Animal models of addiction Flashcards
What are the 3 types of validity that all models should have?
- Construct validity
- Face validity
- Predictive validity
What is construct validity?
the model has a sound theoretical rationale (neurobiological or psychological mechanisms underlining the condition mimics humans, aetiology)
What is face validity?
phenomenological similarity between the model and the disorder being modelled (symptoms)
What is predictive validity?
manipulations known to influence the pathological state should have similar effects in the model (drugs)
What are the different stages of addiction that we can model?
- substance abuse – drug taking
- Drug seeking behaviour
- Drug addiction/drug dependence
- increase in tolerance/sensitisation
- acute withdrawal symptoms
- chronic (long-term) withdrawal
- Compulsion to use
- relapse
- context dependency
- genetic models – KO mice
- Neurochemical models?
How can drug-taking be mimicked in animals?
- taken by the animal (self-administration) – gold standard
2. given by the scientist – simples, easier, less challenging, can control dose
How can self-administration be incoporated in animal models?
- 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)
What are the 5 different ways of administering the drug?
- intravenous (not so common)
- sub-cutaneous (SC, common)
- intraperitoneal (IP, common)
- intra-cerebral (quite common) – shows effect of drug directly on the brain/ in specific brain regions, bypasses peripheral metabolism, (mechanistic, small quantities, BBB)
- intramuscular (not so common)
How can Drug seeking behaviour/Conditioned Place Preference/Avoidance (CPP) be seen or tested in animal models?
Carried out in CPP box; has a white compartment and a black compartment and a door between
CPP protocol has the following stages:
- Initial test for side-preference – let the animal explore each side (pre-conditioning)
- Usually give the drug in non-preferred side (conditioning)
- Give saline in preferred side (conditioning)
- Test for CPP after 5-10 days – measure the amount of time the animal spends in each compartment, and which compartment they prefer
What type of animals are valuable for drug abuse vulnerability?
Inbred mice strains are valuable models of drug abuse vulnerability
What is important in a drug addiction/dependence model?
- 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
What are the 2 types of tolerance?
o Metabolic tolerance
o Cellular tolerance
What is metabolic tolerance?
change in the metabolism of the drug (e.g. enzyme that degrades the drug such as alcohol dehydrogenase)
What is cellular tolerance
change in a receptor or reuptake site e.g. dopamine transporter
What is sensitisation?
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
What is behavioural sensitisation?
Behavioural sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine
What are the molecular mechanisms of sensitisation?
- Increase in dopamine transmission
- Increased D2 receptor activity
- Increased D1 receptor numbers and activity
What does a drug withdrawal/dependence model for opioids look like?
- 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
What is used/seen in models for nicotine addiction?
Mecamylamine precipitate nicotine withdrawal used for nicotine addiction models
What are emotional withdrawal effects?
- Anxiety
- Irritability
- Drug craving
- Cramps
- Hypo-locomotion
- Anhedonia
- Depression
describe a mouse model of emotional impairment during opioid abstinence
- 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
How social interaction is studied in a mouse model?
- 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
How anxiety is measured in mouse models?
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
How is depression assessed in mice?
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
