L6: Biological Adaptation to Drugs

Question 1

How do we biologically adapt to drugs?

Answer 1

1. Develop a tolerance
2. Drug addiction
3. Dependence
4. Withdrawal

Question 2

What is tolerance?

Answer 2

You no longer respond to the drug and/or you need a higher dose to get the same effect.

Question 3

What is drug addiction?

Answer 3

Physiological and/or psychological dependence on a substance.

Question 4

Can you become dependent on a drug that doesn’t act on the brain? Give an example.

Answer 4

Yes.
Ex: nasal spray. Nasal spray causes vasoconstriction of the blood vessels in your nose. If you use it more than indicated on the bottle, you become tolerant, such that you need to keep using it in order to breathe properly (dependence). When you stop using the drug, the adapted nerve endings will cause vasodilation (stuffy nose), therefore to breathe properly, you need to take the nasal spray to vasoconstrict. This dependency makes the problem worse.

Question 5

How can tolerance be studied?

Answer 5

Most commonly through animal models.

Question 6

Give 2 examples for how tolerance can be studies using a rat.

Answer 6

1. A rat has an IV and presses a lever when he wants to deliver a drug. If it’s an addictive drug, the rat will continue to administer it to himself. If the rat gets more tolerant to the drug, he will need to increase the frequency of administration to get the desired effect.
2. A rat has been pre-treated for several days with morphine and has developed a tolerance. Then, the pain relief (analgesia) of the rat is compared to the dose of morphine given. Analgesia becomes smaller and smaller if the rat has had greater amounts of morphine ahead of the test (bc of tolerance).

Question 7

What is chronic tolerance?

Answer 7

The most common type of tolerance. Repeated administration leads to a decreased response to the drug.

Question 8

What is acute tolerance?

Answer 8

Even with one dose, you get adaptations in the body to fight off the drug; this is mostly exhibited by the CNS. Greater effect as drug blood concentration increases.

Question 9

What is pharmacokinetic tolerance? How is the dose response curve and concentration response curve changed?

Answer 9

The body will fight the presence of the drug (Ex: increased metabolism, decreased absorption) and you’ll have lower concentrations of the drug available to do what it does.

The dose response curve is shifted to the right, the concentration response curve has no change.

Question 10

What is pharmacodynamic tolerance? How is the dose response curve and concentration response curve changed?

Answer 10

The site of action of the drug changes by either increasing or decreasing the number of receptors. This causes the drug to be less effective.

The dose response curve and the concentration response curve both shit to the right.

Question 11

What is behavioural tolerance?

Give 2 examples.

Answer 11

A lower affect of the drug as a result of a conditioned response to your environment.

Ex: Get rats tolerant to heroin in a specific environment. Give the rats the lethal dose in the usual environment vs in a new environment. There is higher mortality in the new environment than in the usual environment. Since all the rats were made tolerant, we know it’s not the tolerance that was the problem, it’s the environment the rats were put in.

Ex: Test given to measure cognitive impairment and balance following alcohol administration. Non-drinkers were impaired at low blood alcohol levels. Moderate drinkers had some learned behaviour, so the graph shifted more to the right. Heavy drinkers shifted even more to the right. This is because they often practice walking and keeping balance while drunk, so they have this learned behaviour. They require higher blood concentrations to have the same effect on their impairment as those who drink less.

Question 12

What’s the effect of pharmacokinetic tolerance on the steady state of a drug? Why?

Answer 12

Even when you administer the drug at half life intervals, the drug concentration in the blood decreases below steady state due to increased ADME. Your body is fighting the presence of the drug by synthesizing many more enzymes and thus metabolizing it more rapidly.

Question 13

How can you tell is a person is undergoing pharmacodynamic or pharmacokinetic tolerance?

Answer 13

Look at the concentration (X) vs response (Y) curve. For pharmacokinetics the curve will be the same as a control, but for pharmacodynamics, the curve will be shifted to the right because you need more concentration to elicit the same response as the control.

Question 14

What are the model systems of tolerance?

Answer 14

1. In an organism (ex: humans, rats)
2. Isolated organs
3. Tissue cultures
4. Subcellular fractions (studying vesicles at nerve endings with time).

Question 15

What is drug dependence?

Answer 15

When you have pharmacodynamic tolerance to the drug. The drug doesn’t have the same affect on the body, so you need to keep taking it in order to reach your desired affect and avoid withdrawal symptoms.

Question 16

What is withdrawal?

Answer 16

A series of reactions that are opposite to the effects of the drug.

Question 17

What happens to the equilibrium of the nervous system when you take a drug?

Answer 17

The nervous system is in a balance of excitation and inhibition. If you take a drug that produces inhibition, then it will disturb the balance and the nervous system will increase excitation to restore the balance (you become tolerant bc of adaptation). Because of this, to get a desired response, you would need to take more of the inhibitory drug to further disturb the balance and feel the affects of the drug.

Question 18

What happens to the equilibrium of the nervous system when you stop taking a drug?

Answer 18

if the drug you stopped taking was an inhibitor, then the CNS is going to be imbalanced because there will be more excitation than inhibition (CNS was increasing excitation to compensate for the inhibitory drug). You would then experience withdrawal.

Question 19

What mechanisms of presynaptic functions can be altered with a drug? (and can be adapted to obtain tolerance)

Answer 19

1. Release of neurotransmitters in vesicles from pre-synaptic neuron.
2. Binding of neurotransmitters to post-synaptic neurons
3. Re-uptake of neurotransmitters through re-uptake pumps on the pre-synaptic neuron.
4. Neurotransmitters binding to autoreceptors to activate the pre-synaptic terminal.
5. Altering the level of enzyme, substrates, cofactors, other activators and inhibitors (alters amt of neurotransmitter present in pre-synaptic terminal).

Question 20

What will happen to receptor turnover if you are taking a chronic agonist?

Answer 20

The body will downregulate the number of receptors, thereby resisting the effect of the drug.

Question 21

What will happen to receptor turnover if you are taking a chronic antagonist?

Answer 21

The body will upregulate the number of receptors to allow endogenous agonists to bind and have their affect.

Question 22

Is it possible to overcome the body’s pharmacodynamic adaptations to a drug?

Answer 22

Yes and no. in some cases, it is possible to take more of the drug which would increase the concentration of the drug at the adapted receptors in order to get the desired response. In some cases, no matter how much you increase the dose of drug, you cannot get around the adaptation.

Question 23

Give an example of when an increase in drug concentration won’t surmount pharmacodynamic adaptation.

Answer 23

The body adapted by decreasing the synthesis of the neurotransmitter that the drug acts to release from the presynaptic terminal. It doesn’t matter how much pf the drug you give, there won’t be enough of the neurotransmitters released to give the desired response.

Question 24

What is cross tolerance? Give an example.

Answer 24

For drugs of the same family, you cannot avoid tolerance by switching to a drug in the same family.

Ex: you can’t avoid tolerance of morphine by giving an analog of morphine.

Question 25

What is differential tolerance?

Answer 25

Depending on the area in which the drug is acting, the ability to produce tolerance varies. You do not become equally tolerant to all the different affects of a drug (curves are different for different effects).

Question 26

Does the lethal dose to a drug change with tolerance?

Answer 26

No.

Question 27

What are acute and long-term withdrawal effects?

Answer 27

Acute: the worst of the withdrawal symptoms. They are unpleasant, but usually do not kill.

Long-term: less intense effects but longer in duration. Depending on the drug, long-term withdrawal symptoms can last for years (ex: heroin).

Question 28

What is the severity of the withdrawal syndrome related to? Explain.

Answer 28

1. The dose that was taken.
2. The half life of the drug: if the drug has a longer half-life (long-acting), then withdrawal will be less severe because the body has time to adapt to the slow lowering of drug concentration. If the drug has a shorter half-life (short acting), the body has less time to react, so the counter reaction is much bigger.

Question 29

What can you do to treat drug dependence?

Answer 29

1. Slowly decrease dose
2. Substitute safer drug, then decrease dose
3. Prevent relapse with antagonist or partial agonist.
4. Reduce craving with therapy and altered lifestyle.

Question 30

Why can partial agonists prevent relapse?

Answer 30

Because they bind to the same receptors as the full agonists while giving a smaller affect. This allows the person to not have severe withdrawal effects and helps them not relapse.

Question 31

What two systems appear to modulate drug dependence?

Answer 31

1. Gain reward - activate dopaminergic pathway

2. Avoid punishment - withdrawal

Question 32

What are the signs of addiction?

Answer 32

1. Tolerance
2. Obsession
3. Increased intake
4. Loss of control
5. Abuse despite harm
6. Withdrawal symptoms

Question 33

What makes one drug more addictive than another?

Answer 33

It is more addictive if it has a rapid onset and a higher blood concentration.
Ex: IV, and smoking

It’s less addictive if it has a slower onset and lower blood concentration.
Ex: Chewing tobacco

Question 34

What is the mesolimbic dopaminergic pathway? Where is it located?

Answer 34

It is located in the midbrain in the limbic system. It is the most relevant pathway to addiction. It’s a reward pathway.

Question 35

What parts of the brain are in the classical reward pathway?

Answer 35

1. Ventral tegmental area
2. Nucleus Accumbens
3. Prefrontal cortex

Question 36

Where do dopaminergic neurons synapse? what do they release?

Answer 36

In the nucleus accumbens, where they release dopamine.

Question 37

What kind of inputs can you have on a dopaminergic neuron?

Answer 37

Glutamatergic (+) , or GABA (-)

Question 38

What is neuroplasticity?

Answer 38

The ability of the brain to form nd reorganize synaptic connections.

Question 39

How is neuroplasticity related to tolerance and withdrawal?

Answer 39

Tolerance: The brain modifies its mechanisms in order to counter the affects of a drug.

Withdrawal: The changes that occured in the brain causes withdrawal when you stop taking the drug.