards, you could then move the model animal to condition B and administer the same dose of drug. The same behavioral assay is then used, and if there is a difference in the data between condition B and condition A, conditioned tolerance or sensitization must have occurred assuming all other factors affecting the behavioral assay have been controlled for.

Define cross-tolerance and cross-sensitization and explain what is inferred if 2 drugs produce either phenomenon

Cross tolerance is when tolerance to one drug's effect confers tolerance to another drug's effect. On the other hand, cross-sensitization is when sensitization to one drug's effect confers sensitization to another drug's effect. When either occur, it is implied that both the drugs have a similar mechanism of action for causing the effect.

Comment on the rate of tolerance/sensitiztion development and persistence.

The rate that tolerance/sensitization development differs depending on the effect. In addition, the rate at which tolerance/sensitization disappears also differs depending on the effect.

Compare and contrast tolerance versus sensitization of a drug effect

Tolerance is when a drug is not as potent anymore while sensitization is when a drug is more potent than before. They are literally opposites of each other.

Describe how tolerance/sensitization develops at the cellular level

Tolerance: For agonists, the number of cell surface receptors will decrease over time, and signal transduction pathways will be downregulated. For antagonists the number of cell surface receptors will increase over time, and signal transduction pathways will be upregulated. Sensitization: For agonists, the number of cell surface receptors will increase over time, and signal transduction pathways will be upregulated. For antagonists the number of cell surface receptors will decrease over time, and signal transduction pathways will be downregulated.

Describe an experiment in which one could test whether or not 2 drugs showed cross-tolerance or cross-sensitization

We will use three groups of model animals in this experiment, and we will address sensitization only and assume both drugs sensitize locomotor activity, but a similar experimental method could be used to address tolerance as well. Control group 1: After one month of drug administration in experimental groups, you start this group on drug A and record locomotor activity. Control group 2: After one month of drug administration in experimental groups, you start this group on drug B and record locomotor activity. Group 1: You administer drug A to the animal for one month. During this period, you assay their locomotor activity over time and compare this data with control group 1 in order to confirm that tolerance/sensitization has occurred. Afterwards, you administer drug B. If the animal displays locomotor activity that is sensitized compared to control group 2, then cross-sensitization has occurred. Group 2: You administer drug B to the animal for one month. During this period, you assay their locomotor activity over time and compare this data with control group 2 in order to confirm that tolerance/sensitization has occurred. Afterwards, you administer drug A. If the animal displays locomotor activity that is sensitized compared to control group 1, then cross-sensitization has occurred both ways.

Describe the opponent process theory in relation to tolerance/sensitization.

Your body will try to maintain homeostasis by countering foreign effects caused by drugs (A) with opponent effects (B). At first, A outweighs B at a certain dose, but as time goes on, A decreases in value while B remains the same value or increases. Therefore, certain effects of the drug (A) are now better tolerated, and the body's response to the drug (B), which can also be interpreted as a drug effect, is now sensitized.