Drug Development- Animal efficacy models Flashcards
What is ethology
Study of animal behaviours as a research tool
Face validity
Has features/symptoms of the human disorder
Useful for physiological sx but harder for behaviours (animal behaviours don’t correlate)
Many diseases have multiple symptoms
Predictive validity
Testing new compounds against drugs of known efficacy
Test against similar drug
-Difficult for truly novel compounds
Construct validity
Best possible type of validity but hard to establish
Animal models analogous to human disease
- Same causes, RFs, genes
- Knowledge of human disease relies on animal research
Features of peripheral pain models
Animals show reliable, objective responses to pain
Lack absolute face validity so relies more on predictive validity
Freund’s Adjuvant-Induced Oedema (Paw Swelling) Assay
Tests mechanical pain
Formalin/ Carrageenan/ Capsaicin
Plethysmometer measures water displacement
Paw Withdrawal Test
Adjustable weight placed on paw, time taken for withdrawal recorded
Thermal tests of pain
Hotplate test
- Licking paws
Tail-flick assay
- IR beam
- Confounding variables
Opioids example for testing pain efficacy
MORa vs DORa for pain treatment
SNC80 studies
- Paw withdrawal, tail flick used to predict antinociceptive properties
- Models typically used DOR knock in to overexpress
- Side effects (convulsions, hyperlocomotion)- affect response?
- Measured against morphine (true predictive validity?)
Schizophrenia positive sx
Delusions, hallucinations
-Unmeasurable in animal models
Schizophrenia negative sx
Social withdrawal, decreased motivation/interests
Schizophrenia cognitive sx
Reduced working memory, visual learning
Typical Antipsychotics
Dopamine D2 Antagonists e.g. Haloperidol
SEs: Mainly EPS
Atypical Antipsychotics
D2/Serotonin Antagonists e.g. Clozapine, Olanzapine, Risperidone
Reduced EPS but weight gain, sedation, agranulocytosis
Isolation rearing and PPI (SZ Disease model)
Isolation weaning for 8w causes
- Hyperactivity, impaired cognitive performance, neurochemical changes, neuroanatomical changes
- Sensorimotor gating defects- reduced PPI
- Prepulse inhibition is normally deficient in SZ
- Startle chamber assess PPI with/without antipsychotics
- Face and predictive validity
Catalepsy (SZ side effect model)
EPS produced by typical antipsychotics
Time length of catalepsy indicates efficacy
Apomorphine Induced Climbing (SZ PD assay)
Apomorphine is a DAr agonist; induces climbing behaviour
Climbing behaviour reduced by antipsychotics with D2 antagonism activity
-Predictive but not face validity
APO-SUS rats as a model with construct validity
Ellenbroek et al
APO-SUS rats
- Heightened responses to external stimuli reminiscent of SZ
- Deficits in Latent inhibition (cognitive deficit)
- Increased PPI deficits
Pathological similarities e.g. increased Dopamine binding in striatum
Reduced RA sensitivity- similar to SZ patients
SZ D3R antagonists model for SZ treatment
Sun et al 2016
Y-QA31 development (novel Dopamine-3 R antagonist)
In vivo efficacy tests include:
-MK801-Induced Hyperlocomotion Assay (similar to APO climbing behaviour, APs reduce hyperlocomotion)
-Conditional Avoidance Response (CAR)
-Novel Object Recognition (cognitive defects)
-Catalepsy
Tested predictive validity against Haloperidol/ Clozapine
Dose reqd for alleviation of cognitive sx 10x lower than positive/negative sx
