Animal models of addiction

Question 1

What are the 3 types of validity that all models should have?

Answer 1

• Construct validity
• Face validity
• Predictive validity

Question 2

What is construct validity?

Answer 2

the model has a sound theoretical rationale (neurobiological or psychological mechanisms underlining the condition mimics humans, aetiology)

Question 3

What is face validity?

Answer 3

phenomenological similarity between the model and the disorder being modelled (symptoms)

Question 4

What is predictive validity?

Answer 4

manipulations known to influence the pathological state should have similar effects in the model (drugs)

Question 5

What are the different stages of addiction that we can model?

Answer 5

1. substance abuse – drug taking
2. Drug seeking behaviour
3. Drug addiction/drug dependence
4. increase in tolerance/sensitisation
5. acute withdrawal symptoms
6. chronic (long-term) withdrawal
7. Compulsion to use
8. relapse
9. context dependency
10. genetic models – KO mice
11. Neurochemical models?

Question 6

How can drug-taking be mimicked in animals?

Answer 6

1. taken by the animal (self-administration) – gold standard

2. given by the scientist – simples, easier, less challenging, can control dose

Question 7

How can self-administration be incoporated in animal models?

Answer 7

• Usually done in a skinner box
• Intravenous, usually the jugular vein or brain.
• Rat can tap a lever or poke a nose-hole with infra-red beam to get the drug reward.
• Also self-admin by oral, in drinking fluid, can be forced (1 bottle) or choice (2 or more bottles)

Question 8

What are the 5 different ways of administering the drug?

Answer 8

1. intravenous (not so common)
2. sub-cutaneous (SC, common)
3. intraperitoneal (IP, common)
4. intra-cerebral (quite common) – shows effect of drug directly on the brain/ in specific brain regions, bypasses peripheral metabolism, (mechanistic, small quantities, BBB)
5. intramuscular (not so common)

Question 9

How can Drug seeking behaviour/Conditioned Place Preference/Avoidance (CPP) be seen or tested in animal models?

Answer 9

Carried out in CPP box; has a white compartment and a black compartment and a door between

CPP protocol has the following stages:

1. Initial test for side-preference – let the animal explore each side (pre-conditioning)
2. Usually give the drug in non-preferred side (conditioning)
3. Give saline in preferred side (conditioning)
4. Test for CPP after 5-10 days – measure the amount of time the animal spends in each compartment, and which compartment they prefer

Question 10

What type of animals are valuable for drug abuse vulnerability?

Answer 10

Inbred mice strains are valuable models of drug abuse vulnerability

Question 11

What is important in a drug addiction/dependence model?

Answer 11

• length of time – drug of abuse must be administered over a long period of time because addiction is chronic
• must consider pattern of administration – humans have different patterns of administration for different drugs, must be mimicked in model
• compulsive drug taking/administration of drug
• tolerance – humans develop tolerance after a while so increase dose, must be mimicked in models

Question 12

What are the 2 types of tolerance?

Answer 12

o Metabolic tolerance

o Cellular tolerance

Question 13

What is metabolic tolerance?

Answer 13

change in the metabolism of the drug (e.g. enzyme that degrades the drug such as alcohol dehydrogenase)

Question 14

What is cellular tolerance

Answer 14

change in a receptor or reuptake site e.g. dopamine transporter

Question 15

What is sensitisation?

Answer 15

Sensitisation (aka reverse tolerance):

• when a person’s reaction to a drug increases such that smaller doses are needed to achieve the same effect.
• Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use

Question 16

What is behavioural sensitisation?

Answer 16

Behavioural sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine

Question 17

What are the molecular mechanisms of sensitisation?

Answer 17

• Increase in dopamine transmission
• Increased D2 receptor activity
• Increased D1 receptor numbers and activity

Question 18

What does a drug withdrawal/dependence model for opioids look like?

Answer 18

• Animal is made dependant by getting the drug administered for at least 2/3 weeks
• Then naloxone (opioid receptor antagonist) in injected with the opioid
• Naloxone precipitated opioid withdrawal – naloxone injection in chronic opiod treated mice will precipitate acute physical withdrawal
• Causes symptoms such as shaking, diarrhoea, tremors

Question 19

What is used/seen in models for nicotine addiction?

Answer 19

Mecamylamine precipitate nicotine withdrawal used for nicotine addiction models

Question 20

What are emotional withdrawal effects?

Answer 20

• Anxiety
• Irritability
• Drug craving
• Cramps
• Hypo-locomotion
• Anhedonia
• Depression

Question 21

describe a mouse model of emotional impairment during opioid abstinence

Answer 21

• Chronic Saline or Escalating-Dose Morphine administration – to mimic humans
• Then animal was put in a chamber and not given any drugs
• Assessed emotional-like behaviour (sociability, anxiety, depression) following protracted morphine abstinence

Question 22

How social interaction is studied in a mouse model?

Answer 22

• By using a 3 chamber sociability test – 3 compartments with door, two cages, one will have a mouse and other will be empty/have an object
• The mouse is placed in the chamber for 10 minutes – time spent in each chamber is measured
• if more time spent in empty chamber = less social interaction

Question 23

How anxiety is measured in mouse models?

Answer 23

Elevated plus-maze used:

• The elevated plastic maze used, animal is placed in the middle, and it’s allowed to explore – most mice will eventually explore the platform without the walls/open arms
• Increase of anxiety-like behaviour following long-term opioid abstinence – mice undergoing withdrawal will stay in the closed arms due to anxiety

Question 24

How is depression assessed in mice?

Answer 24

Through a forced swim test

• mouse placed in a water filled beaker, normally mouse will swim and then try to escape, will go into immobility position
• Mice undergoing withdrawal will go into immobility position earlier
• The time the mouse spend in the immobility position is measured
• However there’s criticisms of this method as immobility doesn’t always equate depressive state but it has been used for antidepressant drugs

Question 25

How compulsive drug taking is modelled?

Answer 25

• Rat self-administers cocaine for many days
• It is now so “addicted” that it will suffer electric shocks just to get some cocaine – compulsive drug taking
• If the animal continues self-administering the drug, means there is an established model of compulsive drug taking

Question 26

What is relapse?

Answer 26

In drug abuse/dependency this means that a person starts taking the drug again after a period of abstinence

Question 27

what can trigger relapse?

Answer 27

• Cue: could be a light that comes on when they get i.v cocaine.
• Drug: could be a small dose of cocaine or similar drug.
• Stress: could be tail pinch, foot shock, food or water restriction

Question 28

Animal model for stress-induced reinstatement?

Answer 28

• Animal conditioned with drug so it’s dependant
• Then period of abstinence
• Reintroduce trigger (stress)

Example: CPP used for relapse
• Saline or Carbetocin injection (6.4mg/kg, i.p.)
• Forced-swim stress (6 minutes)
• Test for place preference done after post extinction era and after stress

Question 29

What is microdialysis?

Answer 29

technique measuring all the neurotransmitters in the brain

Question 30

How is microdialysis used in models?

Answer 30

Can link behaviour with microdialysis:

• Measuring neurotransmitter release in vivo
• Association with behaviour parameters/correlate changes in NTs with behaviour

Question 31

How can brain imaging be used in models?

Answer 31

• Allows us to see changes in the brain and correlate them with behaviour
• However some can only happen after the animals death

Question 32

What are the contributions of mouse genetics in the field of drug addiction?

Answer 32

• Identified and confirmed the role of genes in addiction – through knockout mice
• Help with the development of novel pharmacotherapy for the treatment of addiction and relapse
• Identified genes involved in the vulnerability to develop addiction and relapse

Question 33

How was the role of MOP in addiction discovered?

Answer 33

Example: Morphine in MOP knockout mouse:

• Through a MU opioid receptor knockout mouse, it was confirmed that the mu opioid receptor plays a role in addiction/it’s responsible for the rewarding effect in addiction
• Microdialysis was also used to administer the decrease in dopamine release in the knockout mice

Question 34

How was the role of KOP in addiction discovered?

Answer 34

• Kappa opioid receptor knockout mice showed increase in drug taking/place preference for drug compartment
• Confirmed that kappa opioid induces an aversive effect

Question 35

What are some limitations of animal models/past animal models?

Answer 35

• Rats vs mouse – we mostly have knockout mouse/rat tech and not for other animals
• Developmental compensation – taking out a gene could affect other parts of the brain/data may not be entirely accurate
• Background strain and the transgene – many knockouts/recipients are genetically different