Animal models Flashcards
What are the three types of validity assessed in animal models
Remeber CPF:
- Construct validity: does the model has a rationale and theoretical basis- ie in the rat or mice model is there a similar psychological and neurobiological mechanism
-Predictive validity : ‘does it predict the effects of manipulations’ - ie does this drug have the same effect in the the model as it does in humans
-Face validity: Similarity between the model and the disorder being studied
define Addiction
chronic impulsive relapsing disorder
- Compulsion to take the drug
- Inability to limit control
-Negative emotional state (dysphoria, anxiety, irritability)
or further definied with two or more of in a 12 month period
- craving
- tolerance effects
- withdrawal symptoms
- Inability to fulfill major obligations
Stages in an addiction
Addiction is a progressive disorder that happens over many years
Cycle begins with initiation of taking the drug (positive reinforcement) = tolerance
= increased dosing/escalating = dependence (characterised by physical and
emotional withdrawal symptoms) = relapse
Biggest hurdle is maintaining a drug-free state as 70% relapse = current
pharmacotherapy ineffective at maintaining this
Physical withdrawal symptoms decrease over time whereas emotional withdrawal
symptoms persist for months
40% co-morbidity between opioid addiction and anxiety and depression
Impairment of social behaviour in heroin abstinent individuals
Describe the addiction cycle
The addiction cycle begins with initial use of the drug, which is driven by a multitude of factors including a negative emotional state, stress, peer pressure. In this stage the drive to taken the drug is to to attain the euphorogenic, effects of the drug, this is understood as primary reinforcement.
With repeated use the individual may develop tolerance to the drug, whereby higher doses of the drug will be needed to achieve the same effects and the threshold to achieve the effects will be greater. In this case, by taking greater doses, the individual may develop drug dependance, in which upon the cessation of the drug may lead to the development of withdrawal symptoms.
Addiction is a chronic relapsing order in which the individual continues to take the drug despite being aware of the negative consequences of the drug. The individual may continue to take the drug to self medicate their withdrawal symptoms.
Animal models for drug taking
- Given by the scientist
- Intracerebral ventricular injection
-Intravenous: Inject in the jugular vein
- Inject in the skin behind the neck
– adv: easy, you can adjust the dosing, see the effects of drugs that do not cross the blood and brain barrier - Self administration model
- Poke their nose on a infrared beam- administration of the drug
-Press a lever, leads to the administration of the drug
-Bottle- feed
* careful to have a threshold so that the mouse/rat do not overdose
adv:
-more ethical to use this model compared to non-human primates, also less costly
-accurate depiction of drug seeking behaviour- good face validity
disadv: good face validity for some drugs of abuse not all. some mice may not self admister some drugs that are more commonly self administered by human
- mice and human are different species and different behaviour- limit the translational value of the findings
- May get false positives in response to- due to induvidual differences - genetics, psychology,
Drug seeking behaviour
Conditioned place preference/ avoidance: CPP apparatus - put mice in either black box or white box with a seperator.
- Put in white box- inject it with saline - leave for 30 mins
-Put in black box- inject it with the drug of abuse-30 minutes
- Repeat this for 4 days
- Post conditional phase: Remove the seperator and see which box the mouse prefers.
*advantages
-has good face validity: refers to whether thre is phenomenological similarity between the disorder and its effect in the model and in real - life - good face validity as a model of drug seeking behaviour and addiction
-Quantify the extent of the rewarding effect of drugs - compare different treatments
- Cost effective than self administration models - does not require surgery and implantation of cathethers - more ethical
*disadvantages:
- only captures one aspect of addiction – drug seeking - by the preference of one location
- False positives generated by induvidual differences- genetics
- it is important to consider the species difference between mice and humans, which may limit the translational value of such studies. Additionally, the laboratory setting for addiction studies may not accurately depict real-world addiction, as it does not take into account the many factors that influence addiction in human daily life. For instance, in addiction research using mice, they are often placed in an empty box without any other environmental stimulation, which may increase the likelihood of drug-seeking behavior.
Drug addiction and dependence
Chronic administration of a drug to mimic drug addiction-
Animal life span is shorter than a human life span - so chronic administration is 15 days
-chronic intermittent increasing doses of the drug to mimic mechanisms of tolerance
- the time the drug is given should be dependent on the pharmakokinetcis of the drug
- Measure their activity: locomotion
-Adv: good face validity: phenomenogical similarity between the disorder being studies and its effects in the mouse model. Accurate model of tolerance and addiction.
- disadvantages: it may not accurately measure the complex nature of drug addiction which is influenced by social, enviornmental and genetic factors.
- Limited translational application due to different species
- Drugs of abuse- dosing is not carefully titrated- n to an accurate model of drug misuse
Model for Chronic withdrawal symptoms
-Inject mice with the drug, chronically- eg morphine
- Inject the mice with nalaxone (opiod receptor antagonist)
- Observe acute withdrawal symptoms: mice - increased diahorrea scores, loosing weight, wet dog shakes and paw tremors, jumping higher.
- Chronic withdrawal symptoms:
emotional withdrawal symptoms: social ability behaviour - measured using 3 chambered sociality box - social box- with one mouse
- non-social box- cage with just an object (non social chamber)
- let the mouse explore the chambers are see hoe long is spent in each chamber
looking at Depression: forced swim test
mice like to swim, imobile state where they stop swimming , want to escape and become immobile
– put them in a beaker of water
measure time in imobile stage
- swimming is not relevant in human behaviour
disadvantges:
- Not great Face validity- is there phenomenlogical similarity between the effect in the model and the disorder. does not reflect depressive state accurately
- the experiment may induce stress which may effect the results
- the mice may stop swimming because they are tired not because they are in a depressive state
Linking behaviour:
measure direct neurotransmitter. release by placing a probe in the nucleus accumbens - and measuring the neurotransmitter release by plugging into a mass spec machine.
Can be reflected in humans:
MRI scan- measure brain activity
PET scan- measure the levels of receptors
diadv— costly, induviduals have to be imobilised to add the probe. Ethical concerns
- Insitu hybridisation studies- probe to a specific Mrna or DNA molecule- probe binds- histology to see the effects
Disadv-
- mice has to be sacrificed,
-Resolution is not clear
non specific binding - leads to false positives
Knockout mice
knockout mice allow us to identify which receptor is responsible for inducing the rewarding effects of a drug.
limitations
-knock-out mice: rats have a more developed pre frontal cortex - involved in decision making - more similar to humans
- When a gene is knocked out, the brain develops compensatory changes which may increase teh expression of anotehr gene - explain certain responses to - false positive
in the future— develop kncokout mice when the receptor or gene knock out is in a specific brain region
